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The Acute Neurologi

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The

Acute
Neurology
Survival Guide

A Practical Resource
for Inpatient and ICU
Neurology
Catherine S.W. Albin
Sahar F. Zafar
Editors

123
The Acute Neurology Survival Guide
Catherine S. W. Albin • Sahar F. Zafar
Editors

The Acute Neurology

Survival Guide
A Practical Resource for Inpatient
and ICU Neurology
Editors
Catherine S. W. Albin Sahar F. Zafar
Department of Neurology Department of Neurology
Emory University School of Medicine Massachusetts General Hospital
Atlanta, GA, USA Harvard Medical School
Boston, MA, USA

https://doi.org/10.1007/978-3-030-75732-8

© Springer Nature Switzerland AG 2022

This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether
the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and
transmission or information storage and retrieval, electronic adaptation, computer software, or by similar
or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors
or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims
in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Foreword

For the trainee in neurology, neurosurgery, or intensive care medicine—and

even for the seasoned attending physician—there is perhaps no greater
challenge than the care of patients who develop a neurologic emergency.
Whether encountered in the emergency room, on the neurology ward, in the
medical or surgical ICU, or in a dedicated neuro-ICU, patients with acute
neurologic conditions require the clinician to make rapid therapeutic deci-
sions based on the interpretation of complicated neuro-diagnostics that rely
on an extensive knowledge of neuroanatomy and neurophysiology.
Practitioners must not only recognize neurologic syndromes and rapidly
localize them but also understand the complex interactions between neuro-
logic disease and concurrent systemic illness. In addition, they must stay up
to date on a scientific literature that seems to evolve by the month, leading
to a dizzying array of therapeutic options and constantly changing protocols
that can be challenging to apply in individual patients.
In just 400 pages, the reader will find rapid access to all this and more in the
Acute Neurology Survival Guide by Dr. Casey Albin and Dr. Sahar Zafar.
From reviews of brainstem anatomy to concisely written practical approaches
to common acute neurologic conditions and medical complications in criti-
cally ill neurological/neurosurgical patients to tables summarizing the major
trials in stroke management to useful tables of antithrombotics, anti-seizure
medications, and anticoagulation reversal agents, this book has everything
the clinician needs to confidently diagnose and treat neurologic emergencies.
There are many excellent textbooks on emergency neurology and neuro-
critical care, but few provide access to as much information, knowledge, and
wisdom presented as clearly, concisely, and practically as this one—and still
fit into your “neuro bag” with room to spare for your reflex hammer, pen light,
and stethoscope. I will certainly be carrying this phenomenal resource
in mine.

Aaron Berkowitz, MD, PhD

v
Preface

The history of The Acute Neurology Survival Guide goes back 5 years, to
2016, when we recognized our mutual interest in improving the residents’
educational experience in the neuro-ICU.
At that time, I (Sahar) had just joined my first faculty position in the neuro-
ICU and saw that the many rotating residents and interns needed a struc-
tured curriculum and orientation. Witnessing this need, I collaborated with
the medical and nursing ICU directors and residency program director to
develop a systematized orientation and ICU curriculum.
Meanwhile, I (Casey) had just completed my first year of neurology resi-
dency. Like residents all over the country, I had spent most of the year
learning “by doing” and bouncing between various blogs, online orientations,
textbooks left in resident workrooms, and various Epic “dot phrases” to
ensure that I had a reasonable assessment and plan to present, but I never
found a centralized resource to address, in a practical way, the many
questions I had during my nights on call.
Recognizing the absence of a responding-clinician-level source for guid-
ance, we set out to create a centralized, check-list driven “how-to” guide
which we termed the “NeuroICU Survival Guide.” The first version was
printed by our neurology residency program in 2017 and in the years that
followed became the core manual for trainees and advance practice provid-
ers working in the neuro-ICU.
Since that time, with the help and advice of pharmacists, residents, fellows,
and APPs, we have dramatically expanded the content – adding chapters on
common inpatient issues and routine consult questions – but the goal has
always been the same: to create an incredibly easy-to-use, visually acces-
sible how-to manual that covers exactly what every clinician needs to know
to care for the patient in front of them.

vii
viii Preface

Inside you will find checklists, scoring systems, pro-tips, helpful reminders,
as well as concise summary of the pertinent literature. We have included
over 150 images, charts, and diagrams in an effort to distill complex topics
into understandable learning points that are accessible even at 4 AM or at
the end of a 30-hour call.
In Part I, you will find tangible guidance about how to pre-round, structure a
presentation, examine neurologically ill patients, and interpret the core
diagnostics obtained in many neurology patients: CT, MRI, and EEG.
Parts II and III contain chief-complaint oriented chapters that delve into the
care of vascular and non-vascular inpatient admissions. Part IV covers the
topics central to caring for Neuro-Medicine and Neurosurgery patients in the
neuro-ICU.
Part V is a compilation of commonly referenced resources in a useable
format: sections of the brainstem that are oriented the way you would see
them in a radiology image, common drug-drug interactions to be aware of,
and a comprehensive guide to anti-epileptic drugs (AEDs).
As neurology and neurosurgery are rapidly evolving fields, each year there
are hundreds of new studies that refine and transform the care of these
complex patients. We have made every effort to include the latest guide-
lines, terminology, and publications.
This work would not have been possible without the dedication and collec-
tive expertise of the residents, fellows, pharmacists, and APPs that contrib-
uted and the guidance of experienced clinicians who made this work
possible. We are deeply grateful for the time and energy that each author
contributed and acknowledge that their input has made this book stronger.
We would especially like to thank Dr. Aaron Berkowitz and Megan Barra,
PharmD for their insightful revisions and thoughful feedback; the value of
their input cannot be overstated.
Whether you are a fledging clinician or an experienced provider, we hope
that The Acute Neurology Survival Guide will improve your care of each
patient encountered in the ICU, wards, ED, or other acute care settings.
Sincerely,

Atlanta, GA, USA Catherine S. W. Albin

Boston, MA, USA Sahar F. Zafar
Contents

Part I A Comprehensive “How-To” Guide

1 Pre-rounding on and Presenting Neurology Floor Patients �� 3
Catherine S. W. Albin and Sahar F. Zafar
2 Pre-rounding and Presenting NeuroICU Patients�� 5
Catherine S. W. Albin and Sahar F. Zafar
3 The Coma Exam�� 9
Catherine S. W. Albin and Sahar F. Zafar
4 Cranial Nerve Testing in Acute Neurology�� 13
Catherine S. W. Albin and Sahar F. Zafar
5 Stroke and Vascular Anatomy�� 21
Catherine S. W. Albin and Sahar F. Zafar
6 Basics of Computed Tomography (CT)�� 29
Catherine S. W. Albin and Sahar F. Zafar
7 Basics of Magnetic Resonance Imaging (MRI) Ordering
and Assessment�� 37
Catherine S. W. Albin and Sahar F. Zafar
8 Understanding Transcranial Dopplers (TCDs) �� 47
Catherine S. W. Albin and Sahar F. Zafar
9 Tips and Tricks for EEG Interpretation�� 53
Catherine S. W. Albin and Sahar F. Zafar

Part II Vascular Neurology

10 Acute Ischemic Stroke – First Encounter Assessment
and Management�� 61
Catherine S. W. Albin and Sahar F. Zafar

ix
x Contents

11 Perfusion Imaging�� 71

Catherine S. W. Albin and Sahar F. Zafar
12 Ischemic Stroke: Admission Checklist �� 75
Catherine S. W. Albin and Sahar F. Zafar
13 Stroke Workup – Beyond the Basics�� 79
Catherine S. W. Albin and Sahar F. Zafar
14 Ischemic Stroke: Dissection�� 89
Catherine S. W. Albin and Sahar F. Zafar
15 Ischemic Stroke: Symptomatic Carotid Stenosis
(“Hot Carotid”)�� 95
Catherine S. W. Albin and Sahar F. Zafar
16 Ischemic Stroke – Post Stroke Management
of Anticoagulation�� 99
Catherine S. W. Albin and Sahar F. Zafar
17 Selected Anti-platelets and Anticoagulation
in Stroke Prevention�� 105
Catherine S. W. Albin and Megan E. Barra
18 Acute Management Strategies: tPA and Mechanical
Thrombectomy Trials�� 109
Catherine S. W. Albin and Sahar F. Zafar
19 Venous Sinus Thrombosis�� 117
Catherine S. W. Albin and Sahar F. Zafar
20 Posterior Reversible Vasoconstriction Syndrome (PRES)
and Reversible Cerebral Vasoconstriction Syndrome (RCVS)�� 123
Catherine S. W. Albin and Sahar F. Zafar

Part III Nonvascular Inpatient Neurology

21 Altered Mental Status�� 129
Priya Srikanth
22 Framework for Workup of Unknown Brain “Lesion” �� 133
Catherine S. W. Albin and Sahar F. Zafar
23 Approach to First-Time Seizure �� 137
Catherine S. W. Albin and Sahar F. Zafar
24 Pharmacology Tips for Commonly Used AEDS�� 141
Megan E. Barra
Contents xi

25 Approach to Infectious Encephalitis and Meningitis�� 145

Catherine S. W. Albin and Megan E. Barra
26 Non-Infectious Meningitis �� 151
Catherine S. W. Albin and Sahar F. Zafar
27 Inflammatory and Autoimmune Encephalitis �� 155
Catherine S. W. Albin and Sahar F. Zafar
28 Infectious Workup by Neuroanatomical Location:
An Ordering Guide�� 159
James Hillis and Catherine S. W. Albin
29 Autoimmune Encephalitis Testing�� 163
Juan Carlos Martinez Gutierrez and James Hillis
30 Approach to New Onset Weakness �� 167
Catherine S. W. Albin and Sahar F. Zafar
31 Workup of New Demyelinating Lesion�� 175
Kathryn Holroyd and Kristin Galetta
32 Approach to the “Dizzy” Patient�� 179
Eric C. Lawson

Part IV NeuroICU
33 Intracranial Pressure: Theory and Management Strategies �� 187
Melissa Bentley and Catherine S. W. Albin
34 Management of External Ventricular Catheters�� 197
Catherine S. W. Albin and Sahar F. Zafar
35 Malignant Middle Cerebral Artery Infarction�� 199
Catherine S. W. Albin and Sahar F. Zafar
36 Intraparenchymal Hemorrhage�� 205
Catherine S. W. Albin and Sahar F. Zafar
37 Intracranial Hemorrhage – Landmark Trials�� 211
Catherine S. W. Albin and Sahar F. Zafar
38 Reversal of Selected Antithrombotics�� 215
Catherine S. W. Albin and Megan E. Barra
39 An In-Depth Review of Reversing Direct Factor
XA-Inhibitor-Related Hemorrhages�� 221
Megan E. Barra
xii Contents

40 Intracranial Hemorrhage – Management of Anticoagulation �� 225

Juan Carlos Martinez Gutierrez
41 Subarachnoid Hemorrhage – Differential �� 229
Catherine S. W. Albin and Sahar F. Zafar
42 Aneurysmal SAH – Admission and Early Management�� 231
Christopher Reeves and Catherine S. W. Albin
43 Subarachnoid Hemorrhage – Scoring Systems�� 233
Catherine S. W. Albin and Sahar F. Zafar
44 Aneurysmal SAH – Daily Management Principles�� 235
Christopher Reeves and Catherine S. W. Albin
45 Subarachnoid Hemorrhage – Notable Trials�� 241
Catherine S. W. Albin and Sahar F. Zafar
46 Traumatic Brain Injury�� 245
Catherine S. W. Albin and Sahar F. Zafar
47 Trials in TBI�� 251
Catherine S. W. Albin and Sahar F. Zafar
48 Neuroprognosis and Induced Normothermia After Cardiac Arrest�� 253
Priya Srikanth and Catherine S. W. Albin
49 Status Epilepticus�� 259
Catherine S. W. Albin and Sahar F. Zafar
50 Continuous EEG Monitoring, Electrographic Seizures,
and the Ictal-Interictal Continuum�� 263
Catherine S. W. Albin and Sahar F. Zafar
51 Neuromuscular Crises: ICU Management of Guillain-Barré
Syndrome and Myasthenia Gravis �� 269
Catherine S. W. Albin and Sahar F. Zafar
52 Evaluation of C-Spine Trauma �� 273
Catherine S. W. Albin and Sahar F. Zafar
53 ICU Management of Spinal Cord Injuries�� 277
Catherine S. W. Albin and Sahar F. Zafar
54 Management of the Postoperative Craniotomy Patient �� 283
Alison Paolino and Catherine S. W. Albin
55 Postoperative Management of Cerebrovascular Patients�� 291
Alison Paolino and Catherine S. W. Albin
Contents xiii

56 Preparation for Brain Death Testing�� 299

Catherine S. W. Albin and Sahar F. Zafar
57 Nutrition in the NeuroICU�� 303
Carmen Lo
58 Hypernatremia in the NeuroICU�� 307
Melissa Bentley and Catherine S. W. Albin
59 Hyponatremia in the NeuroICU �� 311
Catherine S. W. Albin and Sahar F. Zafar
60 Pressors and Inotropes Commonly Used in the NeuroICU �� 313
Catherine S. W. Albin and Megan E. Barra
61 Seizure Prophylaxis in the NeuroICU�� 315
Amanda Rivera, Stephanie Seto, and Megan E. Barra
62 Venous Thromboembolism Prophylaxis in the NeuroICU�� 317
Stephanie Seto and Megan E. Barra

Part V Important References

63 Brainstem Anatomy �� 323
Catherine S. W. Albin and Sahar F. Zafar
64 NeuroICU Intravenous Fluid Compositions�� 325
Megan E. Barra
65 Anti-Seizure Medication Chart for Use in Adults�� 327
Megan E. Barra and David Fischer
66 Drug-Drug Interactions Common in Neurology Patients�� 339
Stephanie Seto, Amanda Rivera, and Megan E. Barra
67 Myasthenia Gravis: Medications to Avoid �� 343
Megan E. Barra and John Y. Rhee
68 Parkinson’s Disease: Medications to Avoid�� 347
Amanda Rivera and Megan E. Barra
NIH Stroke Scale�� 351
Index�� 359
Contributors

Catherine S. W. Albin, MD Department of Neurology, Emory University School of

Medicine, Atlanta, GA, USA
Megan E. Barra, PharmD Department of Pharmacy, Massachusetts General
Hospital, Boston, MA, USA
Marinus Pharmaceuticals, Inc., Radnor, PA, USA
Melissa Bentley, ACNP-BC Emory University Hospital, Neuroscience ICU,
Atlanta, GA, USA
David Fischer, MD Department of Neurology, Massachusetts General Hospital,
Boston, MA, USA
Kristin Galetta, MD Department of Neurology, Brigham and Women’s Hospital,
Boston, MA, USA
James Hillis, MBBS, DPhil Department of Neurology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, USA
Kathryn Holroyd, MD Department of Neurology, Brigham and Women’s Hospital,
Boston, MA, USA
Eric C. Lawson, MD Department of Neurology, Emory University School of
Medicine, Atlanta, GA, USA
Carmen Lo, MS, RD, LDN, CNSC Nutrition and Food Services, Massachusetts
General Hospital, Boston, MA, USA
Juan Carlos Martinez Gutierrez, MD Department of Neurology, University of
Texas Health Science Center at Houston, Houston, TX, USA
Alison Paolino, ACNP-BC Neuroscience ICU, Emory University Hospital,
Atlanta, GA, USA
Christopher Reeves, NP Neuroscience Intensive Care Unit, Massachusetts General
Hospital, Boston, MA, USA

xv
xvi Contributors

John Y. Rhee, MD, MPH Department of Neurology, Massachusetts General

Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Amanda Rivera, PharmD Department of Pharmacy, Massachusetts General
Hospital, Boston, MA, USA
Stephanie Seto, PharmD Department of Pharmacy, Massachusetts General
Hospital, Boston, MA, USA
Priya Srikanth, MD, PhD Department of Neurology, Massachusetts General
Hospital, Boston, MA, USA
Sahar F. Zafar, MD, MBBS Department of Neurology, Massachusetts General
Hospital, Harvard Medical School, Boston, MA, USA
PART I

A COMPREHENSIVE “HOW-TO” GUIDE

PRE-ROUNDING ON AND PRESENTING NEUROLOGY
FLOOR PATIENTS
Catherine S. W. Albin and Sahar F. Zafar

First and foremost, know how you will communicate with the team. Many hospitals
use pagers, encrypted texting services, special mobile phones, team huddle, etc. It is
critically important that for any rotation you determine how you will reach the bedside
nurse, PT, OT, SLP, nutrition, and case management, and how they will reach you.
You may also need special passwords to access EEG, radiology, telemetry, etc.
Ask early.

PRE-ROUNDING ON NEUROLOGY PATIENTS

Each morning collect and review the following pieces of information:
□□Overnight events with the night provider
□□Overnight events with the nurse
□□Vitals
□□Labs
□□Radiology
□□EEG data
□□Telemetry, ECHO, EKG
□□Medications, including PRNs used
□□That DVT prophylaxis is ordered, as appropriate
□□Perform a focused neurologic and general exam. For tips, see page 9
PRESENTING NEURO FLOOR PATIENTS
Typical presentations of established patients will often be presented in a
“SOAP” style.
Subjective Data, Objective Data, Assessment, Plan.
An Example:
Patients’ “one-liner”: “Mrs. Jones is a 70 yo woman admitted on [date] for a left
internal capsule stroke, felt to be lacunar in etiology. Today is day 2 of admission.
She had no overnight events.”
S (subjective): reports improvement in right arm strength overnight.
O (objective): vitals, neurologic exam, general exam, relevant labs, radiology,
telemetry, ECHO, EEG, micro data (all as relevant and available).

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_1
3
A (assessment): 70 yo woman with likely lacunar infarct secondary to poorly con-
trolled diabetes and hypertension.
P (plan):
# Ischemic Stroke: Review stroke risk factor data such as hemoglobin A1c and LDL
cholesterol data. Discuss relevant neuroimaging. Review management plan, includ-
ing anti-platelet and risk factor management.
# Hypertension: May include plans to increase blood pressure agents
# Diabetes: Plan to increase medications or refer to endocrinology, etc.
# Dysphagia: Might include need for speech therapy and nutrition consult for diet
assessment
# Discharge planning: Recommendations of PT and OT
For all hospitalized patients, what keeps them in the hospital may not be the problem
that brought them into the hospital. Thus the problem list is often reorganized by
what is most pressing to address so that the patient can safely leave the hospital.
Tips for being part of the team:
• Call consults early in the day
• Think early and often about how changes made in the hospital will be tolerated
after discharge: for example, a medicine that is dosed every 6 h in the hospital may
pose challenges for compliance long-term.
• Keep patient sign-outs and hand-offs up to date, especially the neurologic exam
• Communicate frequently with the case-managers and discharge planning team,
know the recommendations from PT/OT as many neuro patients will need inpatient
rehab after discharge.
• Keep a list of outstanding labs. Certain tests may have been sent out to labs, which
may take days to weeks to result, and will need to be followed.

4
PRE-ROUNDING AND PRESENTING NEUROICU
PATIENTS
Catherine S. W. Albin and Sahar F. Zafar

As for floor patients, it is critically important that for any rotation you determine how
you will reach the bedside nurse, PT, OT, SLP, nutrition and case management, and
how they will reach you.
You may also need special passwords to access EEG, radiology, telemetry, etc. Ask early!

PRE-ROUNDING ON ICU PATIENTS

□□Prior to examining the patient, communicate with the nurse about halting any
sedation so that the exam can be performed off sedation. (Exception: Patients
receiving pharmacological sedation for treatment reasons, such as status
epilepticus or refractory ICP.)
□□ Each patient needs a neurologic and general assessment, see page 9 for tips
on the Coma Exam.
□□ Overnight sign-out with night provider.
□□ Bedside events with nurses.
Labs to Rememer
□□ Sedation requirements, restraint requirement.
If on high dose propofol:
□□ EEG (either review manually or discuss with
• Triglycerides, amylase/
lipase, CK
team reading EEGs).
□□ Neuro-radiology (CTs, TCDs, MRIs).
If on AEDs:
□□ External ventricle drain (EVD) Height
• Levels (including
albumin if checking
(0–20 cmH2O) (if applicable).
□□ Range of intracranial pressures (if being
total phenytoin levels)
If intubated:
monitored).
□□ EVD or lumbar drain output (if applicable).
• EtO2, O2 Sat, ABG PRN
□□ ECHO, EKG, Telemetry, as indicated.
□□ Any drips including pressors or anti-hypertensive medications.
□□ Ventilator settings and recent ABG or EtCO2, CXR, and result of spontaneous
breathing trial (SBT), as indicated.
□□ Ins and outs.
□□ Medication list and PRNs given.
□□ In addition to reviewing for the appropriateness of DVT ppx, ICU patients also
need to be screened for the need for ventilator-associated pneumonia (VAP)
ppx, stress ulcer (GI) ppx, foley, and restraints.
□□ Access: confirm that each patient has at least two peripheral lines and, if
indicated, confirm the patient also has central access. It is very important that
lines and drains are inspected daily.
□□ Confirm electrolytes have been repleted.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_2
5
COMMONLY USED DRIPS IN THE NEUROICU
Note that all hospitals have different thresholds for maximum sedation and pres-
sor limits.
See pages 313 for an extended list of pressors that might be used in the NeuroICU

Sedation:
Propofol 5–80 mcg/kg/min
Dexmedetomidine 0.2–1.5 mcg/kg/hour
Fentanyl 25–250 mcg/hour OR 0.5–3 mcg/kg/hour
Midazolam 1–5 mg/hour

Anti-Hypertension:
Clevidipine 1–16 mg/hour
Labetalol 1–4 mg/hour
Nicardipine 2.5–15 mg/hour

Pressors:
Norepinephrine (commonly called “levo”):
• 0–50 mcg/min, IV, continuous
• 0.01–1 mcg/kg/min, if weight based
Phenylephrine (commonly called “neo”):
• 0–300 mcg/min, IV, continuous
• Or 0.1–3 mcg/kg/min, if weight based

PRESENTING NEUROICU PATIENTS

Unlike floor patients, many ICUs prefer to present by a system. Below is an example
of a systems-based presentation.
Example:
One liner: “Mr. Brown is a 76 year old man with a left intracranial hemorrhage [major
issue] and significant cerebral edema and respiratory failure requiring mechanical
ventilation [reasons that the patient requires ICU-level care]. This is ICU day #X.”
NEURO
• Patient’s neuro exam
• Neuro plan by problem, for example in this case:
## ICH: new data (such as new neuroradiology), etiology, management
## Elevated ICP: EVD settings, 24-hour output, Range of ICPs, use of hyperos-
molar agents
• Pain and agitation control, as needed
• Generally, all new neuro-radiology, EEG data, sedatives, TCDs should be
reviewed in this section
• If the patient is being followed by palliative care or another consulting service
• Recommendations of PT/OT/Speech, as applicable

6
CV
• SBP goal, patient’s range
• Pressors or Ant-HTN infusions
• If patient is in shock, address in this section
• EKG, ECHO, and telemetry data, as applicable
PULM
• Ventilator settings and recent ABG and EtCO2
• CXR results
• Diuresis plan, if needed for pulmonary edema
GI
• If the patient is on TFs and if they are at goal
• Last bowel movement
RENAL
• Ins/outs
• Sodium goal and how it is being addressed
• Any CKD or AKI, and how it is being managed: HD, CRRT, monitoring K, renal
diet, etc.
ID
• Tmax, white blood cell count
• Antibiotics as ordered and how many days they have had/are planned
HEME
• Hgb level
• Plts, if significantly high or low
• Coags if they are important to the patient’s neurologic issue
ENDOCRINE
• Blood sugars if DM, baseline HgbA1c
• Treatment for hypothyroidism, if needed
• Diabetes insipidus management (may be covered in renal with sodium
management)
• Adrenal insufficiency treatment, as applicable
MSK/ONC/SKIN: as important or needed
PROPHYLAXIS/ICU Checklist
• Review of peripheral and central access
• DVT prophylaxis plan (with anti-Xa levels or PTT, as needed/monitored)
• GI prophylaxis (often with H2 blockers or PPIs), not needed for all patients, but
should be considered for ventilated patients, patients with coagulopathy, or
patients that are expected to have an extended NPO period.
• Foley (with the goal of always removing, unless it is needed for monitoring of
critical I/Os)

7
THE COMA EXAM
Catherine S. W. Albin and Sahar F. Zafar

In general, all ICU exams should include mental status, cranial nerves, motor
responses, and reflexes. Patients that were admitted with stroke should be tracked
using the NIHSS, found on page 351.
The Glasgow Coma Scale (GCS) is a simple, effective way to communicate and
track progress.

GLASGOW COMA SCALE

RESPONSE SCALE SCORE
Eye Opening Response Eyes open spontaneously 4 pts
Eyes open to verbal command, speech, or shouting 3 pts
Eyes open to pain 2 pts
No eye opening 1 pt
Verbal Response Oriented 5 pts
Confused conversation, but able to answer questions 4 pts
Inappropriate response, words discernible 3 pts
Incomprehensible sounds or speech 2 pts
No verbal response 1 pt
Motor Response Obeys commands for movement 6 pts
Localizes to painful stimulusa 5 pts
Withdraws from pain 4 pts
Decorticate posturingb 3 pts
Decerebrate posturing 2 pts
No motor response 1 pt

Minor brain injury = 13–15 points; moderate brain injury = 9–12 points; severe brain injury = 3–8 points

Note that for a movement to count as “Localizing” the patient should bring their arm up to the site of
a

pain or at least cross midline, if a stimulus is applied to the contralateral side (see figure 3.1)
An easy way to remember that decorticate is upward flexion of the arm is that the patient is pulling
b

their arms to their “Core”

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_3
9
Decorticate Posturing

Decerebrate Posturing

Fig. 3.1 Decorticate and Decerebrate Posturing

MENTAL STATUS
It is always best to describe what the patient can/cannot do. Below are some terms
encountered in neurologic and critically ill patient.
Encephalopathic: Confused, inattentive
Stupor: Unresponsiveness that requires vigorous/continuous stimulation.
Comatose: Cannot be aroused with vigorous stimulus

TIPS FOR THE MOTOR EXAM

Ways to provide central stim:
• Q-Tip swab to nose
• Orbital ridge pressure
• Sternal rub
• Trapezius Squeeze

10
HERNIATION SYNDROMES
NAME PATHOLOGY SIGNS
A. Uncal Medialization of the uncas, the medial/inner most Ipsilateral fixed and dilated
Herniation part of the temporal lobe, towards the tentorium pupil
resulting in compression of the midbrain and 3rd May also have an inability to
nerve. adduct affected eye with
vestibular ocular reflex
B. Central Downward displacement of the diencephalon and Coma
Transtentorial brainstem, resulting in compression of reticular Diabetes insipidus
Herniation activating system and hypothalamus Parinaud’s syndrome (loss of
upgaze + convergence/
retraction nystagmus)
C. Falcine Displacement of the cingulate gyrus, pericallosal Contralateral leg weakness
Herniation arteries, and the ipsilateral anterior cerebral artery.
D. Tonsillar Pressure gradient across the foramen magnum Obtundation
Herniation impacting the cerebellar tonsils resulting in Hypertension
compression of 4th ventricle and brainstem, as well
as hydrocephalus.
E. Kernohan’s Compression of the contralateral cerebral peduncle Weakness that is ipsilateral to
Notch and midbrain against the tentorium cerebelli the injury
Phenomenon Contralateral pupillary
dilatation.

E
D

Figs. 3.2 and 3.3 Above is an MRI obtained on a patient who had herniated from massive ICH and
was taken to the OR for decompressive hemicraniectomy. After decompression there is evidence of
subtle DWI restriction in the lateral midbrain at the level of the cerebral peduncle (dark arrow) which
had been compressed against the cerebellar tentorium (Kernohan’s notch phenomenon).
Additionally, there is a new stroke in the posterior cerebral artery (PCA) territory (light arrow). The
PCA had been compressed by transtentorial herniation

11
CRANIAL NERVE TESTING IN ACUTE NEUROLOGY
Catherine S. W. Albin and Sahar F. Zafar

ANISOCORIA
Step 1: Examine the eyes both in the light and in the dark
Step 2:
THE PUPIL IN LIGHT VS. DARK CAUSES
Difference greater in the dark = Disruption to the sympathetic pathway
MIOSIS First-order neurons: Injury to brainstem and cervical spine, such as
There is a dilation lag meaning in Lateral Medullary Syndrome
the smaller pupil is the Second-order neurons: Pancoast tumor, chest pathology, brachial
abnormal one plexus pathology
Third-order neurons (no associated anhidrosis): internal carotid
artery dissection, neck surgery, cavernous sinus pathology
Difference greater in the light = Disruption to the parasympathetic pathway
MYDRIASIS Cranial nerve III palsy: posterior communicating artery aneurysm,
There is inability of the dilated tumor, temporal lobe uncal herniation
pupil to constrict appropriately Cavernous sinus pathology
Remember that anti-cholinergic drugs can also result in mydriasis.
In hospitalized patients, always look for a scopolamine patch or
recent administration of nebulized ipratropium (in DuoNeb®) to
assess whether the dilated pupil resulted from a medication effect

Step 3: Look for associated pathology.

□ If miosis: look for a Horner’s syndrome (anhidrosis and ptosis), for evidence of a
lateral medullary syndrome (see “Brainstem Syndromes”), or for evidence of
cavernous sinus pathology (testing extraocular eye movement and sensation in
the V1/V2 distribution).
□ If mydriasis: look for disorders of consciousness and consider a STAT scan; if
awake, examine extraocular eye movements and facial sensation, consider CT
angiogram to evaluate for expanding posterior communicating artery aneurysm.

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https://doi.org/10.1007/978-3-030-75732-8_4
13
LOCALIZING EXTRAOCULAR EYE MOVEMENT ABNORMALITIES
LESION PRESENTATION COMMON AREAS OF INJURY BEDSIDE TRICKS
CN III (Oculomotor) Impairment in adduction (medial rectus), Midbrain nucleus, compression of the nerve A compressive etiology leads first to
Nerve Palsy elevation (superior rectus), and depression by posterior communicating artery pupil dilation prior to ophthalmoplegia
(inferior rectus) + ptosis (levator aneurysm, uncal herniation, pathology at
palpebrae) and mydriasis the superior orbital fissure (SOF), cavernous
(parasympathetics) sinus (CVS)

Pupil-sparing/subtle right CN III:

Patient told “look left”

Full right CN III (looking straight):

Full Right CN III:

CNIV (Trochlear) Impaired intorsion and depression in the Dorsal midbrain, pineal mass, pathology at The diplopia worsens with head tilted
Nerve Palsy adducted position (superior oblique) the SOF/CVS toward the side of the lesion

Right CN IV palsy: Patients may complain of diplopia when

Patient told “tilt head to Right” looking down (e.g., when going
downstairs)

14
LESION PRESENTATION COMMON AREAS OF INJURY BEDSIDE TRICKS
CN VI (Abducens) Impaired abduction (lateral rectus) Increased intracranial pressure, cavernous Diplopia is worse with far vision
Nerve Palsy sinus pathology, trauma
Right CN VI palsy:

Patient told “Look right”

Medial Longitudinal Results in an internuclear ophthalmoplegia Most commonly multiple sclerosis, or any A right MLF lesion results in impaired
Fasciculus (MLF) Injury (INO): impairs the coordination of stroke/lesion affecting the MLF right eye adduction when looking left
ipsilateral CN III (impaired ipsilateral
adduction) on contralateral gaze Bilateral INO would result in inability
to adduct either eye on horizontal
Right INO: gaze
On left gaze, the right eye does not
adduct and the left eye usually displays
nystagmus
Difference with CN III there is no ptosis
and convergence is not impaired
Patient told “look left”
Nystagmus

15
LESION PRESENTATION COMMON AREAS OF INJURY BEDSIDE TRICKS
One-and-a-half A lesion affects the crossed MLF + PPRF Lesion in the caudal pons This leaves only one horizontal
Syndrome and/or CN VI movement: abduction of the eye which
is contralateral to the lesion
There is no horizontal gaze to the affected
side because of the CN VI/PPRF Often will cause an ipsilateral LMN
involvement pattern of facial weakness (by affecting
CN VII, which is sometimes termed an
Adduction of the ipsilateral eye on
“eight-and-a-half syndrome” (i.e., 7 +
contralateral gaze is impaired due to MLF
1.5)
disruption between CN VI and CN III

Right one-and-a-half (due to R-INO + R-CN

VI/PPRF lesion):
Only the left eye can abduct
Patient told “look left”

Patient told “look right”

Cavernous Sinus (CS) When severe, results in complete Cavernous sinus thrombosis, carotid-
Pathology ophthalmoplegia on the effected side cavernous fistula, pituitary tumor, Tolosa- ICA
Cavernous sinus
Hunt syndrome, pituitary apoplexy Pituitary

Pathology in the CS usually starts with a III

IV
VI
sixth nerve palsy
V1
V2

Skew Deviation Usually caused by a central lesion Can be caused by lesion to brainstem, Usually the eye on the side of the

16
resulting in vertical misalignment cerebellum or rarely CN VIII injury lesion is higher and intorted
CALORIC TESTING
Both warm and cold water can be used to activate the endolymph of the inner ear
resulting in a current that activates the hair cells. This movement of the hair cells
results in polarization (warm) or hyperpolarization (cold) of the ipsilateral vestibular
verve and apparatus of the brainstem [1]. In the ICU, cold water is preferen-
tially used.
Cold water irrigation of the external auditory canal results in movement of the endo-
lymph in a way that causes hyperpolarization resulting in the inhibition of the vestibu-
lar nerve.
The normal response to cold water:
• A slow movement of the eyes towards from the stimulates, with the fast compo-
nent of nystagmus beating away from the stimulated ear.
In coma:
• There is no corrective saccade because the frontal eye fields are not activated
(due to absent cortical function), thus the eyes will only have the slow movement
towards the cold stimulus.
In brain death testing:
• There is no movement of the eye when the patient’s ear canal is irrigated with
cold water.

17
GENERAL PATTERNS OF FACIAL WEAKNESS
Note that testing facial weakness in less acute patients should involve assessing audi-
tory function (for hyperacusis) and taste. Note that the facial nerve also receives pro-
jections from the extrapyramidal systems and frontal lobe which control emotional
expression. Thus, patients with upper motor pattern of weakness may actually be able
to activate their face involuntarily when associated with an emotional expression.

Test both the patients ability to raise eyebrows and

smile

Smile weak but eyebrow Both smile and eyebrow

raise intact strength weak

Upper Motor Neuron Lower Motor Neuron

Pattern of weakness pattern of weakness

Localizes to an injury Localizes to the 7th

along the corticobulbar cranial nerve or 7th
tract including at the cranial nerve nucleus
motor cortext. (brainstem)

In comatose patients, the seventh and fifth cranial nerves are assessed by
testing the corneal reflex:
The cornea is the clear layer of tissue over the iris. Touching the cornea transmits a
signal to the brainstem via the Trigeminal Nerve (CN V) and the blink motor response
is carried out due to innervation from the Facial Nerve (CN VII). If either of these are
damaged (such as by a stroke or bleed effecting the brainstem) the patient will not
blink to the gentle touch of the cornea with a cotton swab. Often tested at the bed-
side by dropping a drop of a saline flush into each eye, this is less sensitive but does
not risk injury to the cornea. Take care to actually touch the cornea and not just the
sclera (the white of the eye).

18
TESTING THE GAG REFLEX (PHARYNGEAL REFLEX)
Sensation mediated predominantly by the glossopharyngeal nerve (CN IX). Motor
response mediated by the vagus nerve (CN X). In ICU patients, this is best tested by
advancing a tongue depressor around the endotracheal tube and stimulating the
oropharynx.

TESTING COUGH REFLEX

Mediated by the vagus nerve. In intubated patients, it is most easily tested by
advancing in-line suction through the endotracheal tube which will stimulate the
trachea. Be aware that coughing will typically trigger a temporary high airway pres-
sure alarms on the ventilator.

REFERENCE
1. Gonçalves DU, Felipe L, Lima TM. Interpretation and use of caloric testing. Braz J
Otorhinolaryngol. 2008;74(3):440–6.

19
STROKE AND VASCULAR ANATOMY
Catherine S. W. Albin and Sahar F. Zafar

ANTERIOR CIRCULATION ANATOMY

Optic chiasm

Anterior ICA Terminus

communicating
Posterior
artery
communicating
A1 artery
Ant. choroidal
artery

Recurrent artery Lenticulostriate

of Heubner arteries

Classic Syndromes

Adapted from Adams and Victor’s Principles of Neurology [1].

ANTERIOR CIRCULATION – MAJOR BRANCHES

BRANCH TERRITORY
ARTERY OF SUPPLIED CLASSIC SYNDROME IMAGE
Internal Common Anterior Highly dependent on the state of
Carotid Carotid Circulation collateral flow. Headache above
Artery the eyebrow may be present after
(ICA) ICA dissection.
Look for ischemia in the cortical
and deep watershed territories.
Weakness of hips and shoulders
(“man in a barrel” syndrome) may
result from ischemia of the cortical
watershed territory (see image).
Critical stenosis of the ICA may
manifest as ipsilateral transient
monocular blindness due to poor
perfusion to the ophthalmic artery.

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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21
BRANCH TERRITORY
ARTERY OF SUPPLIED CLASSIC SYNDROME IMAGE
Anterior ICA Globus Variable.
Choroidal pallidus, Contralateral hemiplegia,
Artery posterior hemianesthesia loss, homonymous
(AChor) limb of sectorial hemianopia. Language
internal and cortical functions spared.
capsule,
hippocam-
pus ± optic
tract

Anterior ICA Medial Contralateral hemiplegia and

Cerebral frontal and hemianesthesia of leg/foot. May
Artery parietal involve shoulder. Abulia.
(ACA) lobe Transcortical aphasia (with
preserved repetition) possible if
dominant side is involved.

Recurrent ACA Caudate Variable. Weakness of

Artery of head contralateral arm/face,
Heubner dysarthria, hemichorea possible.
If bilateral: akinetic mutism.

Medial Proximal Anterior Variable. Dysarthria, stuttering

Lenticulo- ACA limb of (left sided), inattentiveness,
striate internal hemiparesis, movement disorders
Arteries capsule/ possible.
(Penetrat- caudate
ing head
Branches)

22
BRANCH TERRITORY
ARTERY OF SUPPLIED CLASSIC SYNDROME IMAGE
Middle ICA Cortical M1 occlusion: Contralateral
Cerebral branches: hemiplegia (including leg because
Artery cortex of of posterior limb of internal
(M1) the lateral/ capsule involvement),
inferior hemianesthesia, and homonymous
frontal hemianopsia (lateral geniculate
lobe, nucleus). Eyes are gazing to the
parietal ischemic side
lobe Left side – global aphasia
Deep Right side – hemineglect and
branches: anosognosia; eyelid opening
putamen, apraxia
part of
caudate,
posterior
limb of
internal
capsule,
corona
radiate
MCA – MCA Frontal eye Face/Arm ≫ Leg weakness. Eye
Superior fields, deviation.
Division Broca’s Left side – Expressive vs. global
area (left), aphasia (acutely) that resolves to
motor and an expressive aphasia sub-acutely.
sensory Right side – Sensory neglect
cortex

MCA – MCA Wernicke’s Superior quadrantanopia or

Inferior area (left),homonymous hemianopia
Division optic Left side – Receptive aphasia
radiations, Right side – Left visual neglect,
posterior confusional state
parietal
lobe

23
BRANCH TERRITORY
ARTERY OF SUPPLIED CLASSIC SYNDROME IMAGE
Lateral MCA Putamen, Variable dependent on territory
Lenticulo- part of the affected. Usually hemiplegia,
striate caudate, limited aphasia, homonymous
Arteries posterior hemianopia
(Penetrat- limb of int.
ing capsule,
Branches) outer
globus
pallidus,
corona
radiata

ACA

ACA ICA

MCA
MCA
Midbrain Posterior
communicating
Pons artery
Superior Posterior cerebral
cerebellar artery
artery Basilar artery
Basilar AICA
perforator

Cerebellum PICA

Vertebral artery

Anterior spinal
artery

24
POSTERIOR CIRCULATION
BRANCH TERRITORY
ARTERY OF SUPPLIED SYNDROME IMAGE
Vertebral Subclavian Medial Medial Medulla Syndrome –
Artery medulla, Contralateral hemiparesis
posterior sparing the face,
inferior contralateral loss of position
cerebellum sense, ipsilateral paralysis of
the tongue
Commonly results in an
embolus to the PICA territory,
see below.
Posterior Vertebral Lateral Most commonly affects a
inferior (can be medulla, large posterior territory of
cerebellar Basilar as inferior and the cerebellum (see image)
artery PICA/AICA lateral Lateral Medulla Syndrome –
complex) cerebellum Vertigo, contralateral facial
impaired pain/temp,
Horner’s syndrome,
hoarseness/dysphagia,
vertical diplopia, ipsilateral
ataxia, loss of taste
(Can also occur due to
vertebral artery stroke)
Basilar Intersection Proximal/ In general – crossed
Artery of the Mid symptoms signaling
vertebral Portion – brainstem involvement
arteries penetrating Prox/Mid Portion – Locked-in
branches Syndrome, vertical eye
supply the movements often spared
pons
Top of the Top of the Basilar – Coma
Basilar – (resulting from involvement of
Mid brain the reticular activating
system), disorders of ocular
movement, ptosis, variable
plegia (may be absent),
behavioral abnormalities
(akinetic mutism, visual
hallucinations)

25
BRANCH TERRITORY
ARTERY OF SUPPLIED SYNDROME IMAGE
Anterior Basilar Middle Ipsilateral ataxia; nausea/
Inferior cerebellar vomiting/slurred speech.
Cerebellar peduncle; Occasionally may see loss of
Artery inferolat- pain and temp contralateral,
eral pons, ipsilateral Horners, paresis
flocculus, of conjugate lateral gaze or
anteroinfe- tinnitus.
rior surface
of cerebel-
lum
Superior Basilar Middle and Ipsilateral ataxia; nausea/
Cerebellar superior vomiting/slurred speech.
Artery cerebellar Can see loss of pain and
peduncles, temperature contralateral
rostral due to involvement of the
cerebellum spinothalamic tract.
to the
horizontal
fissure,
portion of
midbrain
Posterior Basilar Cerebral Presentation variable given
Cerebral peduncles, this artery supplies the rostral
Artery CN III and brainstem, inferior medial
(PCA) IV, temporal lobes, and
thalamus, thalamus. Strokes affecting
hippocam- the midbrain can cause
pus and palsies of vertical gaze,
medial stupor/coma, or CN III
temporal palsies. Thalamic syndromes
lobe, can mimic any other
occipital syndrome. Occlusion of the
lobe cortical branches result in
homonymous hemianopia,
alexia without agraphia (left
PCA), anomia. Amnesic
syndromes.

26
BRANCH TERRITORY
ARTERY OF SUPPLIED SYNDROME IMAGE
Artery of P1 A variant in Disorder of consciousness –
Percheron which the usually somnolence,
thalamoper- sometimes with associated
forate hemianesthesia or
branches hemiplegia.
arises from
one side of
the P1
segment
and supply
BOTH
medial
thalami

Lacunar Syndromes
SYNDROME LOCATION
Pure Motor Hemiplegia Internal capsule, corona radiata, ventral pons
Pure Sensory Stroke Lateral thalamus or deep parietal white matter
Ataxic Hemiparesis Anterior pons, midbrain at the cerebral peduncle (rare), internal capsule
Clumsy Hand-Dysarthria Paramedian mid-pons contralateral to symptoms, posterior portion of
internal capsule

REFERENCE
1. Ropper AH, et al. Adams and Victor’s principles of neurology. McGraw Hill Medical; 2005.

27
BASICS OF COMPUTED TOMOGRAPHY (CT)
Catherine S. W. Albin and Sahar F. Zafar

While the detail of neuroanatomy is much more sensitive with MRI, non-contrasted
head CTs (NCHCT) have the advantage of being faster, more readily available, more
affordable, and can be used in patients that have implants/hardware that are not MRI
compatible.
Acute hemorrhage is hyperdense (bright white) on CT, which makes it the ideal
screen for hemorrhage. Vasogenic, interstitial, and cytotoxic edema are hypodense,
which can be more difficult to see, but can be detected by looking for symmetry
between the two sides of the brain. Anatomic distortions, like herniation and hydro-
cephalus, are easily detected with CT, which make it ideal for assessing these
findings. Contrast can be added to look for breakdown of the blood-brain barrier.

Chief Indications for Non-Contrast Head CT (NCHCT)

□□ Ruling out or in acute hemorrhage
□□ Assessment of hydrocephalus
□□ Assessment of midline shift and herniation
□□ Acute stroke assessment and tPA screening
□□ Ruling out of pneumocephalus
□□ Screening for mass lesions/vasogenic edema
Note: A CT Angiogram (CTA) is NOT the same as a CT with contrast.

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29
The first step in reviewing head CTs is to have an understanding of normal neuro-
anatomy on head CT.
Below is a brief review of important structures on CT.

AT THE LEVEL OF THE AT THE LEVEL OF THE

AT THE LEVEL OF THE PONS ROSTRAL PONS MIDBRAIN AND UNCUS

4 4 4

7
3 3
2 2 3
1 2 1 1

5 5 5
6
6 6

1 – Pons 1 – Pons 1 – Midbrain/Cerebral Peduncle

2 – Pre-pontine Cistern 2 – Pre-pontine Cistern 2 – Suprasellar Cistern
3 – Medial Temporal Lobe 3 – Uncus of the Temporal 3 – Uncus of the Temporal Lobe
4 – Orbital Cortex of the Frontal Lobe 4 – Frontal Lobe
Lobe 4 – Frontal Lobe 5 – Cerebral Aqueduct
5 – 4th Ventricle 5 – Fourth Ventricle 6 – Left Cerebellar Hemisphere
6 – Left Cerebellar Hemisphere 6 – Left Cerebellar 7 – Sylvian Fissure
Hemisphere

30
AT THE LEVEL OF THE
AT THE LEVEL OF THE CAUDATE THALAMUS NEAR THE VERTEX

5 6
4
7 5
4 4 1
3 3 7
1 1 2
2
2 6
3

1 – Midbrain 1 – Thalamus 1 – Frontal Lobe

2 – Quadregeminal Cistern 2 – Quadregeminal Cistern 2 – Central Sulcus
3 – 3rd Ventricle 3 – Posterior Limb of the Internal 3 – Parietal Lobe
4 – Basal Ganglia (Putamen and Capsule 4 – Falx Cerebri
Globus Pallidus) 4 – Head of Caudate Nucleus
5 – Anterior Horn of the Lateral 5 – Anterior Horn of the Lateral
Ventricle Ventricle
6 – Head of Caudate Nucleus 6 – Calcification of the choroid
7 – Sylvian Fissure plexus
7 – Sylvian Fissure

31
Acute hemorrhage will appear bright and can be further categorized by the shape of the bleed and
its location.

EXAMPLES OF ACUTE HEMORRHAGE

SUBARACHNOID
HEMORRHAGE SUBDURAL HEMORRHAGE EPIDURAL HEMORRHAGE

Blood fills the cisterns and Crescent-shaped collection. Lens-shaped collection. Often
fissures and layers around the Chronic blood will become formed by damage to the middle
parenchyma. hypo/isodense and is harder to meningeal artery or its collateral
detect. supply.
INTRAPARENCHYMAL INTRAVENTRICULAR
HEMORRHAGE HEMORRHAGE

Often qualified as “deep” “Casting of the Ventricles” refers

meaning within the basal to a state when the ventricles
ganglia and corona radiata or are completely “whited-out” with
“lobar” meaning within the hemorrhage
cortex

32
FEATURES CONCERNING FOR HYDROCEPHALUS
ENLARGEMENT OF THE BOWING OF THE 3RD ENLARGEMENT OF THE
TEMPORAL HORNS VENTRICLE LATERAL VENTRICLES

EXAMPLES OF HERNIATION SYNDROMES ON CT SCAN

UNCAL HERNIATION SUBFALCINE HERNIATION CEREBELLAR HERNIATION

33
USE OF COMPUTED TOMOGRAPHY IN STROKE
The primary use of use of CT in stroke is to exclude hemorrhage. However, CT can
also demonstrate early ischemic changes, by which the patient is assigned an
ASPECTS score (see page 67).
An example of early ischemic changes:

Fig. 6.1 Non-contrast Head CT in Acute Ischemic Stroke: The Image demonstrates subtle blurring
of the gray–white differentiation of the cerebral cortex and white matter tracts (marked with a fat
arrow). There is also effacement of the sulci (marked with skinny arrow)

CT Angiogram Head & Neck is also of paramount importance in stroke workup and
management especially in screening for a Large Vessel Occlusion (LVO) which would
make the patient a candidate for thrombectomy. Although reviewing CT angiograms
is beyond the scope of this chapter, a few important tips for reviewing CTAs:
The “CTA Thins” will provide the source images and should be reviewed first.
Practice reviewing each major extracranial to intracranial artery (right and left internal
carotid arteries, right and left vertebral arteries, and basilar artery), and then tracing
the major branches -- middle cerebral, anterior cerebral, and posterior cerebral
arteries. A helpful tip in distinguishing the internal from external carotid arteries after
they branch from the common carotid is that the external carotid has multiple
branches in the neck, whereas the internal carotid’s first branch is the ophthalmic
artery which is after the artery has entered the skull base.

34
Fig. 6.2 CTA Thin, Neck: at the take-off of the left internal carotid from the common carotid and at
the very distal right common carotid. There is some calcified plaque at the distal right common
carotid (hyperdense, marked with thin arrows). Additionally, there is non-calcified plaque in the
proximal left internal carotid causing significant stenosis in the left take off. The lumen is marked
with a circle and the soft hypodense plaque is marked with a fat arrow). This soft plaque likely
resulted in an embolic stroke to the left MCA territory a so-called artery-to-artery stroke—i.e. the plaque
came from a larger artery and embolized to a distal intracranial artery

35
The “MIP” (maximum intensity projection) reformatting of blood vessels make it
easier to visualize the major intracranial vessels, and these sequences are the
easiest to review when attempting to detect large vessel occlusions.

Fig. 6.3 Axial MIP in Acute Stroke: Image demonstrates complete lack of opacification of the right
intracranial internal carotid artery and middle cerebral artery in a patient with acute thrombus at the
ICA Terminus

36
BASICS OF MAGNETIC RESONANCE IMAGING (MRI)
ORDERING AND ASSESSMENT
Catherine S. W. Albin and Sahar F. Zafar

MRI SEQUENCES
HYPERINTENSITY VS.
SEQUENCE HYPOINTENSITY BEST FOR: EXAMPLE
T1 Sequences White matter is light gray • Anatomy
(spin echo): Gray matter is dark gray • Post-contrasted
MPRAGE T1 Bright: images
images are T1 • Gadolinium contrast (gadolinium is
weighted and • Fat not apparent on
very high • Subacute hemorrhage T2 weighted
special • Protein-rich fluid sequences)
resolution • Early subacute blood
T1 Dark: T1 Post-Gadolinium:
• CSF Heterogeneous cavity
• Inflammation, edema, enhancement seen in a
demyelination patient with a high-grade
• Chronic blood products glioma.
T2 Sequence White matter is dark gray • Anatomy
(spin echo): Gray matter is light gray • Chronic
FLAIR is a T2 T2 Bright: pathology
weighted • Demyelination, axonal loss • Edema
image • Slow-flow through blood vessels • Demyelination
• Cytotoxic and vasogenic
edema
• Subacute to chronic infarcts
• Hyperacute and late subacute T2 FLAIR: Posterior white

blood matter predominate

T2 Dark: edema in a patient with

• Minerals: iron, copper, calcium Posterior Reversible

• Air Encephalopathy

• Highly cellular lesions Syndrome (PRES)

• Acute, early subacute and

chronic blood products

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_7
37
HYPERINTENSITY VS.
SEQUENCE HYPOINTENSITY BEST FOR: EXAMPLE
Diffusion DWI Restriction (Bright): • Acute stroke
Weighted • Acute ischemia • Should be
Imaging (DWI) • Brain abscesses reviewed in all
• Seizure-related cortical cases of
restriction inflammatory
• Tumefactive necrosis pathology, which
• Lymphoma can narrow the
• High-grade gliomas differential
• CJD DWI: Diffusion restriction is
• Hypoxic-ischemic injury demonstrated by the
uniform brightness in the R
• Epidermal cysts MCA territory
Gradient Echo Dark: Assessing for
Sequences • Deoxyhemoglobin, intracellular hemorrhage or
(GRE) methemoglobin, and hemorrhagic
hemosiderin transformation.
• Iron and magnetic metals

GRE: Large R parieto-

occipital intracranial
hemorrhage with IVH
Susceptibility Similar to GRE but higher Detecting very small
Weighted resolution amounts of blood
Imaging (SWI) Dark: or calcium
• Deoxyhemoglobin, ferritin,
hemosiderin
• Calcium and bone minerals

SWI: Small, cortical bleed

concerning for underlying
metastasis

38
MRI IN STROKE
SEQUENCE REVIEW FOR: EXAMPLE
DWI Ischemic core (DWI Bright)

DWI demonstrating restriction in the left frontal lobe

from an L MCA occlusion that spared the deep MCA
territory. The heterogeneity of restriction is secondary to
petechial hemorrhage within the stroke bed.
ADC Ischemic core (ADC Dark).
Tissue that is DWI bright but
ADC isointense is “T2 shine
through” and typically due to
chronic pathology.

ADC dark area confirming ischemia in the same

territory. Patchy darkness is again secondary to
petechial hemorrhagic transformation.
FLAIR After 4.5-6 hours, the ischemic
core will be T2 hyperintense.
Review for prior ischemic
damage:
• Cortical or deep
hyperintensities that suggest
prior embolic/lacunar
infarcts
• Focal atrophy
• leukoaraiosis (small vessel
white matter disease) T2 FLAIR image confirming a subacute stroke. No
• Hyperintensity in the blood evidence of prior embolic infarcts or leukoaraiosis.
vessels of the leptomeninges, There is slight volume expansion and obliteration of
representing slow flow. the sulci suggestive of edema within the stroke bed.

39
SEQUENCE REVIEW FOR: EXAMPLE
GRE/SWI • Hemorrhagic transformation/
petechial (SWI/GRE dark)
• Chronic microbleeds, may
identify chronic hypertension
and/or signature of
possible/probable CAA
• Clot in the artery (identified
by a “blooming artifact”
within the affected vessel)

GRE demonstrating hypointense blood products with

blooming artifact confirming hemorrhagic
transformation.
MRA Can be done with gadolinium
or without. Without employs a
“time-of-flight” image (TOF).
MRA is helpful in defining the
large vessels, but may not
provide the same level of detail
as a CTA and may overcall the
degree of stenosis/occlusion.
MRA demonstrating vessel narrowing in the left A1
segment. This may be caused by slow flow,
vasospasm, or stenosis.
Some centers may also use MR Perfusion to assess ischemic lesions. See page 71 for more
information.

40
MRI IN HEMORRHAGE
SWI/GRE These sequences can demonstrate
hemorrhage; SWI imaging is the
most sensitive for detecting small
amounts of blood and can be used
to detect microhemorrhages and
help differentiate between CAA and
hypertensive hemorrhages.

GRE sequence demonstrating focal blood

products in the R temporal-parietal region
(dark).
T1/T2 Can be used to date hemorrhage
FLAIR can be used to identify
underlying vasogenic edema
(suggestive of tumor), prior strokes
(suggestive of hemorrhagic
transformation), inflammatory white
matter changes (such as seen in
inflammatory CAA), and cytotoxic
edema (suggestive of venous
congestion, PRES, venous sinus
thrombosis). If contrasted, T1 images T2 FLAIR image demonstrating a combination
will help demonstrate areas of blood of vasogenic/cytotoxic edema around a
brain barrier breakdown. cortical bleed.
MR Helpful in suspected cases of venous
Venography sinus thrombosis
w/and w/o
gad

MR Venography demonstrates patchy filling

defect of the superior sagittal sinus.

41
MRI IN INFECTIOUS/INFLAMMATORY/NEOPLASTIC CONDITIONS
T1 As gadolinium can demonstrate active
w/gadolinium areas of blood brain barrier breakdown,
T1 with gadolinium should always be
obtained in cases suspected of
demyelination (such as MS, ADEM,
hereditary demyelinating conditions),
neoplastic conditions (gliomas,
lymphomas, menigiomas, etc.), and
encephalitis/meningitis. These images
also demonstrate inflammation of T1 Post-Gadolinium: Contrast-enhancing
meninges such as seen in meningitis and meningioma in the extra-axial space
leptomeningeal carcinomatosis, and may causing compression and midline shift
reveal characteristic “ring enhancement” of the left frontotemporal lobe.
patterns that help narrow the differential
diagnosis. For examples of T1 post-
gadolinium patterns, see below.
T2 FLAIR Essential in determining the pattern of
inflammation and thus providing a major
diagnostic clue to the etiology.
Encephalitis patterns may be more
specifically described as limbic,
rhomboencephalitic, cerebellitis, and
basal ganglia inflammation.

T2 FLAIR: Medial Temporal Lobe T2

hyperintensity from HSV encephalitis
DWI As above, not all that restricts is ischemic.
Restricted diffusion may be observed with
lymphomas, abscesses, tumefactive
necrosis, and other pathology.

DWI: Diffusion restriction due to an

infected surgical cavity

42
MRI IN INFECTIOUS/INFLAMMATORY/NEOPLASTIC CONDITIONS
MR Perfusion Advanced imaging technique that
measures the degree of angiogenesis and
capillary permeability, it is particularly
helpful in grading gliomas and can
provide prognostic information.

Reconstructed Perfusion Image

demonstrating poor perfusion to the
region adjacent to a large AVM
resection cavity.
MR Advanced imaging technique which
spectroscopy provides metabolic information about the
pathologic tissue. CNS tumors have a
characteristic MRS signature that is
different than inflammatory lesions or
abscesses and thus can refine the
differential diagnosis prior to having MR Spectroscopy of a midline
surgical pathology gadolinium-enhancing mass which
demonstrated a decrease in the
N-acetylaspartate peak and increase
choline peak in the bilateral thalami,
highly suggestive of a neoplastic
process.
MR Vessel Vessel wall imaging is an advanced
Wall Imaging imaging technique with high spatial
resolution which evaluates the vessel wall.
Although this is a newer imaging
modality, it has shown promise in
differentiating between atherosclerotic
plaque, vasculitis, RCVS, moya-moya
disease, radiation-induced arteriopathy,
and dissection [1]. VW MR: Enhancement seen in the
bilateral MCAs as a result of vasculitis

43
EXAMPLES OF DIFFUSION RESTRICTION PATTERNS
ACUTE ISCHEMIA HYPOXIC-ISCHEMIC DAMAGE ABSCESS

SEIZURE-RELATED DIFFUSION FOCAL VASCULAR TERRITORY CNS LYMPHOMA

RESTRICTED CORTICAL ISCHEMIA, SEEN
OCCASIONALLY
POST-THROMBECTOMY

44
EXAMPLES OF CONTRAST ENHANCEMENT
RING-ENHANCEMENT VENTRICULITIS MENINGITIS

LEPTOMENINGEAL DISEASE UNIFORM ENHANCEMENT ACTIVE DEMYELINATION

OF MENINGIOMA

REFERENCE
1. Mandell DM, et al. Intracranial vessel wall MRI: principles and expert consensus recommenda-
tions of the American Society of Neuroradiology. Am J Neuroradiol. 2017;38(2):218–29.

45
UNDERSTANDING TRANSCRANIAL DOPPLERS (TCDS)
Catherine S. W. Albin and Sahar F. Zafar

BASIC PRINCIPLES [1]

• Ultrasound waves admitted from the probe are transmitted to the flowing intracra-
nial vessels. The difference between the waves emitted and those reflected back is
directly proportional to the blood’s velocity.
• Blood flow is laminar, so the reflected waves have a range of frequencies which
forms a spectral display representing the mixture of velocities which can be used to
calculate:
–– Peak systolic Velocity
–– End diastolic Velocity
–– Pulsatility index
–– Time-averaged mean maximum velocity (Vmean)
• Each artery has a characteristic appearance.
• The Doppler equation involves cosine of the angle of insonation.
This angle is assumed to be 0 degrees, so that the cosine (0) = 1.
If the angle of insonation is not exactly 0 (meaning the probe is not directly in line
with the blood vessel), the speed calculated is slower than the actual flow.
–– Thus, when velocities are reported, we know the flow is AT LEAST that fast, and
may be faster if the angle was not exactly 0 degrees.

Blood velocity is impacted by:

• Arterial diameter and stenosis
• Age
• Gender
• Hematocrit
• Viscosity
• CO2
• Blood pressure
• Activity

COMMON APPLICATION OF TCDS

• Most commonly used to assess for vasospasm in SAH, but also can be used to
measure focal vascular stenosis, hyperemia and reperfusion, embolic signals, flow
reversal, and vascular reactivity.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_8
47
EXAMPLES OF ARTERIES ON TCD

-60

Fig. 8.1 Posterior Cerebral Artery

-60

Fig. 8.2 Middle Cerebral Artery

48
MONITORING
• There are four standard TCD “acoustic windows.” The transtemporal window (for
the MCA, ACA, and PCA), transorbital (carotid siphon and ophthalmic artery),
suboccipital window (basilar and vertebral arteries), and sometimes, the subman-
dibular window (distal ICA)
• The different branches of the Circle of Willis are identified by the speed of flow,
direction of flow, and a characteristic depth at which the artery should be found.

APPLICATION IN SAH
• TCDs can be used to help evaluate and diagnose a patient with vasospasm. In
studies, moderately elevated mean velocities (120–199 cm/s) in the MCA did not
always correlate with angiographic spasm; however, the positive predictive value of
mean velocities ≥200 cm/s was 87%. The negative predictive value for mean
velocities <120 cm/s was 94%. Thus, very elevated or low cerebral artery flow
velocities reliably predict angiographically significant vasospasm or the lack
thereof [2].
• The Lindegaard Ratio (LR) is an important ratio in evaluating for vasospasm:
Since velocities can also be influenced by hematocrit, blood pressure, and CO2,
etc., the Lindegaard Ratio accounts for the difference in flow velocity in the ICA and
MCA. The MCA and ICA should be equally affected by patient factors, but the ICA
should not be affected by vasospasm.
–– A Lindegaard Ratio (LR) of <3 is normal. An LR of 3–6 is suggestive of mild-
moderate spasm.
–– An LR >6 is considered to be indicative of severe spasm.
• Institutions use slightly different cut offs for acceptable upper limits of normal;
however, a general guide is:

CONCERNINGLY ELEVATED, SIGNIFICANTLY ELEVATED, LIKELY

VESSEL PROBABLE VASOSPASM (VMEAN) VASOSPASM (VMEAN)
Anterior >120 cm/sec; >200 cm/sec;
Vessels Lindegaard Ratio 3-6 Lindegaard Ratio ≥6
Posterior >80 cm/sec No consensus,
Vessels (Basilar Artery Velocity)/(Vertebral Artery
Velocity) >3 significant [3]

• It is also important to take into account the degree of change and the amount of
time that change occurred over. For example, a 20% increase in velocity in one
day, even if not reaching a threshold of LR >3, should still raise concern.
• TCD reports will also include the pulsatility index (PI). The pulsality index reflects
the change between systolic and diastolic pressures. An increase in the pulsatility
index may represent downstream resistance to flow. This is often as a result of
distal vasospasm or increased intracranial pressure. An abrupt rise in the PI or a
PI>1.5 should alert you to these possibilities.

49
OVERVIEW OF OTHER TCD APPLICATIONS
• In ischemic stroke: TCDs can be used to track arterial occlusion before and after
tPA [4]. TCDs with emboli detection (HITS – high-intensity transient signals) can be
used to assess the risk for ongoing thrombo-embolic disease and may be helpful in
determining the need for aggressive therapy (such as anticoagulation) [5].
• Brain death testing: As ICP rises, CPP approaches zero leading to cerebral
circulatory arrest. When ICP is equal to the diastolic perfusion pressure, the dia-
stolic perfusion drops to 0 and there is no diastolic flow seen on TCDs. As the ICP
continues to rise, the diastolic flow reverses resulting in net forward flow of zero,
which is consistent with cerebral circulatory arrest [6].

Fig. 8.3 The above Transcranial Doppler display demonstrates oscillating flow and thus cessation of
cerebral perfusion. There is forward flow, but ICP is equal or greater than SBP, and thus during dias-
tole there is flow reversal of the same magnitude and the net forward flow is 0. This is consistent with
cerebral circulatory arrest

REFERENCES
1. Purkayastha S, Sorond F. Transcranial doppler ultrasound: technique and application. In:
Seminars in neurology, vol. 32. Thieme Medical Publishers; 2012.
2. Vora YY, et al. Role of transcranial Doppler monitoring in the diagnosis of cerebral vasospasm
after subarachnoid hemorrhage. Neurosurgery. 1999;44(6):1237–48.
3. Sviri GE, et al. Transcranial Doppler grading criteria for basilar artery vasospasm. Neurosurgery.
2006;59(2):360–6.
4. Christoe I, et al. Timing of recanalization after tissue plasminogen activator therapy deter-
mined by transcranial doppler correlates with clinical recovery from ischemic stroke. Stroke.
2000;31(8):1812–6.

50
5. Daffertshoker M, et al. High-intensity transient signals in patients with cerebral ischemia. Stroke.
1996;27(10):1844–9.
6. Ducrocq X, Hassler W, Moritake K. Consensus opinion on diagnosis of cerebral circulatory arrest
using Doppler-sonography: Task Force Group on cerebral death of the Neurosonology Research
Group of the World Federation of Neurology. J Neurol Sci. 1998;159:145–50.

51
TIPS AND TRICKS FOR EEG INTERPRETATION
Catherine S. W. Albin and Sahar F. Zafar

Please note a comprehensive review of EEG is outside of this guide’s scope. Below
is an abbreviated overview.
Frequencies (named for the order in which they were discovered)
Large peaks counted between 1 sec intervals

Beta >13 hz Seen normally in the frontocentral leads when awake. In the ICU, often a result of
sedation (benzodiazepines classically, propofol)
Alpha 8–13 hz Normal background activity best seen in the posterior leads when a healthy
patient’s eyes are closed
Theta 5–7 hz Slower frequency that can be associated with normal drowsiness or
encephalopathy
Delta <5 hz Seen normally in sleep. In the ICU, associated with encephalopathy and structural
lesions (focal delta)

Electrographic seizures are abnormal, sustained, rhythmic electrical

discharges that interrupt the background. They have an evolution in
morphology, frequency, and/or location.

Fig. 9.1 EEG demonstrating 3Hz spike-and-wave discharges consistent with seizure

Note that sometimes an EEG may be noted as becoming “faster,” which can mean
one of two things:
1. The BACKGROUND may be faster, such as moving from mainly delta to theta, for
example. This is a good thing as generally this suggests the patient is waking up.

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_9
53
2. The PATHOLOGY is becoming faster and thus more concerning for seizure risk:
–– For example, a post-op patient may have continual 1hz lateralized periodic dis-
charges (LPDs) over the site of their hemicraniectomy. However, if these periodic
discharges increase in frequency from 1 Hz to 2 Hz (meaning there are two
spikes per second) that is concerning for increasing seizure risk (example below).
Make sure you clarify with the EEG team what rhythms and findings are being
observed. For more tips on the interictal continuum, see page 267.

Fig. 9.2 Lateralized Periodic Discharges at 1hz

Fig. 9.3 Lateralized Periodic Discharges at 2hz

54
ELECTRODES
Even electrodes are on the right, odd electrodes are on the left

Fp1 Fp2

F7 F8
F3 F4
Fz

A1 T3 C3 Cz C4 T4 A2

P3 Pz
P4
T5 T6

O1 O2

OPTIMIZING EEG DATA

• EEG can be viewed in different montages. A “Double Banana” montage is one that
is commonly used as it allows for easy comparison between the left and right
hemispheres.
• Set the sensitivity (how “loud” the data is): the default is 7 uV/mm, you can use the
keyboards “up” and “down” arrows to change this (for example, 15 uV/mm will
make the amplitude lower)
• Scroll through by either arrowing “left” and “right” or by hitting the space bar to play
the data. Note that you can find out the exact time by looking at the very top of
the screen.
• The HFF (high frequency filter) can “clean up” data and is a way to reduce muscle
artifact. The brain does not generate frequencies much faster than 15hz. This
allows you to “filter out” any data that is faster than whatever this is set to.
However, note that by minimizing artifact, you are also compromising the data and
may also reduce “signal” while reducing “noise”

55
GETTING THE BIG PICTURE (THE SPECTROGRAM AND SEIZURE DETECTION)
The spectrogram is a way to help comb through hours and hours of data by giving a
power analysis. At least a snippet of the EEG should be reviewed for each part of the
spectrogram that appears different.

What Is It:
• The spectrogram is a computer algorithm (the details of which are beyond the
scope of this chapter) that processes the sinusoids of the EEG and represents the
amplitude of the sinusoids as a function of frequency
• The x-axis=time; the y=frequency, color corresponds to power
• The seizure detection feature is at the bottom of this toolbar. It does not replace
review of raw EEG data. However, it can be used to pinpoint time to review
the data.
How to Use It:
• Using the Spectrogram:
–– The window of time to view can be adjusted (see image, next page)
–– How does the pattern change when sedation is held? Or when are the
AEDs loaded?
–– Are there any periods of sharp changes?
• Using the Seizure Probability feature
–– Click a red “spike” to take you to this time and scroll a bit before. What does the
background look like? How does it change as you move towards the
“Seizure” spike?
–– What is the patient doing? Check by the video camera!
Tips for Reading EEG:
• Given limited time in pre-rounding, select sections of the EEG can be reviewed
based on clinical changes, bedside nursing annotation, medication administration,
or changes seen in the spectrogram. Note: this does not replace a detailed review
of all EEG data and should be performed per institutional practice
• Assess the overall organization: What is the dominant background frequency -
Theta? Delta? Is a Posterior Dominant Rhythm (alpha activity in the posterior leads)
present?
• Assess the symmetry, what is the predominant frequency on the right side /
left side?
• Are there any periods of burst suppression?
• Are there any sharp waves, periodic discharges?
• Seizures? And if so, how many?
• Page 267 reviews some of the findings on the inter-ictal continuum and discusses
an algorithm for their management.

56
Fig. 9.4 A Spectrogram

57
PART II

VASCULAR NEUROLOGY
ACUTE ISCHEMIC STROKE – FIRST ENCOUNTER ASSESSMENT
AND MANAGEMENT
Catherine S. W. Albin and Sahar F. Zafar

EMERGENCY DEPARTMENT MANAGEMENT

The chief priority is to ensure that the patient is registered and screened for eligibility
of tissue plasminogen activator (tPA) and/or mechanical thrombectomy as soon as
possible.

Note that Tenecteplaste (TNK) is a genetically modified variant of alteplase

which has the advantage of ease of administration (a single IV push over 5
seconds) and has been shown to be noninferior to tPA [1] and may have better
outcomes in severe strokes [2]. Although it has not been FDA at the time of
publication, the text tries to make note of any differences as applicable.

For eligible patients, the goal door to needle time for IV tPA/TNK is <60 min (Class I
Evidence) [5]
Multiple tasks should be performed by the ED team (physician, advanced practice
provider/resident, radiologist, CT tech, pharmacy, registrar, and nursing):
• EMT/ED teams flag possible acute stroke and notify neurology and radiology teams
• Patient is registered and assigned a medical record number
• ED team assesses ABCs and stabilizes patient
• Radiology is contacted about need for STAT CT/CTA/CTP (imaging protocols vary
by institution).
• Screening labs and a POCT glucose are obtained. Labs should be sent STAT.
• At least an 18G IV is placed for administration of contrast
• Ideally a travel bedside monitor is set up so that the patient can be immediately
transferred to the CT scanner
• Pharmacy is alerted about potential need for tPA and someone with experience
mixing tPA is available/ready to mix tPA if needed Mixing is not required for TNK.
In addition to working with the ED team to ensure the above tasks are being carried
out, the neurologist’s role is to:
□□Arrive to assess the patient as soon as possible
□□Confirm that the patient is ordered for a noncontrast head CT and standard
institutional protocol for additional imaging
□□Establish time of onset/last seen well (LSW)
□□Document National Institute of Health Stroke Score (NIHSS)
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_10
61
□□Investigate if the patient is on anticoagulation, and if it cannot be determined
but there is a high likelihood based on the patient’s known medical history,
confirm that coags, including anti-Xa assay for novel oral anticoagulants (if
available), are sent.
□□ Review patient’s history for contraindications for IV tPA/TNK (see next page),
□□ Discuss risks/benefits of tPA/TNK and other treatment options with family/
patient (see next page). Note that it may be required to have documentation of
consent in the chart.
□□ Review if patient is an endovascular therapy candidate (see page 67). If CTA is
not readily available, do not delay tPA/TNK administration for vessel imaging.
If the Patient has no hemorrhage and is within 4.5 h of last seen well and meets
other criteria for TPA:
□□ Weigh patient
□□ Confirm (again!) the patient’s blood pressure is <185/110, if not, use labetalol,
nicardipine, or clevidipine to lower.
□□ Dosing tPA: 0.9 mg/kg IV; not to exceed 90 mg total dose; administer 10% of
the total dose as an initial IV bolus over 1 min; remainder is infused
over 60 min
□□ Dosing TNK: There are variable dosing strategies. 0.25 mg/kg (max 25mg) was
used in NEJM trial [3] administered over 5 seconds
□□ Once tPA/TNK is administered, let BP autoregulate no higher than 180/105 for
24 h post-tPA. Blood pressure should be monitored every 15 min for the first
24 h, then every 30 min for 6 h, and then every 60 min until 24 h after
treatment.

TPA (TNK) SCREENING

TPA Contraindictions (Majority from the Original NINDS Trial [4] with Updates
from the ASA/AHA 2018 Guidelines [5]) Most TNK trials have used the same
exclusion criteria.
□□ Significant head trauma or prior stroke in previous 3 months
□□ Symptoms suggest subarachnoid hemorrhage
□□ Intracranial hemorrhage or history of intracranial hemorrhage
□□ Intra-axial intracranial neoplasms and unruptured >10 mm aneurysm,
□□ Intracranial or intraspinal surgery within 3 months
□□ Aortic dissection
□□ Bacterial endocarditis (or high concern for)
□□ GI or GU hemorrhage within 21d
□□ Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg)
despite aggressive management
□□ Acute bleeding diathesis, including but not limited to: Platelet count
<100,000/mm3
□□ Elevated aPTT greater than the upper limit of normal

62
□□Current use of anticoagulant with INR >1.7 or PT >15 s
□□Treatment doses of a low molecular weight heparin (ie enoxaparin) within 24 h,
or current use of direct thrombin inhibitors or factor Xa inhibitors, if last dose
within 48 h
□□ Extensive hypodensity on CT, suggesting that the new infarct has already
completed. Prior strokes (> 3 months prior) do not exclude the patient
from tPA/TNK.
Relative Contraindications (From ASA/AHA Guidelines [5])
□□ Only minor or rapidly improving stroke symptoms
□□ Seizure at onset with post-ictal residual neurological impairments
□□ Major surgery or serious trauma (within previous 14 days)
□□ Intracranial vascular abnormalities that do not meet threshold for absolute
contraindication per AHA 2018 guidelines
□□ Pregnancy
□□ Blood glucose <50 or >400 mg/dL
Other Considerations if Dosing TPA in the Extended Window (3–4.5 h)
The original ECASS III trial [6] for extended window tPA excluded patients >80 years,
patients on anticoagulation, and patients with a history of stroke and diabetes;
however, follow up data [5] has demonstrated:
□□ Patient >80 y.o. also benefit from tPA in extended window (Class IIA Evidence)
□□ In patients with prior stroke and diabetes, extended window tPA may be
reasonable (Class IIB evidence)
□□ If patient is taking warfarin but INR ≤1.7, tPA appears safe and may be benefi-
cial (Class IIB)
□□ The benefit of IV tPA for patients with a very high NIHSS (>25) is unknown
(Class IIB)

Plain Language to Consent a Patient/Next of kin for TPA

If using TNK consent the patient’s family that TNK has been shown to be noninfe-
rior and potentially safer, but has not been FDA approved.
Major points for standard 3-h window (based on NINDS Data [4]):
• tPA is a clot-busting drug administered with the goal of breaking up the blood
clot in the brain, which is causing the stroke.
• Of patients that receive tPA, about 30 of 100 patients will have a better
long-term outcome than if they did not receive tPA.
• A small number of patients will have brain bleeding within 36 h as a result of
the treatment. Only about 3 of 100 patients will be significantly wors-
ened by tPA.
• The time to treatment matters, and it is important that we begin this treatment as
soon as possible.

63
For Extended Window (3–4.5 h) (based on ECASS III Data [6]):
• tPA administered in this window is associated with a modest improvement in
favorable outcomes. Of patients treated with tPA in this timeframe about 7 of
100 patients will have a better outcome than if they did not receive tPA.
• Patients that receive tPA in this time window have a higher rate of brain bleed-
ing, but only about 3 patients of every 100 patients treated have a symptom-
atic bleed.
• The FDA has not approved tPA to be given after 3 h, but we have trial data that
suggest it is still safe and efficacious.

ENDOVASCULAR TREATMENT AND SCREENING

Multiple clinical trials [7–10] have demonstrated that endovascular thrombectomy
within 6 h of symptom onset dramatically improved the outcomes of patients with a
large vessel occlusion (LVO). In 2018, the DAWN [11] and DEFUSE3 [12] Trials
revolutionized stroke treatment by demonstrating that patients treated as late as 24 h
after symptom onset with a median treatment time of 12.5 h and 11 h could benefit
from thrombectomy, if appropriately selected. These trials demonstrated a 35.5% and
28% increase in functional independence, respectively.
As such, screening candidacy for thrombectomy is of utmost importance. The
degree of screening should be governed by the capabilities of the center.
In centers where endovascular treatment is NOT performed: Any patient with an
NIHSS ≥6 and a LSW within 24 h should be considered a potential candidate for
reperfusion. Whenever possible, obtain CT angiography with the non-contrast head
CT to evaluate for an LVO. However, obtaining CTA should not delay the prompt
consultation with a thrombectomy-capable center.
• In late window cases and/or low NIHSS, CTA may be recommended to assess for
the LVO and grade collaterals, prior to transfer
• For patients with high NIHSS and shorter duration of LSW, the thrombectomy center
may prefer to obtain vessel imaging after transfer so as not to delay the transfer.
Regional practices vary and it is most important to discuss these cases as soon as
possible!

64
For thrombectomy capable centers assessing patients either in the ED or for
transfer: Both clinical and radiographic data determine how likely the patient is to
benefit from thrombectomy:

CLINICAL INFORMATION TO OBTAIN RADIOGRAPHIC EVIDENCE TO HELP STRATIFY

□□
Age □□
Alberta Stroke Program Early CT Score (ASPECTS)
□□Time since LSW Score from non-contrasted head CT [13]
□□Baseline function (often discussed If a transfer:
as modified Rankin Score) □□Location of occlusion (if referring hospital has
□□NIHSS and Syndrome already obtained vessel imaging)
(e.g. ”L MCA” syndrome) □□Degree of collaterals (if referring hospital has
□□Approximate fastest time from the obtained vessel imaging)
referring hospital to the treatment Once arrived at thrombectomy center:
center if the patient is being □□Location of occlusion (if not previously known)
transferred. □□Degree of collaterals (if not previously known)
□□Perfusion imaging to compare core to isch-
emic tissuea
a
here are several different ways to determine ischemic core-to-penumbra mismatch. CT per-
T
fusion is widely used and is discussed on page 71. MRI can also be used to establish a small
core ischemic area on DWI. Follow institutional standard imaging protocol to ensure rapid
imaging is obtained. New studies have suggested that deferring imaging studies and moving
directly to the angio suite after a non-contrasted Head CT exonerates bleed, and this may
become a paradigm shift in acute stroke care [14].

SUMMARY OF WHO IS LIKELY TO BENEFIT FROM THROMBECTOMY IN ANTERIOR

A
CIRCULATION LARGE VESSEL OCCLUSION [5]
THROMBECTOMY SHOULD BE CONSIDERED IN ANY PATIENT WITH:
– A Large Vessel Occlusion (ICA, M1 or M2 occlusion)
– Within 24 hours of last seen well
– A baseline mRS of 0-1 (see page 67)
– ASPECTS score >5 (see page 67)*

The use of advanced neuroimaging (most often CTP) should be done based on hospital protocols

*Note that a recent retrospective analysis showed that with recanalization even patients with
ASPECTS <5 could achieve good mRS scores at 90 days and were nearly 5 times more likely to
achieve favorable outcome [20].

As such, discussion with an endovascular capable center is advised even in patients with a less
favorable ASPECT score. Large-core randomized trials are currently underway to further guide this
management.

65
TPA+MECHANICAL THROMBECTOMY (MT) VS. ONLY MT
Three trials (DEVT [15], DIRECT-MT [16], SKIP [17]) came out in early 2021 that
looked for non-inferiority of mechanical thrombectomy (MT) alone when compared to
IV tPA+MT (tPA+MT). This is referred to as “bridging” with tPA.
Although two of these trials demonstrated non-inferiority of bypassing IV tPA there
was also major criticism that the non-inferiority margins were overly generous, and
that SKIP was underpowered.
There is nuance and local preference but some factors that may favor MT alone
include situations in which peri-procedural dual-antiplatet therapy may be needed:
such as for tandem ICA/MCA occlusion, dissections, and significant intracranial
atherosclerosis, or when the MT team is rapidly available. IV tPA may offer higher
benefit to patients with very early presentations, long travel time to MT capable
center, or when there is a borderline low NIHSS for thrombectomy [18].
At the time of this publication, IV tPA/TNK is still the standard of care for all
patients presenting within the appropriate window whether or not MT is
being pursed.

POSTERIOR CIRCULATION OCCLUSIONS

There have been no randomized trials yet (BASICS and BAOCHE are enrolling) that
looked exclusively at reperfusion of posterior circulation large vessel occlusions.
However, the BASILAR registry [19] reported data on prospectively enrolled acute
symptomatic basilar occlusions (non-randomized) who were treated with
Endovascular Treatment (EVT) + Standard Medical Treatment (SMT) (647) vs. SMT
(182) in China. Based on the reported experience, among patients with a relatively
high median pc-ASPECT score of 8 and severe symptoms (78% in coma or tetraple-
gic) EVT+SMT resulted in a lower median 90-day mRS: 5 (severe disability) com-
pared to 6 (dead) in the SMT alone. There was a higher proportion of favorable
outcomes mRS ≤3 in the EVT group (32%) vs (9.3%). The number needed to treat
for 1 additional patient to be able to walk unassisted was 4.4.
The median time from symptom onset to revascularization was 441 min (328–627).
The rate of symptomatic intracerebral hemorrhage was 7.1% in the EVT group. Given
this data, acute basilar thrombosis presenting within 24 h of suspected symptom
onset should be considered for endovascular treatment on a case-by-case review

66
MAJOR SCORING METRICS FOR ACUTE STROKE

Modified Rankin Scale

0 = No residual symptoms.
1 = No significant disability; able to carry out all pre-stroke activities.
2 = Slight disability; unable to carry out all pre-stroke activities but able to look
after self without daily help.
3 = Moderate disability; requiring some external help but able to walk without
assistance of another individual.
4 = Moderately severe disability; unable to walk or attend to bodily functions
without assistance of another individual.
5 = Severe disability; bedridden, incontinent, and requiring constant nurs-
ing care.
6 = Dead

ASPECTS SCORING
Calculating an Alberta Stroke Program Early CT Score (ASPECTS) [6]
Each of the 10 areas shown below is assigned a point.
Whenever there is blurring of the gray–white differentiation of an area (suggestive of
early ischemic change) then a point is subtracted for that area.
A score of 10 is a normal head CT.
A score of 0 suggests radiographically detectable ischemic change in the entire MCA
territory.

Fig. 10.1 Example of ASPECTS Territories. C = Caudate, L = Lentiform Nucleus, IC = Internal capsule

67
REFERENCES
1. Burgos AM, Saver JL. Evidence that tenecteplase is noninferior to alteplase for acute ischemic
stroke: meta‐analysis of 5 randomized trials. Stroke. 2019; 50:2156–62.
2. Campbell BC, Mitchell PJ, Churilov L, Yassi N, Kleinig TJ, Yan B, Dowling RJ, Bush SJ, Dewey
HM, Thijs V, et al. Tenecteplase versus alteplase before endovascular thrombectomy (EXTEND‐
IA TNK): a multicenter, randomized, controlled study. Int J Stroke. 2018; 13:328–34.
3. Campbell, Bruce CV, et al. Tenecteplase versus alteplase before thrombectomy for ischemic
stroke. N Eng J Med 2018;378(17):1573-82.
4. National Institute of Neurological Disorders and Stroke rt-PAStroke Study Group. Tissue plas-
minogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–7.
5. Powers WJ, et al. 2018 guidelines for the early management of patients with acute ischemic
stroke: a guideline for healthcare professionals from the American Heart Association/American
Stroke Association. Stroke. 2018;49(3):e46–99.
6. Hacke W, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J
Med. 2008;359(13):1317–29.
7. Jovin TG, Chamorro A, Cobo E, et al. Thrombectomy within 8 hours after symptom onset in isch-
emic stroke. N Engl J Med. 2015;372(24):2296–306. https://doi.org/10.1056/NEJMoa1503780.
8. Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. T-PA
alone in stroke. N Engl J Med. 2015;372(24):2285–95. https://doi.org/10.1056/NEJMoa1415061.
9. Campbell BC, Mitchell PJ, Kleinig TJ, et al. Endovascular therapy for ischemic stroke with
perfusion-imaging selection. N Engl J Med. 2015;372(11):1009–18. https://doi.org/10.1056/
NEJMoa1414792.
10. Goyal M, Demchuk AM, Menon BK, et al. Randomized assessment of rapid endovascular
treatment of ischemic stroke. N Engl J Med. 2015;372(11):1019–30. https://doi.org/10.1056/
NEJMoa1414905.
11. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a
mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11–21. https://doi.org/10.1056/
NEJMoa1706442.
12. Albers GW, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging.
N Engl J Med. 2018;378(8):708–18.
13. Pexman JHW, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing
CT scans in patients with acute stroke. Am J Neuroradiol. 2001;22(8):1534–42.
14. Thon, Jesse M., and Tudor G. Jovin. “Imaging as a selection tool for thrombectomy in acute isch-
emic stroke: pathophysiologic considerations.” Neurology 97.20 Supplement 2 (2021): S52-S59.
15. Zi W, et al. Effect of endovascular treatment alone vs intravenous alteplase plus endovascular
treatment on functional independence in patients with acute ischemic stroke: the DEVT random-
ized clinical trial. JAMA. 2021;325(3):234–43.
16. Yang P, Zhang Y, Zhang L, Zhang Y, Treurniet KM, Chen W, Peng Y, Han H, Wang J, Wang
S, DIRECT-MT Investigators, et al. Endovascular thrombectomy with or without intravenous
alteplase in acute stroke. N Engl J Med. 2020;382:1981–93.

68
17. Suzuki K, et al. The randomized study of endovascular therapy with versus without intravenous
tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study). Int J Stroke.
2019;14(7):752–5.
18. Nogueira RG, Tsivgoulis G. Large vessel occlusion strokes after the DIRECT-MT and SKIP trials:
is the alteplase syringe half empty or half full? Stroke. 2020;51(10):3182–6.
19. Writing Group for the BASILAR Group. Assessment of endovascular treatment for acute basilar
artery occlusion via a nationwide prospective registry. JAMA Neurol. 2020;77(5):561–73.
20. Almallouhi E, Al Kasab S, Hubbard Z, et al. Outcomes of Mechanical Thrombectomy for Patients
With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in
the Early and Extended Window. JAMA Netw Open. 2021;4(12):e2137708.

69
PERFUSION IMAGING
Catherine S. W. Albin and Sahar F. Zafar

The goal of perfusion imaging is to determine the extent of territory at risk of infarction
so as to correctly triage the patients that are most likely to benefit from endovascular
reperfusion therapies [2].

Terms
Cerebral Blood Volume (CBV): Total cerebral blood volume in a given unit of
brain volume (mL/100 g)
Cerebral Blood Flow (CBF): Total volume of blood moving through a given unit of
brain volume per unit time (mL/100 g/min)
Mean Transit Time (MTT): Average transit time of blood through a given brain
region in seconds
Perfusion–Diffusion Mismatch: Finding a difference in the tissue that is ischemic
and the tissue that is at risk of infarction (the penumbra)

TECHNIQUES [1]
• CT Perfusion: Uses iodinated contrast to generate MTT, CBV, and CBF measure-
ments. Main benefit is that it can be rapidly obtained. Major limitations are that it is
less sensitive in detecting the ischemic core as MRI and exposes patients to
contrast.
• MR Perfusion: Uses gadolinium contrast agent to trace the perfusion of blood and
generate the above measurements. The three types are described below.
–– Dynamic Susceptibility Contrast (DSC) MR Perfusion: registers the susceptibility-
induced signal loss on T2-weighted sequences after a bolus of gadolinium-based
contrast passes through a capillary bed.
–– Dynamic Contrast-Enhanced (DCE) MR Perfusion: measures T1 shortening due
to gadolinium-based contrast passing through tissue.
–– Arterial Spin Labeling (ASL): Water molecules are magnetically “labeled” by
selective radiofrequency (RF) irradiation pulse applied to the neck, and then a
downstream measurement of the labeled water molecules are collected in the
brain. This generates a map of cerebral blood flow. Benefits include that it requires
no contrast agent. Major limitation is that there is a low signal-to-noise ratio which
can make the data difficult to interpret.

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_11
71
T WO ACUTE STROKE CASES THAT DISTINGUISH A COMPLETED INFARCT
FROM PENUMBRA
EXAMPLE OF IMAGING IN A PATIENT EXAMPLE OF IMAGING IN A PATIENT THAT
THAT HAS ALREADY ESTABLISHED AND HAS A SMALL ISCHEMIC CORE AND A
ISCHEMIC CORE: LARGE PENUMBRA:
MTT Markedly increased Mildly increased

CBV Mildly decreased Mildly increased or normal

72
EXAMPLE OF IMAGING IN A PATIENT EXAMPLE OF IMAGING IN A PATIENT THAT
THAT HAS ALREADY ESTABLISHED AND HAS A SMALL ISCHEMIC CORE AND A
ISCHEMIC CORE: LARGE PENUMBRA:
CBF Markedly decreased Mildly decreased

DWI Restricted diffusion No restricted diffusion

(MRI)

REFERENCES
1. Campbell BC, Christensen S, Levi CR, et al. Comparison of computed tomography perfusion
and magnetic resonance imaging perfusion-diffusion mismatch in ischemic stroke. Stroke.
2012;43(10):2648–53.
2. Menon BK. Neuroimaging in acute stroke. Continuum. 2020;26(2):287–309.
73
ISCHEMIC STROKE: ADMISSION CHECKLIST
Catherine S. W. Albin and Sahar F. Zafar

REVIEW
Note class of evidence based on the ASA/AHA 2018 Acute Ischemic Stroke
Guidelines [1]
□□Review non-contrasted head CT (NCHCT), CTA head & neck, and perfusion
imaging (as available)
□□Confirm the patient received tPA/TNK (Class I), if no contraindications (see
page 63) or received ASA 325 mg, if not eligible for tPA/TNK and no contraindi-
cation for aspirin. If the patient received tPA/TNK, the first dose of aspirin
should be held until a 24 hour head CT demonstrates no significant intracranial
hemorrhage
□□If s/p thrombectomy, review imaging and receive sign-out from endovascular
team, clarify blood pressre goals. Note: Recent trial comparing SBP goals in
thrombectomy found no difference in outcomes for patient with an avg BP of
128 mmHg (intensive BP loweing group) vs 138 mmHg (control group [3]).
□□EKG (Class I)

CONFIRM PATIENT ORDERED FOR

□□Most patients will get an MRI; however, note that per the ASA/AHA 2018
guidelines, the routine use of brain MRI in all patients with AIS is not cost-
effective (Class III)
□□ Consider ordering: Lipids (Class IIb), HgbA1c (Class IIa), Troponin (Class I)
□□ Dysphagia screen (Class IIa)
□□ Telemetry monitoring (Class I)
□□ Aspirin (unless s/p tPA) (Class I)
□□ High-intensity statin, if stroke presumed to be atherosclerotic in origin. (Class I)
□□ Consider the potential benefit of dual-antiplatelet therapy if patient has a minor
ischemic stroke or high-risk TIA [2]
□□ Consider ECHO (Class IIb) if high concern for intracardiac thrombus or high
concern for paradoxical embolus. Order with agitated saline for if evaluating for
PFO (usually patients <60 years old)
□□ DVT prophylaxis (hold pharmacologic prophylaxis until 24 h NCHCT if s/p tPA).
Note that SCDs have Class I evidence; the benefit of chemical DVT ppx is
uncertain (Class IIb evidence)
□□ PRN medications for glucose, fevers, constipation

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_12
75
□□Hold home antihypertensives and use PRNs for BP > 220/120; Unless: Trop
elevated, h/o severe CAD, CHF, aortic dissection, hemorrhagic transformation,
s/p tPA (goal <180/105) or s/p thrombectomy (usually a lower goal is set to
prevent reperfusion injury).
□□ Restart antihypertensives in patients with BP > 140/90 to target normotension
once neurologically stable, usually after 24 h (Class IIa)
□□ Treat hyperglycemia to target glucose between 140 and 180 (Class IIa)

SPECIAL CONSIDERATIONS
□□If s/p tPA: no foley unless necessary to prevent obstructive acute kidney injury
□□if s/p tPA: 24-h head CT to confirm no hemorrhagic transformation
□□If severe carotid stenosis or extracranial dissection, consider anticoagulaton
(Class IIb). See Symptomatic Carotid Stenosis, page 95 and Dissection,
page 89
□□ Consider if early hemicraniectomy is warranted for malignant cerebral edema
(see page 199) and consider the need for hyperosmolar therapy (see
page 195).
□□ Consider the age, stroke risk factors, and comorbidities of a patient before
sending additional lab work (see page 79)

Guide to Acute Neurologic Worsening After Acute Ischemic Stroke:

□□If s/p tPA/TNK, consider tPA/TNK-related bleed (see page 219 for
reversal guide). Although less common, even patients not treated with tPA/
TNK or mechanical thrombectomy, reperfusion injury or spontaneous
bleeding may occur post-stroke
□□ Consider if patient has a blood pressure dependent exam. If concerned for
BP-dependent exam, flatten head of bed, bolus IVF, consider pressors, and
document exam before and after these interventions
□□ If s/p endovascular intervention, consider reperfusion injury (hemorrhage)
or re-occlusion of the prior large vessel occlusion
□□ If symptoms or images are suggestive of a lacunar infarct, the patient may
have worsening that is refractory to blood pressure augmentation as the
stroke “completes” – this phenomenon is referred to as a “stuttering
lacunar infarct”
□□ Consider non-convulsive seizures or a post-ictal state (rare)
Depending on the clinical scenario, repeat NCHCT with repeat CTA may be
indicated.

76
Notes for Hypercoagulation Testing:

Heparin and LMWH Affect:

ATIII testing

Warfarin Affects:
Protein C & S testing

Any Anticoagulation Affects:

APC resistance, DRRVT, and phospholipid dependence

Acute Thromboembolism Affects:

Protein S, Protein C, and ATIII

REFERENCES
1. Powers WJ, et al. Guidelines for the early management of patients with acute ischemic stroke:
2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a
guideline for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2019;50(12):e344–418.
2. Johnston SC, et al. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT)
trial: rationale and design. Int J Stroke. 2013;8(6):479–83.
3. Mazighi, M et al. Safety and efficacy if intensive blood pressure lowering after successful endo-
vascular therapy in acute ischaemic stroke (BP_TARGET): a multicentre open-label, randomized
controlled trial. The Lancet Neurology 2021;20(4):265–74.

77
STROKE WORKUP – BEYOND THE BASICS
Catherine S. W. Albin and Sahar F. Zafar

ISCHEMIA DUE TO ARTERIAL HYPERCOAGULABLE STATE

ANTIPHOSPHOLIPID ANTIBODY
MALIGNANCYA SYNDROME(APLS)A
Etiology Varies by age, exposures, and sex. Can be primary or secondary.
Brain, pancreatic, and Secondary can result from autoimmune
myeloproliferative neoplasia are high conditions, malignancies, drugs or
risk for VTE infections
Clues B-type symptoms, weight loss, others Recurrent vascular events or miscarriages
depending on cancer type (>10 weeks into pregnancy)
Lab evaluation ESR/CRP ESR/CRP
D-dimer Lupus anticoagulant (confirmed with
Dependent on age/sex but could DRVVT), anticardiolipin IgG/IgM, beta-2-
include: glycoprotein IgG/IgM,
• Flow cytometry/cytology/ other antibodies are not routinely checked
peripheral smear by commercial labs, but do exist including
• Myeloproliferative neoplasms: anti-phosphatidyl-ethanolamine,
JAK2 mutation, CALR, MPL phosphatidylinositol IgG, IgA, IgM,
• Adenocarcinomas: CA125, CEA, phosphatidylserine antibody panel
CA 19-9, CA 15-3, PSA
• Germ cell tumors: hCG, AFP
• Other: PSA
Additional Age/sex dependent, could include: Testing for underlying rheumatologic
testing • Skin exam conditions, malignancy or infections
• Cervical exam + transvaginal u/s depending on risk factors and presentation.
• Breast exam + mammogram Extended APLS panel
• CT chest/Ab/Pelv with contrast
• Whole body PET
• Endoscopy/colonoscopy
Notes Diagnosis requires a vascular event or
miscarriage + high antibody titers on two
occasions 12 weeks apart. Testing has a
high false negative rate. If high suspicion,
continue checking [2].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_13
79
ISCHEMIA DUE TO ARTERIAL HYPERCOAGULABLE STATE
HEPARIN INDUCED OTHER HEMATOLOGIC
THROMBOCYTOPENIA(HIT)A HYPERHOMOCYSTEINEMIAA CONDITIONS
Etiology History consistent with first Associated with use of TMAs:
exposure to heparin fibrates and nicotinic acid • TTP
5–10 days before platelet treatment, smoking, B6/ • HUS
drop. Or platelet drop B12/folate deficiency [1] • Shiga-associated HUS
immediately if heparin given Sickle cell anemia
in last 30 days.
Clues Exposure to heparin Can cause both large and TMAs: schistocytes,
small vessel vascular disease thrombocytopenia, AKI
Lab PF4 antibody Homocysteine level, B6, TMAs:
evaluation B12, folate levels ADAMTS13 activity
If Shiga-related: E. coli
O157:H7
CBC / BMP
LDH
Bilirubin
Coagulation tests
DAT/coombs
Sickle cell:
Hemoglobin S
(electrophoresis)
Additional Confirmatory testing with None Peripheral smear
testing the serotonin release assay
Notes Probability of HIT should be
predicted by the 4T score,
prior to testing
VTE venous thromboembolism; ESR erythrocyte Sedimentation Rate; CRP C-reactive protein test;CALR
calreticulin; CEA carcinoembryonic antigen; PSA prostate specific antigen; TTP thrombotic thrombo-
cytopenic purpura; HUS hemolytic uremic syndrome; TMAs thrombotic microangiopathies; DAT direct
antiglobulin test

80
ISCHEMIA DUE TO VENOUS HYPERCOAGABLE STATE (REQUIRES R → L SHUNT)
STATE- SYSTEMIC
DEPENDENT DISEASES
INHERITED (I.E. (INCLUDING BUT
THROMBOPHILIAS [7] PROVOKED) DRUGS NOT LIMITED TO)
Etiology Factor V Leiden mutation, Trauma, Oral contraceptive Peripheral noctural
prothrombin gene pregnancy, pills, hormonal hemoglobinuria
mutation, protein C/S surgery, therapy, (PNH)
deficiency, antithrombin III prolonged testosterone, Nephrotic syndrome
deficiency immobility lupus-inducing Inflammatory bowel
medications, disease
bevacizumab
Clues Personal or family history Evident by Appropriate Often evident by
of venous thrombosis history medication list history or comorbid
findings.
Lab Tests for above etiologies, None needed None needed Beyond the scope of
evaluation often available as a this chapter
hypercoaguable panel
(see page 77 for how
anticoagulation and acute
disease effects this testing)
Imaging Deep vein thrombosis DVT screen DVT screen DVT screen
evaluation (DVT) screen
Notes: Factor V Leiden mutation
is 5–10× more common
than the others.
Acquired causes of
protein C/S and anti-
thrombin deficiency (DIC,
acute thrombosis,
cirrhosis, nephrotic
syndrome, ECMO, drug
interaction) are much
more common than
inherited causes

81
ISCHEMIA DUE TO LESS COMMON CAUSES OF THROMBOEMBOLIC DISEASE [8]
INFECTIVE MARANTIC PARADOXICAL
ENDOCARDITIS ENDOCARDITIS DISSECTION EMBOLUS
Etiology Most common Deposition of sterile Injury to great vessels Venous clot – assess
pathogens: thrombi often due to either by trauma or for the risk factor
• Staphylococcus endothelial injury genetic connective described above
(MSSA and from a tissue disorder (many that traverses a
MSRA) hypercoagulable have probable right-to-left shunt
• Streptococcus state. association, but such as a PFO or
(viridians and Often seen with SLE fibromuscular ASD
bovis) and adenocarcinoma dysplasia (FMD) is
• Enterococcus likely the most
Culture negative common)
pathogens:
• HACEK
organisms
• Coxiella
• Bartonella
• Tropheryma
whippelii
Clues Fevers, chills, night
Depends on etiology, Horner’s syndrome if DVT, risk factors for
sweats + new may have no carotid involved venous
murmur associated symptoms Neck trauma by hypercoagable
history, or neck pain state (as per above)
or posterior orbital
pain/headache
Lab Blood cultures, ESR/CRP, screen for Per above section
evaluation ESR/CRP malignancy and
rheumatologic
conditions
Imaging TTE and if negative TTE and if negative MRA with T1 fat TTE with agitated
evaluation TEE TEE suppression saline
Consider diagnostic Renal artery
cerebral angiogram ultrasound if concern
to evaluate for for FMD
mycotic aneurysms
Notes See page 89 for For further
management management see
page 114
HACEK Haemophilus, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella
corrodens, Kingella kingae, TTE trans-thoracic echocardiography, TEE transesophageal echocardiog-
raphy, SLE systemic lupus erythematosus, FMD fibromuscular dysplasia, PFO patent foramen ovale,
ASD atrioseptal defect

82
Fig. 13.1 Paradoxical Embolus: Transesophageal echocardiogram showing a large clot traversing
a PFO This patient presented with an acute R MCA stroke in the context of prolonged immobility
after orthopedic surgery. Further workup demonstrated multiple DVT and transesophageal ECHO
demonstrated this finding

83
ISCHEMIA DUE TO VASCULOPATHY
VASCULITIS DUE TO INFECTIOUS
NONINFECTIOUS VASCULITIS [6] SYSTEMIC DISEASE VASCULITIS
Etiology Large vessel: Takayasu & Giant Cell SLE HIV (human
Arteritis (GCA) Rhumatoid arthritis immune-deficiency
Medium vessel: Polyarteritis nodosa & (RA) virus)
Kawasaki disease (present in children) Sjogrens VZV (Varicella
Small vessel: ANCA-associated, Solid organ Zoster Virus)
immune complex-mediated, neoplasms Bacterial meningitis
cryoglobulinemia Clonal B cell
lympho-proliferative
disorders
Behcet’s disease
Clues Dependent on syndrome, but Dependent on Dependent on
generally: constitutional symptoms, syndrome, often infection, assess for
athralgias, hypertension constitutional nuchal rigidity
For GCA: temporal pain, jaw symptoms
claudication, elderly patient, strokes
uncommon but predilection for
posterior circulation
Lab evaluation ESR/CRP, ANCA, cryoglobulins, ESR/CRP, ANA, Lumbar puncture (LP)
complement level dsDNA, RF, SS-A, for CSF cultures
SS-B, RNP, anti-smith Blood cultures
HIV antibody test
CSF VZV IgG/IgM
and PCR
Further CTA of great vessels Sjogrens: parotid
investigations Ultrasound and biopsy of temporal gland biopsy
artery if GCA suspected Neoplasms: workup
Evaluation for HCV (hep C virus) if per above
cryoglobulin being considered Behcets: pathergy test
Notes Consider MR-vessel wall imaging

84
ISCHEMIA DUE TO VASCULOPATHY
PRIMARY VASCULITIS INTRAVASCULAR
OF THE CNS LYMPHOMA GENETIC VASCULOPATHIES [9]
Etiology Primary CNS Lymphoma cells Moya-moya
vasculitis (PACNS) proliferate in the Cerebral autosomal dominant
Susac’s syndrome vessel wall of small arteriopathy with subcortical infarcts
(categorized more blood vessels and leukoencephalopathy (CARASIL)
specifically as a rare CARASIL (recessive)
form of COL41A mutation [3]
microangiopathy) Fabry’s disease
Hereditary Hemorrhagic
Telangiectasia (HHT)
Fibromuscular displasia (FMD)
Retinal vasculopathy with Cerebral
Leukodystrophy
Clues Primary CNS Subacute Moya-moya: progressive stenosis of
vasculitis often encephalopathy, the terminal and proximal ACA/
presents with subcortical infarcts, MCA. Vessels have a “puff of smoke
subacute constitutional B appearance” (see image below) [4]
encephalopathy + symptoms, skin CADASIL: family history of migraines,
headache lesions early onset strokes, dementia and
Susac’s syndrome is depression, subcortical infarcts
the triad of Fabry: Posterior circulation strokes,
encephalopathy, neuropathy, painful acroparasethesias
branched retinal CARASIL: subcortical infarcts
artery occlusion, and
hearing loss
Lab evaluation Rule out of other CSF for cytology and NOTCH3 (CADASIL)
causes of vasculitis flow cytometry and Fabry: Leukocyte alpha-galactosidase
IgH gene A activity
rearrangement
HTRA1 (CARASIL)
Retinal vasculopathy
Cerebral Leukodystrophy: TREX1
Further Brain biopsy for Dermatology consult MRI can demonstrate the pulvinar
investigations PACNS for skin biopsy sign in Fabry’s disease
Fluorescein PET scan to detect MRI shows temporal pole
angiogram for Susac subclinical systemic leukoaraiosis in CADASIL
lymphoma
Notes Consider MR-vessel wall imaging
ANCA antineutrophil cytoplasmic antibodies; ANA antinuclear antigen; dsDNA double stranded
DNA antibody; RF rheumatoid factor; SS-A Anti-Ro antibodies; SS-B Anti-La antibodies; RNP ribonu-
cleoprotein antibodies; PET positron emission tomography

85
Fig. 13.2 Moya-Moya: Patient demonstrates the characteristic loss of large vessels at the circle
of Willis (absence of MCA demonstrated by the arrow) and “puff of smoke” abnormal vasculature
(depicted by arrowheads)

86
OTHER ETIOLOGIES OF ISCHEMIA
REVERSIBLE CEREBRAL POSTERIOR REVERSIBLE
VASOCONSTRICTION ENCEPHALOPATHY SYNDROME
SYNDROME (RCVS) [5] (PRES) [5] ANEURYSMAL SAH
Etiology Unknown Failure of cerebral vaso- Can result in delayed
pathophysiology – autoregulation and endothelial cerebral ischemia
altered vascular tone and dysfunction
vasomotor control are
invoked
Clues Recurrent thunderclap Headache accompanied by Higher grades of SAH
headache encephalopathy +/− vision have increasing
Associated drugs: SSRIs, changes. incidence of delayed
cocaine, amphetamines, Accompanying conditions: cerebral ischemia and
diet pills hypertension, pregnancy clinically significant
Associated conditions: (hypertensive encephalopathy and vasospasm (see page
Pregnancy, migraine eclampsia are related conditions 235)
that may share the same
pathophysiology)
Precipitating medications:
immunomodulators (tacrolimus,
sirolimus), chemotherapeutic
agents
Lab Urine and serum drug Urine and serum drug screen, drug N/A
evaluation screen levels may be helpful in
appropriate cases
Imaging CTA demonstrating MRI demonstrating posterior TCD, cvEEG, CTA, and
evaluation vasospasm dominate leukoencephalopathy angiography as
warranted
Notes More commonly causes Strokes are an infrequent See page 229 for
convexity SAH than complication, posterior cerebral prevention and
ischemic infarcts edema without infarct is typical management
SSRIs selective serotonin reuptake inhibitor, SAH subarachnoid hemorrhage, TCDs transcranial doppler,
cvEEG continue video electroencephalogram

REFERENCES
1. Jeon S-B, et al. Homocysteine, small-vessel disease, and atherosclerosis: an MRI study of 825
stroke patients. Neurology. 2014;83(8):695–701.
2. Moore GW, et al. Further evidence of false negative screening for lupus anticoagulants. Thromb
Res. 2008;121(4):477–84.
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87
4. Fukui M, et al. Moyamoya disease. Neuropathology. 2000;20:61–4.
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7. Voetsch B, et al. Inherited thrombophilia as a risk factor for the development of ischemic stroke
in young adults. Thromb Haemost. 2000;83(02):229–33.
8. Ji R, et al. Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic
yield, neuroimaging, and thrombolysis. JAMA Neurol. 2013;70(1):51–7.
9. Putaala J. Ischemic stroke in young adults. Continuum (Minneap Minn). 2020;26(2):386–414.
https://doi.org/10.1212/CON.0000000000000833.

88
ISCHEMIC STROKE: DISSECTION
Catherine S. W. Albin and Sahar F. Zafar

ISTORICAL POINTS, SIGNS, AND SYMPTOMS THAT SHOULD RAISE CONCERN

H
FOR DISSECTION [1]

Both
□□History of trauma
□□History of connective tissue disease: fibromuscular dysplasia, Ehlers Danlos
type IV, Marfan’s, cystic medial necrosis, osteogenesis imperfecta, polycystic
kidney disease
□□ Systemic cause of vessel wall inflammation: infectious or rheumatologic/
autoimmune conditions
□□ Stroke in the absence of traditional vascular risk factors
□□ Young age (patients average ~40 years old in case series)

Internal Carotid
□□Headache/facial pain – may be referred to supraorbital ridge
□□Neck pain – commonly along the anterolateral neck
□□Partial Horner’s syndrome – ipsilateral miosis and ptosis
□□Anterior circulation stroke syndrome
Vertebral Artery
□□Headache – often ipsilateral occipital
□□Neck pain – commonly posterior lateral neck
□□Cerebellar or brainstem symptoms

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_14
89
PATHOPHYSIOLOGY
A tear in the vessel intima allows blood to form a sub-intimal or sub-adventitial
hematoma. An overlying thrombus forms which puts the patient at risk for thrombo-
embolic stroke and hypoperfusion, if severe narrowing occurs.

“Flame sign”
Pathophysiology of dissection
(tapering of the ICA)

Fig. 14.1 Pathophysiology of Dissection

ADMISSION CHECKLIST
□□ Review vessel imaging
• Angiography is the gold standard, but infrequently performed given procedural
risks; CT angiography is preferable when GFR >35.
• MRA TOF may overcall the degree of vessel narrowing and occlusion as this
is a flow-dependent study.
• MRI T1 Fat Suppression can help to highlight the vessel wall hematoma.
Being stationary blood, the hematoma will be T1 hyperintense.
□□ Determine if the dissection is extra- or intracranial as this may impact manage-
ment decisions (see below)
• Traditional teaching was that given the risk of subarachnoid hemorrhage with
sub-adventitial extension, dissections that were even partially intracranial
should not be treated with anticoagulation.
• However, a case-series of 81 patients with intracranial dissections (carotid or
vertebral) with no SAH at the time of presentation, who were subsequently
treated with anticoagulation, found no events of SAH during treatment [2].
□□ Review parenchymal imaging
• DWI MRI preferable to determine the size of ischemic core
• SWI MRI may be helpful to exonerate SAH
□□ Provide adequate analgesia
□□ Determine use of aspirin vs anticoagulation (see below)

90
DETERMINING WHEN A VESSEL IS EXTRACRANIAL VS. INTRACRANIAL

Carotids
• The carotid artery is named based on the segment classification proposed by
Bouthillier [3].
• It is considered intracranial when it enters the skull base at the petrous portion.
• The carotid is not intradural until passing the distal dural ring, which anatomically
demarcates the end of the clinoid (C5) portion.
• Distal to the dural ring, there is a risk of SAH with dissection extension. However,
subadventitial dissection in the cavernous segment (C4) could result in a
cavernous-carotid fistula, which would also have serious consequences.
• While intradural dissections do result in SAH, the likelihood that subarachnoid
hemorrhage develops as a result of treatment is small and has not been well-
documented in case-series [2].

Vertebrals
• Pierces the dura after passing through the transverse foramen and the posterior
atlanto-occipital membrane of C1.

INTERNAL CAROTID ANATOMY VERTEBRAL ANATOMY

C7 – Communicating
Distal Dural C6 – Ophthalmic
Ring V4 –
C5 – Clinoid Intradural

C4 - Cavernous V3 –
C2 to Dura

C3 - Lacerum

C2 - Petrous V2 - Foraminal

C1 – Cervical
V1 – pre-
foraminal

91
ASPIRIN VS. ANTICOAGULATION
TRIAL METHODS FINDINGS
CADISS [4] 250 patients with extracranial Anti-platelet therapy was
(Lancet 2014) vertebral or carotid dissections non-inferior, but the rate of stroke
randomized within the first 7 days was only 2%, which was
of symptom discovery to anti- significantly lower in both groups
platelet treatment (aspirin, than expected.
ASA + clopidogrel, dipyridamole
at the discretion of the physician)
or anticoagulation.
Take away from CADISS: The trial was underpowered and the antiplatelet group was not
standardized. Additionally, patients were randomized at a mean of 3.25 days after symptom onset,
which misses the highest risk period for stroke when anticoagulation might prove more efficacious.
There is still considerable practice variation, anticoagulation (most often as heparin to warfarin) or
antiplatelet (most often ASA 325 mg) can be justified on a case-by-case basis.
TREAT-CAD [5] 194 patients with cervical artery Non-inferiority of aspirin was not
(Lancet 2021) dissection (not specified intra- or found, suggesting superiority of
extracranial) within 2 weeks anticoagulation although the trial
before enrollment were was NOT designed to prove
randomized to 300 mg of aspirin that. The observed absolute
or a vitamin K antagonist for difference in the primary
90 days. Used composite primary endpoint rate between groups
endpoints: clinical events (stroke, was 8%. Ischemic stroke, major
major hemorrhage, death) and hemorrhage, or MRI surrogates
MRI outcomes at 14 days. occurred in 23% in the ASA
group and 15% in the Vitamin K
group.
Take away from TREAT-CAD: This trial was not designed to show the superiority of a vitamin K
antagonist, but it was not able to demonstrate non-inferiority of aspirin. Unfortunately, two commonly
used practices: dual-antiplatelet therapy and direct oral anticoagulants were not investigated. Some
trial notes for consideration: 13% of patients were treated with acute revascularization prior to
enrollment. The time between onset of first dissection symptom and treatment was, on average,
7 days in both groups.

92
REFERENCES
1. Silbert PL, Mokri B, Schievink WI. Headache and neck pain in spontaneous internal carotid and
vertebral artery dissections. Neurology. 1995;45(8):1517–22.
2. Metso TM, Metso AJ, Helenius J, Haapaniemi E, Salonen O, Porras M, Hernesniemi J, Kaste M,
Tatlisumak T. Prognosis and safety of anticoagulation in intracranial artery dissections in adults.
Stroke. 2007;38(6):1837–42.
3. Bouthillier A, van Loveren HR, Keller JT. Segments of the internal carotid artery: a new classifica-
tion. Neurosurgery. 1996;38(3):425–32; discussion 432–3.
4. CADISS Trial Investigators. Antiplatelet treatment compared with anticoagulation treatment for
cervical artery dissection (CADISS): a randomised trial. Lancet Neurol. 2015;14(4):361–7.
5. Engelter ST, et al. TREAT-CAD Investigators. Aspirin versus anticoagulation in cervical artery
dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial. Lancet Neurol.
2021;20(5):341–50. https://doi.org/10.1016/S1474-4422(21)00044-2. Epub ahead of print.

93
ISCHEMIC STROKE: SYMPTOMATIC CAROTID STENOSIS
(“HOT CAROTID”)
Catherine S. W. Albin and Sahar F. Zafar

“SYMPTOMATIC” DEFINITION
A focal, acute event (stroke, TIA, or amaurosis fugax) resulting from a perfusion
deficit or embolic event in the territory of an internal carotid artery with significant
atherosclerotic burden (at least 50% stenosis by NASCET criteria). Note that patients
with moderate or severe strokes (with persistent disabling neurologic deficits) have
been excluded from trials of carotid artery stenting (CAS)/carotid endarterectomy
(CEA). For many trials, patients were considered symptomatic if an index event had
happened within 180 days prior to treatment.

INTERVENTIONAL VS. MEDICAL TREATMENT

• The NASCET trial [1] demonstrated the superiority of CEA to medical management
in preventing recurrent stroke, reducing the stroke rate from 26% to 9% in patients
with 70–99% stenosis. There was also a milder benefit favoring CEA in patients
with 50–69% stenosis, which was most evident in male patients. Note, however,
statins were not in wide use at the time, and the number needed to treat may be
higher now that the medical management has improved.
• Patients with complete occlusion had no benefit with surgery
• The CREST-2 trial [2] is an ongoing trial aimed at determining the best manage-
ment for asymptomatic carotid stenosis.
Maximal medical treatment includes aggressive management of blood pressure, high
cholesterol, diabetes, tobacco use, and sedentary lifestyle.

CAROTID ENDARTERECTOMY (CEA) VS. CAROTID STENTING (CAS)

Multiple trials (CREST, ACT I, EVA-ES, ICSS, SAPPHIRE) have compared CEA and
CAS. Composite analysis has demonstrated similar benefits in long-term outcome.
Peri-procedurally (i.e., within the first 30 days), endovascular treatment was associated
with a higher risk of death and stroke (OR 1.72, 95% CI 1.29–2.31, P = 0.0003); how-
ever, the rate of ipsilateral stroke after the periprocedural period did not differ. This risk
was largely seen in patients older than 70 years, and most strokes were nondisabling.
Endovascular treatment was associated with lower rates of myocardial infarction (OR
0.44, 95% CI 0.23–0.87, P = 0.02) and cranial nerve palsy (OR 0.08, P < 0.00001) [3].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_15
95
TAKEAWAY
CONDITIONS THAT FAVOR CEA CONDITIONS THAT FAVOR CAS
• Need for urgent revascularization • High risk for anesthesia (cardiac and pulmonary
• Older age (age > 70 years) conditions)
• Patients in whom DAPT is • Recent myocardial infarction
contraindicated • Patients with neck lesions too high to be easily surgically
accessible
• Prior CEA
• Radiation-induced stenosis
• Difficult surgical anatomy

TREATMENT PRIOR TO SURGERY

□□At least single antiplatelet therapy (ASA 81–325 mg).
□□The addition of clopidogrel or another P2Y12 inhibitor may reduce the risk of
stroke before CEA/CAS but should be discussed with the surgical team.
□□In a prospective audit of 100 consecutive CEA patients, early implementation
of dual antiplatelet therapy was associated with a fivefold reduction in recurrent
events in the 2 to 3-day period between transfer from the TIA clinic and
undergoing CEA from 13% to 3% (odds ratio [OR] = 4.9; 95% confidence
interval [CI], 1.5–16.6; P = 0.01) [4].
□□ Liberal blood pressure goals so as to prevent hypoperfusion.
□□ Smoking cessation counseling.
□□ Statin therapy for goal LDL <70 [5].
A note about anticoagulation: Multiple trials (IST, TOAST, HAEST) have demon-
strated that anticoagulation confers no benefit, but does increase the risk of hemor-
rhage. The exception was that in a prespecified secondary analysis of the TOAST
data, there was a potential benefit seen in the subgroup of patients with large artery
atherosclerosis treated with danaparoid. Because of this data and personal treatment
experience, many vascular experts will use unfractionated heparin with no bolus in
conditions deemed high risk for embolization and low risk of hemorrhagic conversion.
In a recent retrospective review of 443 patients with symptomatic carotid stenosis,
short-term anticoagulation as a bridge to CEA was protective against recurrent TIA/
stroke compared with antiplatelet therapy. Consider on a case-by-case scenario [6].

FACTORS THAT DEMONSTRATE PLAQUE INSTABILITY

□□Positive HITS with TCD study [7]
□□Plaque hemorrhage as detected on MRI [8]
□□Plaque irregularity on U/S [9]

96
TIMING OF SURGERY
The risk of neurologic worsening is estimated between 8% and 27% in the first
2 weeks [10]. Multiple studies have confirmed that the benefit of CEA is most appar-
ent if offered within the first 2 weeks of index symptom. The periprocedural stroke
risk of CAS is higher within the first 2 weeks after index symptom, up to 9.4% [11].
Although management is often institution and operator-dependent, CEA may be
preferable in the urgent setting.

TREATMENT AFTER SURGERY OR STENTING

□□If CAS: Aspirin 81–325 mg and a P2Y12 inhibitor, such as ticagrelor or clopido-
grel, are prescribed to prevent stent re-occlusion.
□□If CEA: Aspirin monotherapy. Escalated therapy may be considered based in
patients with other stroke risk factors.
□□ Some institutions will check a PRU (platelet reactivity) test to confirm adequate
platelet suppression with dual antiplatelet therapy.
□□ BP control, usually goal SBP < 140 to prevent reperfusion injury or intracranial
hemorrhage.
• Both are rare, but more common in patients with ischemic injury and high-
grade stenosis.
□□ Intensive vascular risk factor modification: weight, hypertension, cholesterol,
smoking, and diabetes management.

Evidence of watershed infarcts which may be due Reformatted CT angiogram demonstrating L

either to hypoperfusion (caused by critical stenosis of ICA severe stenosis and a near-floating
the carotid) or embolic phenomena from carotid thrombus just distal to the carotid bifurcation.
plaque.

97
REFERENCES
1. Moneta GL, et al. Correlation of North American Symptomatic Carotid Endarterectomy Trial
(NASCET) angiographic definition of 70% to 99% internal carotid artery stenosis with duplex
scanning. J Vasc Surg. 1993;17(1):152–9.
2. Howard VJ, et al. Carotid revascularization and medical management for asymptomatic carotid
stenosis: protocol of the CREST-2 clinical trials. Int J Stroke. 2017;12(7):770–8.
3. Sardar P, Chatterjee S, Aronow HD, Kundu A, Ramchand P, Mukherjee D, et al. Carotid artery
stenting versus endarterectomy for stroke prevention: a meta-analysis of clinical trials. J Am Coll
Cardiol. 2017;69(18):2266–75.
4. Batchelder AJ, Hunter J, Robertson V, et al. Dual antiplatelet therapy prior to expedited carotid
surgery reduces recurrent events prior to surgery without increasing peri-operative bleeding com-
plications. Eur J Vasc Endovasc Surg. 2015;50:412–9.
5. Amarenco P, et al. Benefit of targeting a LDL (low-density lipoprotein) cholesterol <70 mg/dL dur-
ing 5 years after ischemic stroke. Stroke. 2020;51(4):1231–9.
6. Martinez-Gutierrez, Carlos J, et al. Preoperative antithrombotic treatment in acutely symptomatic
carotid artery stenosis. Journal of Stroke and Cerebrovascular Diseases 31.5 (2022): 106396.
7. Salem MK, et al. Spontaneous cerebral embolisation in asymptomatic and recently symptomatic
patients with TIA/Minor stroke. Eur J Vasc Endovasc Surg. 2011;41(6):720–5.
8. Altaf N, et al. Detection of intraplaque hemorrhage by magnetic resonance imaging in symptom-
atic patients with mild to moderate carotid stenosis predicts recurrent neurological events. J Vasc
Surg. 2008;47(2):337–42.
9. Prabhakaran S, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern
Manhattan study. Stroke. 2006;37(11):2696–701.
10. Ois A, Cuadrado-Godia E, Rodríguez-Campello A, Jimenez-Conde J, Roquer J. High risk of early
neurological recurrence in symptomatic carotid stenosis. Stroke. 2009;40(8):2727–31.
11. Rantner B, Goebel G, Bonati LH, Ringleb PA, Mas JL, Fraedrich G, Carotid Stenting Trialists’
Collaboration. The risk of carotid artery stenting compared with carotid endarterectomy is great-
est in patients treated within 7 days of symptoms. J Vasc Surg. 2013;57(3):619–26.

98
ISCHEMIC STROKE – POST STROKE MANAGEMENT
OF ANTICOAGULATION
Catherine S. W. Albin and Sahar F. Zafar

Despite the fact that “when to start/restart anticoagulation?” is a common question

for both patients on the neurology ward and on our consultation patients, there is still
ongoing controversy about the timing and safety of restarting anticoagulation after an
ischemic event. For data about the risk and benefit of restarting/starting anticoagula-
tion after a intracerebral hemorrhage, see page 225.

PART 1: RISK AND BENEFIT OF ANTICOAGULATION BY POPULATION SUBGROUP:

DATA ABOUT THE RISK OF WITHHOLDING ANTICOAGULATION

Atrial Fibrillation
The patient’s annualized risk of stroke from atrial fibrillation can be estimated using
the CHA2DS2-VASc score [2].
Congestive heart failure +1
Hypertension (includes current antihypertension +1
pharmacologic treatment)
Age ≥ 75 +2
Diabetes mellitus +1
Stroke or TIA +2
Vascular disease (prior MI, PAD, aoritc plaque) +1
Age 65–74 +1
Sex (female) +1

ANNUAL STROKE RISK BY SCORE

Annualized Stroke Risk (%)

14 12.2
12 11.2 10.8
9.7
10
8 7.2
6 4.8
4 3.2
2.2
2 0 0.6
0
0 1 2 3 4 5 6 7 8 9
CHA2DS2-Vasc Score

Chart above demonstrating the annualized stroke risk, unadjusted for aspirin use
based on the Swedish Atrial Fibrillation cohort study [3].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_16
99
Although patients with a score of 1 or higher (unless the point was for female sex)
should be strongly considered for anticoagulation, the “weekly risk” of stroke from
atrial fibrillation is still very low. However, in the IST trial, among 1612 patients with a
presumed cardioembolic stroke due to atrial fibrillation and not treated with early
anticoagulation, 4.9% had a recurrent ischemic event within the first 14 days [4].

ATA ABOUT THE EFFECTIVENESS OF ANTICOAGULATION IN ATRIAL FIBRILLATION

D
IN THE LONG TERM
DRUG DATA ABOUT EFFECTIVENESS
Warfarin Stroke reduction by 62% (95% CI 48–72%); Absolute risk reduction 2.7%/year for
primary prevention and 8.4%/year for secondary prevention [1]
Aspirin Stroke reduction of 22% (CI 2–38%) [1]
DOACS All have demonstrated non-inferiority in stroke prevention when compared to warfarin
(see Major Trials, page 105)

Mechanical Valves
In a large meta-analysis of complications of mechanical valves, the annualized risk of
a “Major Embolism” (classified as one causing death, persistent neurologic deficit or
peripheral disease requiring surgery) was 4 per 100 patient-years among all patients
with any mechanical value when not on antithrombotic therapy [5]. The RR of
embolism was twice as high with a valve in the mitral position. With coumadin the
risk dropped to 1.4 per 100 patient years.

Symptomatic Carotid Stenosis

Among patients with >50% stenosis of the ICA and recent stroke, TIA, or ocular TIA,
the risk of a recurrent ipsilateral event was approximately 14% within the first 2 weeks
[6]. Older age was associated with an increased risk of recurrence. Another study,
looking at patients with >70% stenosis found that the risk at 1 week was 4%, and the
risk at 30 days was only 7.5% [7]. Use of anticoagulation in this population is contro-
versial and many stroke neurologist would opt for anti-platelet therapy. However, in a
prespecified secondary analysis of the TOAST[1] data there was a potential benefit
seen in the subgroup of patients with large artery atherosclerosis treated with dan-
aparoid, and anticoagulation should be considered on a case-by-case basis.

1
Adams Jr, Harold P., et al. “Classification of subtype of acute ischemic stroke. Definitions for use in
a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.” stroke 24.1
(1993): 35-41.

100
PART 2: UNDERSTANDING THE PATIENT’S PERSONAL RISK OF BLEEDING

DATA ABOUT PROBABLE PREDICTORS OF HEMORRHAGIC TRANSFORMATION (HT)

Data from a retrospective analysis by Marsh et al. [8] predictors of hemorrhagic
transformation included:
□□Age (OR = 1.50 per 10-year increment)
□□Infarct volume (OR = 1.10 per 10 ccs)
□□Renal impairment by estimated GFR (OR = 1.95)
In their cohort, all HT did not differ between the group that was anticoagulated and
the group that was not anticoagulated, but all intracerebral hematomas (PH1/PH2,
see below), and symptomatic bleeds occurred in the anticoagulated group.

The HeRS score for predicting hemorrhagic transformation is based on this data
and can be helpful in determining risk
(Available as an iPhone app “Johns Hopkins HeRS”)

Other clinical information that may be helpful in risk stratifying:

□□Evidence of hemorrhagic conversion before addition of anticoagulation (see
ECASS grading system, below)
□□Blood pressure in hyperacute phase
• Although not proven for anticoagulation, this was associated with tPa-related
hemorrhage in acute ischemic stroke
□□ Evidence of microbleeds, superficial siderosis, or leukoaraiosis on MRI
• all of which may make the patient at higher risk of ICH (see page 225 for more
information on high risk hemorrhage patients)
□□ Location of the stroke
• In a post hoc analysis of the Triple AXEL trial, location in the posterior circulation
was the only factor significantly associated with risk of hemorrhagic transforma-
tion [9].

101
Grading Hemorrhagic Conversion
Proposed for use in the ECASS trial [10]
HEMORRHAGIC
CLASSIFICATION RADIOGRAPHIC APPEARANCE EXAMPLE
Hemorrhagic Small, hyperdense petechiae without
infarction type 1 mass effect
(HI1)

Hemorrhagic More confluent hyperdensity through

infarction type 2 the infarct zone, without mass effect
(HI2)

Parenchymal Homogenous hyperdensity occupying

hematoma type 1 <30% of the infarct zone; some mass
(PH1) effect

102
HEMORRHAGIC
CLASSIFICATION RADIOGRAPHIC APPEARANCE EXAMPLE
Parenchymal Homogeneous hyperdensity occupying
hematoma type 2 >30% of the infarct zone; significant
(PH2) mass effect; or, any homogenous
hyperdensity located beyond the
borders of the infarct zone

PART 3: WEIGHING RISK/BENEFIT OF EARLY ANTICOGAULATION

WEIGHING RISK/BENEFIT OF EARLY ANTICOGAULATION

A meta-analysis of 7 RCT (Camerling, IST, HAEST, TOAST, FISS bis, TAIST, CESG)
[11] demonstrated that death and disability were not reduced in the first 2 weeks by
early anticoagulation treatment in patients with a presumed cardioembolic acute
ischemic stroke.
• Anticoagulation with heparinoids resulted in a nonsignificant reduction in recurrent
ischemic stroke within 7–14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI:
0.44–1.06, P = 0.09, number needed to treat = 53)
• Anticoagulation resulted in a significant increase in symptomatic intracranial
bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19–7.01, P = 0.02, number
needed to harm = 55).
More recently, the Triple AXEL Trial [12] randomized patients with a small DWI-
confirmed stroke (average NIHSS 2 and volume 7.9 mL at time of treatment) to either
warfarin or rivaroxaban with 14 days (median time 3 days) after symptomatic stroke.
Patients with baseline HT (grade HI1 or HI2) were included. There was no symptom-
atic hemorrhage in either group.
The European Heart Rhythm Association takes a more liberal approach to resuming
anticoagulation. They recommend restarting of anticoagulation as follows: 1 day after
transient ischemic attack, 3 days after mild stroke, 6 days after moderate stroke, and
12 days after severe stroke [13].

103
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stroke and an indication for anticoagulation. Eur J Neurol. 2013;20:962–7.
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associated stroke treated with early anticoagulation: post hoc analysis of the Triple AXEL Trial.
Clin Neurol Neurosurg. 2018;174:156–62.
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J, Gress D, Otis SM. Recombinant tissue plasminogen activator in acute thrombotic and embolic
stroke. Ann Neurol. 1992;32:78–86.
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ment in acute cardioembolic stroke: a meta-analysis of randomized controlled trials. Stroke.
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12. Hong KS, Kwon S, Lee SH. Rivaroxaban vs warfarin sodium in the ultra-early period after
atrial fibrillation-related mild ischemic stroke: a randomized clinical trial. JAMA Neurol.
2017;74(10):1206–15.
13. Heidbuchel, Hein, et al. EHRA practical guide on the use of new oral anticoagulants in patients
with non-valvular atrial fibrillation: executive summary. European heart journal 34.27 (2013):
2094–106.

104
SELECTED ANTI-PLATELETS AND ANTICOAGULATION
IN STROKE PREVENTION
Catherine S. W. Albin and Megan E. Barra

MECHANISM
NAME (ABBREVIATED) DOSING NOTES/TRIAL DATA
Anti-platelet drugs
Aspirin (ASA) Irreversible inhibition 325 mg or 81 mg PO QD CAST (Lancet 1997) [1]
of formation of IST (Lancet 1997) [2]
thromboxane A2;
↓platelet (plt)
aggregation
Clopidogrel Irreversible P2Y12 Variable in trials some load POINT (NEJM 2018) [3]
(Plavix) adenosine 300 or 600 mg PO ×1; CHANCE (NEJM 2013) [4]
diphosphate (ADP) followed by 75 PO QD SAMMPRIS (NEJM 2011) [5]
antagonists; ↓plt
aggregation
Ticagralor Reversibly binds ADP 180 mg PO ×1 followed by THALES (NEJM 2020) [6]
(Brilinta) P2Y12 receptor; ↓plt 90 mg PO BID
aggregation
Dipyridamole Dipyridamole is 200 mg PO BID ESPRIT (Lancet 2006) [7]. Use
+ ASA XR phosphodiesterase often limited by headache.
(Aggrenox) inhibitor
Anticoagulants
Warfarin Vitamin K antagonist Target INR usually 2–3 SPAF III (Circulation 1991)
(Coumadin) (decreased synthesis [13]
of factor II, VII, IX, X, ACTIVE W (Lancet 2006) [8]
and protein C and S)
Unfractionated Primarily potentiates High-intensity therapy often IST (Lancet 1997) [2]; Can
heparin action of ATIII used for thromboembolic monitor with anti-Xa if
inhibition of clotting disease. However, in the setting prolonged baseline
factors (primarilyXa/ of acute stroke a low-intensity PTT (e.g. lupus anticoagulant)
IIa) goal may be targeted. or pseudo-heparin resistance
Prevents fibrin (elevated VIII or fibrinogen)
Post-stroke often dosed
formation
without boluses. Follow Short duration of action:
institution-specific dosing and T1/2 = 60–90 min
titration protocols for PTT
and/or anti-Xa targets

VTE prophylaxis: 5000 units

SQ BID-TID

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_17
105
MECHANISM
NAME (ABBREVIATED) DOSING NOTES/TRIAL DATA
Enoxaparin Primarily potentiates Therapeutic dosing: 1 mg/kg Avoid in CKD, can monitored
(Lovenox) action of ATIII SQ Q12H with anti-Xa level (esp.
inhibition of clotting VTE prophylaxis: 40 mg SQ obesity).
factors (primarily QD (adj high or low BMI) Check peak anti-Xa 4 h after
Xa ≫ IIa) the third or fourth dose for
efficacy. May check trough
30 minutes prior to fourth or
fifth dose if concerned for
accumulation.

TEACH (JAMA 2018) [9]

Fondaparinox Inhibition of factor Xa Therapeutic dosing: 7.5 mg Not preferred for
(Arixtra) SQ QD (if avg. body weight) anticoagulation in acute
stroke given no reversal
VTE prophylaxis: 2.5 mg SQ
agent. If heparin induced
QD
thrombocytopenia, preference
for argatroban or bivalirudin.
Argatroban Direct thrombin Therapeutic dosing: Monitor with the aPTT after
(Acova) inhibitor 1–2 mcg/kg/min continuous 2 h; goal 1.5–3× baseline
IV infusion. In critically ill, value.
multi-organ failure patients,
Advantage is very short
hepatic dysfunction start much
half-life.
lower: 0.2–0.5 mcg/kg/min
T1/2: 39–51 min if normal
hepatic function
Bivalirudin Direct thrombin Therapeutic dosing: Monitor with aPTT; goal
(Angiomax) inhibitor 0.15 mg/kg/h continuous 1.5–2.5× baseline value.
IV infusion
Advantage is very short
Reduce dose renal failure.
half-life:
T1/2: 25 min if normal renal
function
Dabigatran Direct thrombin 150 mg PO BID; Avoid in CKD
(Pradaxa) inhibitor RE-LY (NEJM 2009)a [10]
CrCl 15–30 mL/min: 75 mg
T1/2: 12–17 h
PO BID
Rivaroxaban Factor Xa inhibitor 20 mg PO QD with evening Avoid in CKD (no patients
(Xarelto) meal with CrCl < 30 included in
trials)
CrCl 15–50 mL/min: 15 mg
PO QD ARISTOTLE (NEJM 2011)a [11]

T1/2: 5–13 h

106
MECHANISM
NAME (ABBREVIATED) DOSING NOTES/TRIAL DATA
Apixaban Factor Xa inhibitor 5 mg PO BID Not well studied in CKD
(Eliquis)
Dose reduce if ≥ 2 patient ROCKET-AF (NEJM 2011)a
criteria met: ≥80 yo, ≤60 kg, [12]
Cr ≥ 1.5, reduce dose to
T1/2: 8–15 h
2.5 mg BID

a
Trial compared the oral anticoagulant to warfarin to demonstrate non-inferiority in stroke pre-
vention for non-valvular atrial fibrillation

REFERENCES
1. Chen Z-M. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with
acute ischaemic stroke. Lancet. 1997;349(9066):1641–9.
2. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised
trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute isch-
aemic stroke. Lancet. 1997;349(9065):1569–81.
3. Johnston SC, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J
Med. 2018;379(3):215–25.
4. Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl
J Med. 2013;369(1):11–9.
5. Chimowitz MI, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis.
N Engl J Med. 2015;365(11):993–1003.
6. Johnston SC, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl
J Med. 2020;383:207–17.
7. Halkes PH, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arte-
rial origin (ESPRIT): randomized controlled trial. Lancet. 2006;367(9523):1665–73.
8. Connolly SJ, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the
Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W):
a randomised controlled trial. Lancet. 2006;367(9526):1903–12.
9. Navi BB, et al. Enoxaparin vs aspirin in patients with cancer and ischemic stroke: the TEACH pilot
randomized clinical trial. JAMA Neurol. 2018;75(3):379–81.
10. Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med.
2009;361(12):1139–51.
11. Granger CB, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med.
2011;365(11):981–2.
12. Patel MR, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
2011;365(10):883–91.
13. SPAF Investigators. Stroke prevention in atrial fibrillation study. Final results. Circulation.
1991;84(2):527–39.

107
ACUTE MANAGEMENT STRATEGIES: tPA AND MECHANICAL
THROMBECTOMY TRIALS
Catherine S. W. Albin and Sahar F. Zafar

TRIAL TRIAL DESIGN MAJOR FINDINGS

Selected tPA trials
NINDS Randomization to tissue No difference in outcomes at 24 h. At
(NEJM 1995) [1] plasminogen activator (tPA) or 3 months patients given tPA were
placebo if stroke onset <3 h 30% more like to have minimal or no
prior to tPA administration disability. However, 6.5% of patients
given tPA had symptomatic
hemorrhagic converstion. Mortality
difference did not reach statistical
significance
ECASS III Randomization to tPA or placebo Bleeding rates were higher in both the
(NEJM 2008) [2] if stroke onset 3–4.5 h prior to treatment and placebo group
tPA administration. Excluded
Treatment with tPA in the 3–4.5 h
patients age >80 yo, diabetics if
window conferred benefit on about
h/o stroke, and NIHSS >25
half as many patients as treatment
under 3 h (7% vs. 13% increase in
patients with mRS 0–1). Not FDA
approved
WAKE-UP Patients presenting >4.5 h from At 90 days, 53.3% of tPA patients
(NEJM 2018) [3] LSW with DWI changes but no had mRS 0–1 compared to 41.8%
FLAIR changes randomized to who received medical therapy. No
tPA or standard medical significant difference in hemorrhage
treatment (no tPA) or death, but trend toward more in tPA
group
Selected mechanical thrombectomy trials
PROACT II Patients with MCA cut off on Recanalization rates (TIMI 2 or 3)
(JAMA 1999) [4] diagnostic angiogram w/in 6 h were 66% in the r-proUK group vs.
of onset were randomized to IV 18% in controls; however, ICH
heparin vs. IA r-proUK occurred in 10% of r-proUK group vs.
(thrombolytic) + heparin 2% in heparin alone. Difficult to
interpret as heparin is not the standard
of care. This study was felt to pave the
way for future thrombectomy trials

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_18
109
TRIAL TRIAL DESIGN MAJOR FINDINGS
IMS III Patients eligible to receive tPA Ultimately stopped early for futility
(NEJM 2013) [5] (LSW ≤3 h, and NIHSS ≥8 But flawed trial: selection bias
≥10 (if no
(with M1 clot) or removed favorable candidates from
visualized clot)) were the trial, only half of patients had a
randomized to tPA or tPA+ CTA prior to tPA, and a quarter of
endovascular treatment patients randomized to endovascular
therapy did not actually get the
treatment. Positive results for
NIHSS > 19
MR CLEAN Patients with ant. circ. prox. First endovascular trial to demonstrate
(NEJM 2015) [6] occlusions were randomized to efficacy. Endovascular therapy
standard of care (SoC) increased the number of patients with
(including tPA) or SoC + an mRS outcome of 0–2 by about
endovascular therapy (IA 14%. There was no difference
thrombolytic +/ − retrievable between treatment and control group
≤
stent). Initiation of IA 6 h for mortality and symptomatic ICH
ESCAPE Randomized to SoC or Median time from CT to reperfusion
(NEJM 2015) [7] endovascular tx (retrievable was 84 min. Median 90 day mRS
stents recommended). CT/CTA was 2 in intervention group and 4 in
had to demonstrate prox. artery the SoC group
occlusion, small infarct core, and
Rapid endovascular therapy increased
moderate/good collaterals.
the number of patients with an mRS
Goal: CT to first reperfusion in
outcome of 0–2 by 23.7%. Mortality
90 min
at 90 days was nearly half (10% in IA
group vs. 19% in SoC)
EXTEND-IA Patients with ant. circ. prox. Median time for endovascular therapy
(NEJM 2015) [8] occlusions and ischemic core initiation was 210 min after stroke
<70 cc on CT perfusion, who onset. 80% of patients in the IA group
presented within 4.5 h of LSW had early neurologic improvement vs.
were randomized to tPA + IA or 37% in the tPA group. Endovascular
tPA alone. Evaluated early therapy increased the number of
neurologic improvement patients with an mRS outcome of 0–2
by 31%
DAWN TRIAL Patients with ICA/M1 occlusion At 90 days, 73% relative reduction of
(NEJM 2018) [9] presenting 6–24 h from LSW dependency in ADLs in patients
with Clinical Imaging Mismatch treated with thrombectomy/clot
(Core infarct size smaller than retriever. NNT for any lower disability
degree of symptoms + core of 2.0. 35% absolute increase in the
<51 mL) and NIHSS ≥10 number of patients achieving mRS
randomized to clot retrieval vs. score 0–2
medical management

110
TRIAL TRIAL DESIGN MAJOR FINDINGS
DEFUSE 3 Patients with ICA/prox M1 At 90 days, 45% of patients in the
(NEJM 2018) [10] occlusion presenting 6–16 h clot retrieval group were functionally
from LSW with infarct <70 mL independent (mRS 0–2) vs. just 17%
and perfusion imaging showing in the medical management
an ischemic tissue to infarcted
No difference in ICH
tissue ratio of 1.8 were
randomized to clot retrieval vs.
medical management
Mechanical thrombectomy has revolutionized stroke care for patients with large vessel occlusion.
Pooled data from DAWN and DEFUSE-3 has reinforced that endovascular therapy is superior to
medical management in patients with AIS from LVO beyond 6 h of LSW, if appropriately selected
[11]
Selected tPA or no-tPA prior to mechanical thrombectomy (MT) – (“bridging” trials)
DIRECT MT Patients either treated with MT Non-inferiority (changed from
(NEJM 2020) [12] alone (n = 326) or IV tPA superiority). Non-inferior for a mRS @
(<4.5 h, standard dose) 90 days (20% margin). Lower
(n = 328). Included patients with successful reperfusion before
ICA, M1, M2 occlusions thrombectomy (2.4% vs. 7%) and
lower successful reperfusion (79.4%
vs. 84.5%) when no IV tPA given. No
stat sig change in ICH or 90-day
mortality with or without tPA

Large non-inferiority margin. Almost

10% of patients in the bridging group
did not receive the full dose or any tPA

The mean time between tPA bolus and

arterial puncture was 26.5 min (very
little time for tPA to take effect)
SKIP Patients either treated with MT Non-inferiority (margin of odd ratio of
(JAMA 2021) [13] alone (n = 101) or MT + IV tPA 0.74) achieved for a favorable
(n = 103) outcome mRS 0–2 at 90 days.
Favorable outcome in 59.4% patients
tPA dose was 0.6 mg/kg (which
in the MT and 57.3% patients in the
is 30% lower than the
IVT + MT
recommended dose)
ICH within 36 h from onset was high
ICA/M1 occlusions only. DWI
aspect≥ 5, CT ≥ 6, in the IVT + MT (0.5%) but the rate of

NIHSS ≥ 6
symptomatic ICH was not statistically
different

In 21% of the combined group, groin

puncture occurred before the start of
IV thrombolysis

111
TRIAL TRIAL DESIGN MAJOR FINDINGS
DEVT Trial Patients either treated with MT Non-inferiority trial set at 10% for
(JAMA 2021) [14] alone (n = 116) or IV tPA+ MT achieving 90-day functional
(n = 118), standard tPA dose ≤
independence (mRA 2). Trial
given, and the full infusion was stopped early as the interim analysis
given even if reperfusion (20% of total sample, 194 patients)
happened during the infusion demonstrated non-inferiority

ICA/M1 only Average time to tPA start was 61 min.

Average time of tPA given to groin
puncture was 44 min

DUAL ANTIPLATELET FOR MINOR STROKE/TRANSIENT ISCHEMIC ATTACK

CHANCE Chinese patients with high risk Looked at 90-day outcomes. The
(NEJM 2013) [15] TIA (ABCD2 > 4) or small stroke addition of Plavix within 24 h of
(NIHSS < 4) randomized to ASA symptom onset resulted in an absolute
(day 1: 300 or 75 mg, day risk reduction of 3.5% (NNT = 29),
2–21: 75 mg) or ASA + Plavix the survival curves split very early,
(Plavix dose day 1: 300 mg, suggesting that it may be the initial
day 2–21: 75 mg) 300 mg dose of Plavix that makes a
difference
POINT 4881 patients with minor ASA + clopidogrel reduced the risk of
(NEJM 2018) [16] ischemic stroke (NIHSS of 3 or major ischemic events. Hazard ratio,
less) or high-risk TIA (ABCD2 0.75; 95% CI: 0.59–0.95; P = 0.02.
score ≥ 4) were assigned Most of these events occurred during
clopidogrel (load of 600 mg the first week
followed by 75 mg daily) + ASA
ASA + clopidogrel also increased the
(50–325 mg) or ASA alone.
risk of major hemorrhage: Hazard
Time to major ischemic event was
ratio, 2.32; 95% CI: 1.10–4.87;
tracked (either ischemic stroke,
P = 0.02. Most of these events were
MI, or death from vascular event)
not intracranial and most occurred later
THALES 11,000 patients in this Primary outcome was stroke or death
(NEJM 2020) [17] randomized, placebo-controlled, within 30 days. 5.5% of the patients
double-blind trial for in the ticagrelor + ASA group, 6.6%
noncardioembolic ischemic of patients in ASA group. Stroke
strokes. Included pt with NIHSS occurred 5% in ticagrelor + ASA and
≤ 5 or TIA. Excluded if 6.3% in ASA alone group
thrombolysis/thrombectomy.
Severe bleeding occurred in 0.5% in
Either received ticagrelor
the ticagrelor-aspirin group and seven
(180 mg ×1, 90 mg BID) + ASA
patients (0.1%) in ASA group
(325 ×1, 75–100 mg daily) or
placebo + ASA

112
Meta-analysis of randomized controlled trials [18] comparing the outcomes of early initiation of
short-term DAPT (aspirin + a P2Y12 inhibitor for up to 3 months) vs. aspirin monotherapy
demonstrated that patients treated with DAPT had a lower risk of recurrent stroke (RR 0.76 [95% CI
0.68–0.83]; P < 0.01), but a higher risk of major bleeding events (RR 2.22 [95% 1.14–4.34])

EXTRACRANIAL DISEASE
NASCET Patients age <80 w/ 26% of those in the medical treatment
(NEJM 1991) [19] extracranial ICA stenosis group had a recurrent stroke in 2
70–99% were randomized to years vs. 9% in CEA group.
medical therapy (ASA 1300 mg Preoperative morbidity ~6%. NASCET
+ lipid/dm/HTN control) vs. II demonstrated some efficacy of CEA
medical therapy + Carotid in patients w/ ICA stenosis 50–69%.
Endarterectomy (CEA) Note that statsin were not in wide use
at the time and medical tx was not
standardized
CREST Patients with symptomatic or There was no difference in composite
(NEJM 2010) [20] asymptomatic carotid stenosis outcomes (stroke, death, MI) between
(variably measured, but >70% the two treatment arms; however,
on carotid U/S for both groups) there was a higher rate of
randomized to CEA or stenting. periprocedural stroke in the stenting
DAPT given prior to procedure group, and higher rate of MI in the
CEA group
CREST II Patients with asymptomatic Unknown as still enrolling. Important
(Enrolling) carotid stenosis (>70% on U/S) to know as this trial as asymptomatic
randomized to medical carotid disease can be treated with
management + CEA or CAS vs. interventional treatments due to
medical management alone clinical equipoise at this point
LDL Targets after Patients with ischemic stroke in 2860 patients were enrolled and
Ischemic Stroke previous 3 months or TIA in followed for median 3.5 years.
(NEJM 2020) [21] preceding 15 days assigned to Stopped early. 8.5% endpoints in
LDL target of <70 mg/dL or <70 mg/dL group and 10.9% in the
target 90–110 mg/dL. All higher target group. 34% of patients
patients had evidence of in the <70 mg/dL group required
cerebrovascular or coronary ezetimibe in addition to statins
artery diease (CAD). Outcome No statistically significant difference
was major cardiovascular event between new diabetes or ICH
(stroke, MI, coronary or carotid although a numerically higher number
revascularization) or death of ICH in the lower-target group

113
SEVERE INTRACRANIAL STENOSIS
WASID Patients with recent TIA or Stopped early because increased
(NEJM 2005) [22] non-disabling stroke with hemorrhage in the warfarin group.
intracranial stenosis of >50% Subgroup analysis demonstrated
randomized to either warfarin or lower primary outcome (not just
1300 mg ASA strokes) in the basilar subgroup; those
with therapeutic INRs in the basilar
group may have had lower stroke risk
SAMMPRIS Patients with recent TIA or Medical tx: Aspirin 325 mg + Plavix
(NEJM 2011) [23] non-disabling stroke with 75 mg for 90 days + “lifestyle
intracranial stenosis of >70% modification program” resulted in
randomized to either medical tx significantly less strokes than stenting
or medical tx + stenting at 1 year

Stenting is not typically offered; DAPT

is preferred management

PFO CLOSURE TRIALS

Gore REDUCE (NEJM 664 patients, <60 years old w/ Within 2 years recurrent stroke
2017) [24] PFO and cryptogenic stroke w/ occurred in 1.4% of the PFO closure
in 180 days prior to group and 5.4% in the antiplatelet
randomization. TEE was used to group. Clinically silent strokes
identify PFO: 81% had moderate occurred in 4.3% of the PFO group
(6–25 microbubbles) or large and 5.9% of the antiplatelet only
(>25 microbubbles) PFOs. group. Risk of Afib was higher in the
Patients randomized 2:1 to PFO PFO closure group (6.6%) after
closure + antiplatelet therapy vs. closure
antiplatelet therapy only
CLOSE 663 patients, ≤60 years old w/ The mean duration of follow-up was
(NEJM 2017) [25] cryptogenic stroke and PFO 5.4 ± 1.9 years in PFO group &
associated with atrial septal 5.2 ± 2.1 year in antiplatelet group.
aneurysm or large (>30 No patients in the PFO closure group
microbubbles) interatrial shunt had recurrent stroke vs. 6.3% in the
w/in 6 months of randomization. antiplatelet group. Kaplan-Meier
TTE or TEE was used to identify analysis put the probability of 5-year
shunt stroke at 4.9% in the antiplatelet alone
group and 1.5% in the
Patients randomized 1:1:1 to
anticoagulation group. 5.9% of
PFO closure + antiplatelet
closures were associated with Afib
therapy vs. antiplatelet therapy
alone vs. oral anticoagulation

114
RESPECT 980 patients, ≤60 years old w/ The PFO closure group was
(NEJM 2017) [26] cryptogenic stroke within 270 associated with 0.58 ischemic events
days prior to randomization and per 100 patient-years vs. 1.07 per
PFO confirmed by TTE. Patients 100 patient- years in the medical
randomized 1:1 PFO + management group. (P = 0.046).
antiplatelet vs. medical Estimated NNT of 42 to prevent 1
management (ASA, warfarin, stroke within 5 years
clopidogrel, ASA+dipyridamole)
A meta-analysis of randomized controlled trials [27] comparing PFO closure with medical therapy
(anticoagulation or antiplatelet therapy) for cryptogenic stroke demonstrated superiority of PFO
closure to prevent stroke recurrence; however, the annual absolute risk reduction was low. PFO
closure was associated with an increased risk of atrial fibrillation

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mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21.
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S, DIRECT-MT Investigators, et al. Endovascular thrombectomy with or without intravenous
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treatment on functional independence in patients with acute ischemic stroke: the DEVT random-
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15. Wang Y, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl
J Med. 2013;369:11–9.
16. Johnston SC, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J
Med. 2018;379(3):215–25.
17. Johnston SC, et al. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA. N Engl
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1991;325(7):445–53.
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JAHA.117.008356.

116
VENOUS SINUS THROMBOSIS
Catherine S. W. Albin and Sahar F. Zafar

ANATOMY OF THE VENOUS SINUSES

Superior sagittal sinus

Cortical veins
Inferior sagittal

Straight Vein of galen

sinus

Transverse
sinus

Internal julgar

Fig. 19.1 Venous Sinus Anatomy

ISTORICAL POINTS AND NEUROIMAGING FINDINGS THAT RAISE

H
CONCERN FOR VST
Risk Factors

□□Female gender
□□Risk factors for hypercoagulable state [1]:
□□Personal or family history of blood clots
□□Pregnancy, post-partum, oral contraceptives (particularly high estrogen)
□□Malignancy
□□Systemic inflammatory diseases: particularly SLE, APLS, nephrotic syn-
drome, inflammatory bowel disease, and hematologic diseases (DIC, HIT,
JAK2 mutations, etc.)
□□ Dehydration
□□ Trauma to or neurosurgical manipulation near the sinuses
□□ Sinus infection (particularly if concern for a cavernous sinus thrombosis)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_19
117
Inherited Causes of Thrombophilia
–– Prothrombin G20210A mutation
–– Factor V Leiden
–– Protein C deficiency
–– Protein S deficiency
–– Anti-thrombin III deficiency
Acquired Causes of Thrombophilia (Most common, not all inclusive)
–– Malignancy
–– Antiphospholipid antibody syndrome
–– Hyperhomocysteinemia
–– Anticardiolipin antibodies
–– Anti-beta-2-glycoprotein antibodies

Note that in ISCVT, 44% of the patients had more than one cause or predisposing
factor. Genetic thrombophilias were present in 22% of patients [2].

Symptoms
□□Headache
□□Altered mental status
□□Cranial neuropathy of II, III, IV, VI (nerves that run in the cavernous sinus)
□□Seizure/post-ictal state (in a large series about 1/3 of patients had early
seizures) [3]
□□Focal neurologic symptoms if stroke, hemorrhage or edema develop
Neuroimaging Findings That Should Raise Concern for VST
Note: Non-contrast head CT may be normal in nearly half of the cases [4]
□□Cortical infarcts, particularly those with hemorrhagic transformation
□□Deep infarcts
□□Bilateral infarcts
□□Cortical SAH
□□CNS tumor near the sinuses
□□See examples on page 120

118
WORKUP AND TREATMENT
Workup [5]

□□CT Venography (less sensitive for thrombosis in smaller veins and corti-
cal veins)
□□ MRI and MR Venography (more sensitive for detecting thrombosis and impact
on the surrounding parenchyma)
□□ Workup for thrombophilia should be considered in collaboration with
hematology.1
□□ Search for underlying malignancy, infection, or inflammatory condition as
indicated by clinical circumstances

Acute Treatment
□□Anticoagulation: often IV unfractionated heparin due to the ability to titrate the
dose, target a specific level using either PTT or anti-Xa levels, and reverse if
needed. Studies suggest that acute anticoagulation does not seem to worsen
VST-related ICH [6].
□□ Frequent neuroimaging as therapeutic targets are met or for any new symptoms
□□ Management of elevated ICP (see page 187)
□□ Seizure treatment as indicated [7]
□□ Hydration
□□ Endovascular treatment for target clot lysis or extraction in very limited
circumstances.

Chronic Treatment
Duration of treatment is determined by the likelihood of re-thrombosis and underlying
risk factors. Vitamin K antagonism was the mainstay of treatment prior to direct oral
anticoagulants (DOACs). RE-SPECT CVT [8] was the first open-label randomized
trial to compare rates or bleeding and recurrent CVT and VTE in 120 VST patients
treated with warfarin versus dabigatran.
Over the 25 months of observation there was no recurrence of VTE in either group,
no worsening of CVT in either group. Bleeding was a complication in 20% of patients
in both groups. Of the patients that had baseline ICH, one new major bleed occurred
in the warfarin group and one patient in the dabigatran group had significant worsen-
ing of bleed.
This was a small trial, but it did suggest non-inferiority of a DOAC to warfarin.
Importantly, though, warfarin is still preferred for clots associated with antiphospho-
lipid antibodies.

1
Given that acute thrombosis disrupts the coagulation cascade, many tests that eval for underlying
thrombophilia are inaccurate in the acute period. Deferred testing may be recommended.
119
MRV demonstrating loss of opacification along CTV demonstrating filling defect within the
the superior sagittal sinus superior sagittal sinus

CT head demonstrating the vasogenic/cytoxic Post-gadolinium T1-weighted imaging (MP Rage)

edema (white arrow) resulting from increased demonstrating blood brain barrier breakdown
vascular pressure and resultant hemorrhage (white arrow) in the ischemic tissue resulting from
(black arrow). superior sagittal sinus thrombosis.

120
REFERENCES
1. Dentali F. Thrombophilic abnormalities, oral contraceptives, and risk of cerebral vein thrombosis:
a meta-analysis. Blood. 2006;107(7):2766–73.
2. Ferro JM, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International
Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35(3):664–70.
3. Ferro JM, et al. Seizures in cerebral vein and dural sinus thrombosis. Cerebrovasc Dis.
2003;15(1–2):78–83.
4. Kumral E, Polat F, Uzunköprü C, Çallı C, Kitiş Ö. The clinical spectrum of intracerebral hema-
toma, hemorrhagic infarct, non-hemorrhagic infarct, and non-lesional venous stroke in patients
with cerebral sinus–venous thrombosis. Eur J Neurol. 2012;19:537–43.
5. Bousser M-G. Cerebral venous thrombosis: diagnosis and management. J Neurol.
2000;247(4):252–8.
6. Saposnik G, Barinagarrementeria F, Brown RD Jr, et al. American Heart Association Stroke
Council and the Council on Epidemiology and Prevention. Diagnosis and management of
cerebral venous thrombosis: a statement for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2011;42:1158–92.
7. Ferro JM, Canhao P, Bousser MG, Stam J, Barinagarrementeria F, ISCVT Investigators. Early
seizures in cerebral vein and dural sinus thrombosis: risk factors and role of antiepileptics.
Stroke. 2008;39:1152–8.
8. Shulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute
venous thromboembolism. N Engl J Med. 2009;361:2342–52.

121
POSTERIOR REVERSIBLE VASOCONSTRICTION SYNDROME
(PRES) AND REVERSIBLE CEREBRAL VASOCONSTRICTION
SYNDROME (RCVS)
Catherine S. W. Albin and Sahar F. Zafar

While PRES and RCVS are not the same disease, there is likely some overlap in the
pathophysiology of the vasoreactivity and endothelial dysfunction that leads to blood
brain barrier breakdown in both [1]. They are also often stroke mimickers. In each,
stopping potentially offending medications and prevention of ischemic and hemor-
rhagic complications are equally important, so they are grouped here for comparison.

CORE CLINICAL FEATURES

PRES RCVS
− Encephalopathy and disorders of − Thunderclap headache, often recurrent
consciousness − Secondary symptoms may arise if ischemia or
− Headache hemorrhage develop and include disorders of
− Visual changes (cortical blindness, Balint’s consciousness and focal neurologic signs
syndrome, hemianopsias, or hallucinations)
− Seizures
− Rarely, focal neurologic deficits
ASSOCIATED CONDITIONS AND MEDICATIONS
PRES [2] RCVS [3]
− Hypertension (particularly acute changes in − Pregnancy and post-partum
blood pressure) − Intracranial procedures or pathology: including
− Renal failure neurosurgical procedures, post-carotid
− Pregnancy and pre-eclampsia endarterectomy, dissection, venous sinus
− Systemic diseases including SLE, TTP/HUS thrombosis
− Cyclosporine A − Vasoactive medications: most commonly SSRIs,
− Tacrolimus/Sirolimus SNRIs, diet pills, cough/cold suppressants,
− Bevacizumab, Subitinib, Sorafnib cocaine, amphetamines, ergots, triptans
− Cisplatin − Chemotherapeutic agents: interferon alpha,
− IVIG cyclosporine, sulprostone
− Methotrexate − Others
− Rituximab
− Others

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_20
123
IMAGING CHARACTERISTICS
PRES RCVS
Somewhat symmetric T2 hyperintensities that The hallmark is cerebral vasoconstriction seen in
tend to be predominantly within the posterior multiple vascular territories. While digital
aspect but do not respect the PCA territory. subtraction angiography is the gold standard, CT
Hyperintensities and edema may also be found angiogram and MR angiogram can also be used.
in the deep gray matter, cerebellum, and
30–70% of patients will have a normal MRI, and
anterior circulation. Contrast enhancement is
up to one-third of patients may have no evidence
seen in 20% of patients [4]. Ischemia and
of angiographic spasm in the first week following
diffusion restriction may be seen in severe cases.
initial headache [6]. Subarachnoid hemorrhage is
Angiography may demonstrate vasospasm and
usually confined to the cortical sulci (in contrast to
beading, most commonly in the posterior fossa
peri-mesencephalic/Circle of Willis distribution
[5].
seen in SAH) [7]

124
MANAGEMENT PRINCIPLES IMPORTANT IN BOTH CONDITIONS
□□Review medications and stop offending potentially offending agents; often
requires collaboration with transplant, oncology, or psychiatry team. It is unclear
if medications need to be permanently discontinued or temporarily ceased.
Generally, if there is an equivalent medication, an alternative therapy is tried.
□□ Address any underlying precipitants such as sepsis, acute kidney injury,
(pre)eclampsia
□□ Avoid hypomagnesesmia, aim for high normal range
□□ If excessive hypertension, consider secondary workup (renal artery stenosis,
pheochromocytoma, Cushing’s disease, etc.)

MANAGEMENT PRINCIPLES FOR PRES

□□Consider cEEG monitoring if altered consciousness
□□In patients with hypertension as a driving factor, consider acute reduction in
blood pressure by ~20%, evidence for the speed of correction is lacking

MANAGEMENT PRINCIPLES FOR RCVS

□□Consider chief differential diagnoses: Aneurysmal SAH (from a distal aneu-
rysm), piarmy angiitis of the CNS (PANCS), or CNS manifestations of systemic
vasculitis. LP may be warranted
□□ Consider transcranial Dopplers to monitor for worsening of vasospasm
□□ Magnesium drip or bolus IV magnesium may be helpful in reducing headache
severity [9]
□□ Calcium channel blockers such as verapamil and nimodipine have also been
utilized to reverse vasospasm, evidence from randomized controlled trials are
lacking.
□□ For cases with focal neurologic changes, consider catheter-directed intra-arte-
rial vasodilators
□□ AVOID glucocorticoids as they may contribute to worsening [10]

REFERENCES
1. Lee MJ, et al. Blood–brain barrier breakdown in reversible cerebral vasoconstriction syndrome:
implications for pathophysiology and diagnosis. Ann Neurol. 2017;81(3):454–66.
2. Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome. J Neurol.
2017;264:1608–16.
3. de Boysson H, Parienti JJ, Mawet J, Arquizan C, Boulouis G, Burcin C, et al. Primary angiitis of
the CNS and reversible cerebral vasoconstriction syndrome: a comparative study. Neurology.
2018;91:e1468–78.
4. Karia SJ, Rykken JB, McKinney ZJ, Zhang L, McKinney AM. Utility and significance of gadolinium-
based contrast enhancement in posterior reversible encephalopathy syndrome. AJNR Am J
Neuroradiol. 2016;37(3):415–22.

125
5. Bartynski WS. Posterior reversible ecenphalopathy syndrome, part 1: fundamental imaging and
clinical features. AJNR Am J Neuroradiol. 2008;29(6):1936–042.
6. Chen SP, Wang SJ. Hyperintense vessels: an early MRI marker of reversible cerebral vasocon-
triction syndrome? Cephalalgia. 2014;34:1038–9.
7. Ansari SB, Rath TJ, Gndhi D. Reversible cerebral vasoconstriction syndromes presenting with
subarachnoid hemorrhage: a case series. J Neurointerv Surg. 2011;3:272–8.
8. Singhal AB, et al. Reversible cerebral vasoconscriction syndromes: analysis of 139 cases. Arch
Neurol. 2011;68(8):1005–12.
9. Miljalski C, Dakay K, Miller-Patterson C, Saad A, Silver B, Khan M. Magnesium for treatment of
reversible cerebral vasoconstriction syndrome. Neurohospitalist. 2016;6(3):111–3.
10. Singhal AB, Topcuoqlu MA. Glucocorticoid-associated worsening in reversible cerebral vasocon-
striction syndrome. Neurology. 2017;88(3):228–36.

126
PART III

NONVASCULAR INPATIENT NEUROLOGY

ALTERED MENTAL STATUS
Priya Srikanth

Categories of AMS

Drugs/toxins/ Hospital-acquired
Metabolic/systemic medications delirium Primary neruologic

Pulmonary: Ilicit substance Associated with Vascular:

hypoxemia, intoxication or pain, constipation, intracerebral
hypercarbia withdrawal urinary retention, hemorrhage,
sleep-wake ischemic stroke,
disturbance, venous thrombosis,
unfamiliar PRES
environment,
Cardiac: limited
Carbon monoxide
hypoperfusion, CHF, communication
hypertensive (lack of access to
encephalopathy hearing aids,
glasses, etc.) Traumatic brain
Benzodiazepines, injury
opioids, muscle
relaxants
Renal: uremia,
hypo/hypernatremia, Elevated
hypercalcemia, intracranial
acidemia/alkalemia Antibiotics (esp. pressure
cephalosporins,
fluoroquinolones,
penicillins)
Seizure:
Gastrointestinal:
convulsive or
hepatic
nonconvulsive
encephalopathy,
Antihistamines, seizures, post-ictal
elevated ammonia,
anticholinergics state, non-epileptic
nutritional deficiencies
spells
(thiamine, B12)

Antiepileptics,
MAOIs, dopamine Infectious:
Infectious: agonists, lithium meningitis,
bacteremia, encephalitis, brain
pneumonia, UTI, abscess
colitis
Steroids, calcineurin
inhibitors
Autoimmune:
paraneoplastic or
Endocrinologic:
other autoimmune
hypo/ hyperglycemia,
encephalitis
hypo/
hyperthyroidism,
hypo/hyperthermia
Neoplastic:
parenchymal brain
mass, dural lesion,
Psychiatric: leptomeningeal
catatonia, carcinomatosis
pseudodementia

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_21
129
WORKUP OF AMS
Consider the Time Course

Chronic Subacute Acute Hyperacute

Neurodegenerative CNS infection Post-ictal state

CNS neoplastic, CNS autoimmune Obstructive Hydrocephalus

Delirium, drugs/toxins/medications Trauma, intracerebral

hemorrhage, ischemic
Metabolic/systemic stroke, seizure

REVIEW CHART/HISTORY ESPECIALLY

PMH: Evaluate for comorbid conditions that might contribute to AMS (COPD, ESLD,
epilepsy, malignancy, dementia, any cause of immunosuppression, substance use
disorder)
Medications: Review current medications for possible offending agents as above
Delirium risk: Evaluate for pain, constipation, urinary retention, sleep–wake cycle
disruption

HIGH YIELD EXAM

• ABCs and vital signs and fingerstick glucose
• General exam: evaluate for meningismus (defer if possible C-spine injury), evi-
dence of head trauma (ecchymoses, Battle sign, racoon eyes), asterixis/myoclo-
nus, tongue bite, stigmata of endocarditis, or IV substance use
• Mental status: Arousal, ability to follow commands, attention
• Cranial nerves, with particular attention to pupils:

° Pinpoint: consider opioids, brainstem pathology

° Fixed and midposition: consider brainstem pathology
° Fixed and dilated: consider uncal herniation, anticholinergics
• Motor: tone, spontaneous movements (and any asymmetry), response to nox-
ious stimuli (withdrawal vs. flexor/extensor posturing or reflexive movements
e.g. triple flexion)
• Sensory: response to noxious stimuli
• Reflexes: particularly Babinski, clonus

130
TESTING TO CONSIDER [1]
Labs For all patients: CBC with differential, BMP, Mg, Phos, LFTs, ABG/VBG, lactate,
troponin, ammonia, UA/UCx, serum/urine tox
To consider by patient history/risk factors: Extended toxicology, ESR, CRP,
BCx, TSH, CK, B12, B1, treponemal Ab, HIV, drug levels for possible offending
home meds, TPO Ab, thyroglobulin Ab
Imaging CTA head & neck if hyperacute-acute change in mental status, and/or focal
neurologic deficits with concern for intracranial hemorrhage or ischemic stroke
MRI brain with contrast if subacute change in mental status and/or focal neurologic
deficits with concern for structural lesion, CNS infection, or above workup without
clear cause
LP (after head Opening pressure (patient should be in lateral decubitus with legs straightened after
imaging) entry into CSF space)
Protein, glucose, cell count & differential, gram stain & culture, HSV 1/2 PCR
If concern for infectious encephalitis: see page 145
If concern for leptomeningeal disease: cytology, flow cytometry, IgH gene
rearrangement, and MYD88 mutation (for CNS lymphomas)
If concern for autoimmune encephalitis: IgG index, oligoclonal bands, autoimmune
encephalopathy panel
EEG Routine EEG if mental status improving, following commands; continuous EEG if
concern for nonconvulsive status epilepticus

MANAGEMENT
Management will primarily depend on etiology. For example, see page 145 for
management of presumed meningitis, 138 for management of seizures, 187 for
elevated ICP, etc.

For Delirium
–– The best treatment is prevention
–– Eliminate precipitating factors, provide frequent reorientation
–– Minimize restraints, lines
–– Promote daytime wakefulness and sleep overnight, minimize nighttime
interruptions

Agitation
–– A Cochrane meta-analysis [2] found that there was no evidence that antipsychot-
ics resolved delirium or altered mortality.
–– However, for severe agitation, atypical antipsychotics like quetiapine are proba-
bly best tolerated and can be considered.
–– Note that given the side effects without demonstrated efficiacy, medications
should not be used when patients can be managed with nonpharmacological
interventions.
131
REFERENCES
1. Douglas VC, Josephson A. Altered mental status. Continuum. 2011;17(5):967–83.
2. Burry L, et al. Antipsychotics for treatment of delirium in hospitalised non-ICU patients. Cochrane
Database Syst Rev. 2018;6(6):CD005594.

132
FRAMEWORK FOR WORKUP OF UNKNOWN BRAIN
“LESION”
Catherine S. W. Albin and Sahar F. Zafar

This is not meant to be an all-inclusive differential for all the pathologies that can
result in brain lesions (meaning FLAIR changes with or without associated post-
gadolinium enhancement), but as a way to take an appropriate history to target the
most likely pathology. Very often a tissue diagnosis is needed, but some lesions
preclude biopsy given location in elegant tissue.

Chart 1: Major categories of unknown lesions. Examples are not all inclusive but
highlight some more common etiologies.

Metastasis

Primary brain tumors (astrocytomas,

Neoplastic oligodendrogliomas, glioblastoma multiforme, etc)

CNS Lymphoma

Multiple Sclerosis and other demyelinating diseases (NMO,

anti MOG, ADEM, etc)

Inflammatory Sarcoidosis, vasculitis, parainfectious inflammation

Autoimmune / paraneoplastic encephalitis

Abscess (consider bacterial etiologies, tuberculosis,

toxoplasmosis, fungal causes)
Major Categories of "Lesions"

Infectious Infectious embolic disease (endocarditis)

Infectious encephalitis (see page 145)

Arterio-venous malformations, dural AV fistulas, Cavernous

malformations
Vascular /
Stroke (paritcularly subacute)
Vasculopathy
PRES

Adrenoleukodystrophy

Hereditary MELAS

Wernicke's Encephalopathy (thiamine deficiency)

Chasing the Dragon (Spongeiform leukoencephalopaty from

Heroin inhalation)
Nutritional
Deficiencies /
Hyperammonemia / Hepatic Encephalopathy
Toxins
Wilson's Disease

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_22
133
IMPORTANT FACTORS TO GAIN FROM H&P
TIMING?
Progressive or relapsing and remitting? Acute, subacute, or chronic in duration?

HOST FACTORS
Immune status HIV status? Poorly controlled diabetes? Organ transplant? Review exposure
to any immunomodulators or chemotherapeutic agents, even remote
Exposures Consider location and season. Also inquire about travel, pet/insect/rodent
exposure
Comorbidities Specifically clarify autoimmune history, cancer history, diabetes
Age/sex For example, new onset MS is much more likely in a 30-year-old woman
than a 70-year-old man
Medications/drugs Particularly immunosuppressants and drugs that may result in PRES, PML,
IRIS as well as illicit substances which may put the patient at risk for
endocarditis, vasculopathy, or direct neurologic inflammation
Family history Can provide clues for diseases like leukodystrophies, MELAS, CADASIL

ASSOCIATED SYMPTOMS
Fever Highly concerning for infectious encephalitis or abscesses, but can also be
seen in ADEM, select autoimmune encephalitis cases (NMDA, CASPR2),
and with systemic malignancies
Rashes (or history Rocky Mountain spotted fever, meningococcal meningitis, intravascular
of rash) lymphoma, Bechet’s (oral and genital lesions)
Cough or Sarcoidosis, lung cancer, tuberculosis, aspergillosis, and other fungal
respiratory infections
symptoms
Vision changes Consider demyelinating diseases linked with optic neuritis – NMO, anti-
MOG, MS (see page 175)

All testing should be based on the history and physical. Unless there is a strong
contraindication, all patients should undergo MRI brain with gadolinium
contrast.

ADVANCED NEUROIMAGING TECHNIQUES

Lesions of unclear etiology can be understood better by leveraging advanced
imaging techniques. These include MR perfusion, MR spectroscopy, and vessel
wall imaging. 18FDG-PET brain can also be helpful in understanding the metabolic
pattern of the lesion, especially in cases where there is an epileptogenic focus.
Special sequences such as Constructive Inference in Steady State (CISS) and
Fast Imaging Employing Steady-state Acquisition (FIESTA) can also be utilized
for high resolution cuts through the brainstem. Digital subtraction angiography
(DSA) can be high yield in defining vessel characteristics when AVM, dural A-V
fistula, or other vascular malformations are suspected.
134
FURTHER TESTING TO CONSIDER
INFLAMMATORY/
AUTOIMMUNE MALIGNANCY INFECTION VASCULAR
CSF studies See page 163 for See page 151 for See page 145 for full Consider digital
in addition more details on more details workup of suspected subtraction
to routine autoimmune Cytology and encephalitis/meningitis angiography
studies (cell encephalitis flow cytometry for higher yield
For mass lesions
count, TP, IgH gene
IgG index consider evaluation for Can also
glucose, rearrangement
Oligoclonal bands toxoplasmosis, taenia consider vessel
culture) Paraneoplastic
solium, tuberculosis, wall imaging.
panel
norcardia, aspergillus, For an extended
Serum Anti-aquaporin 4 LDH
cryptococcus, workup of
studies antibody (NMO) ESR
histoplasmosis, inflammatory
Anti-MOG CEA, CA 125-5,
coccidiodes, HIV status, stroke
ESR CA 19-9, AFP
syphilis. etiologies, see
CRP Paraneoplastic
page 84
ANCA panel
C3/C4
Radiology CT chest if Contrasted CT Trans-thoracic echo
respiratory symptoms chest, abdomen, CT chest/sinuses
pelvis
Mammogram
Pelvic u/s
Scrotal u/s
PET-CT vertex to
mid-thigh if high
suspicion for
lymphoma

Other: Dilated
ophthalmologic
exam (CNS
lymphoma)

135
APPROACH TO FIRST-TIME SEIZURE
Catherine S. W. Albin and Sahar F. Zafar

Remember that not all that shakes or causes a transient spell is a seizure! When
called to evaluate a patient after a first ever “seizure,” remember to keep an open mind
and consider these alternative diagnoses:
□□Transient ischemic attack (particularly limb-shaking TIAs or basilar occlusions
that can result in loss of consciousness)
□□Convulsive syncope (Arrhythmia? PE? Outflow tract obstruction?)
□□Migraine aura or acephalgic migraine
□□Narcolepsy
□□Cerebral Amyloid Angiopathy spells (Transient Focal Neurologic
Episodes (TFNE))
□□Transient global amnesia
□□Psychogenic nonepileptic seizures
□□Panic attack
□□Tremors, rigors, dystonia
□□Fasciculations (particularly with neuromuscular blockers like succinylcholine)
□□Intoxications/withdrawal
CATEGORIES OF FIRST-TIME SEIZURES [1]
REMOTE UNPROVOKED/
ACUTE SYMPTOMATIC SYMPTOMATIC NO CLEAR
PROVOKED SEIZURE SEIZURE SEIZURE ETIOLOGY
Triggered by drugs of Triggered by acute Related to an existing No structural
abuse, toxins, medication- neurologic illnesses such brain lesion – prior lesion, may be
related, acute metabolic as meningitis, traumatic stroke, tumor, remote first presentation
factors (i.e. hyponatremia), brain injury (TBI), or traumatic brain injury of an epilepsy
severe sleep deprivation stroke syndrome

WORKUP
□□History to determine if there have been prior, unrecognized seizures (nocturnal
events? Focal events? Auras?)
□□Review patient’s history about history of meningitis/encephalitis, TBI, strokes,
and prior CNS surgeries
□□Screen patient’s medication lists (clozapine, cephalosporins, fluoroquinolones,
bupropion, tramadol)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_23
137
□□BMP, CBC, LFTs, urine and serum tox screens
□□UA
□□Neuroimaging:
–– Emergency imaging (often CT) is needed when structural brain lesion is sus-
pected or if there are persistent neurological defects, ongoing altered mental
status, trauma, or prolonged headache [2]
–– If available, MRI with and without gadolinium with coronal FLAIR “thin cut”
through the medial temporal lobe (often called an “Epilepsy Protocol” scan) is
the most sensitive for the detection of epileptic inducing brain lesions [3].
□□ EEG monitoring [4]:
–– Emergency EEG monitoring is needed when the patient does not return to
baseline within 30–60 min or has a persistent new neurologic deficit [5].
–– Standard routine 30 min monitoring can be helpful in defining seizure type
and determining the risk of recurrence.
–– Within 24–48 h does have a slightly higher yield than further out.
□□ Although not routinely done, consider the need for lumbar puncture for enceph-
alitis/meningitis evaluation, especially needed if the patient is febrile.

WHO NEEDS AN ANTI-EPILEPTIC DRUG?

Based on AAN Practice Guidelines [6]

Generally accepted that after two unprovoked seizures (spaced apart by >24 h)
AEDs should be initiated as the risk for additional seizures is high (57% at 1 year,
73% by 4 years). However, for a patient with an isolated first seizure, the risk of
future epilepsy needs to be balanced against the risk of AED therapy. Generally, if
just one unprovoked seizure, therapy is only started if there is a high (>60%) likeli-
hood of recurrence.
Factors that raise the risk for future seizures:
–– Prior brain insult or lesions (level A)
–– An EEG with epileptiform abnormalities (level A)
–– Significant neuroimaging abnormality (level B)
–– Nocturnal seizures (level B)
Counseling:
–– Approximately 8–10% of the population experiences 1 seizure; 2–3% go on to
develop epilepsy
–– The risk of recurrence is highest within the first 2 years
–– AEDs each have side effects and risks, most of which are mild and reversible
–– Immediate treatment does not affect the long-term prognosis for epilepsy
** IMPORTANTLY, REMEMBER: Seizures often legally affect patients’ driving
privileges. The duration and extent are state dependent, but patients should be
made aware of these restrictions if they are impacted!**

138
REFERENCES
1. Bergey GK. Management of a first seizure. Continuum (Minneap Minn). 2016;22(1):38–50.
2. Quality Standards Subcommittee of the American Academy of Neurology in cooperation with
American College of Emergency Physicians, American Association of Neurological Surgeons,
and American Society of Neuroradiology. Practice parameter: neuroimaging in the emergency
patient presenting with seizure—summary statement. Neurology. 1996;47(1):288–91.
3. Wellmer J, Quesada CM, Rothe L, et al. Proposal for a magnetic resonance imaging protocol for
the detection of epileptogenic lesions at early outpatient stages. Epilepsia. 2013;54(11):1977–87.
4. Schreiner A, Pohlmann-Eden B. Value of the early electroencephalogram after a first unprovoked
seizure. Clin Electroencephalogr. 2003;34(3):140–4.
5. Gavvala JR, Schuele SU. New-onset seizure in adults and adolescents: a review.
JAMA. 2016;316(24):2657–68.
6. Krumholz A, et al. Evidence-based guideline: management of an unprovoked first seizure
in adults: report of the Guideline Development Subcommittee of the American Academy of
Neurology and the American Epilepsy Society: evidence-based guideline. Epilepsy Curr.
2015;15(3):144–52.

139
PHARMACOLOGY TIPS FOR COMMONLY USED AEDS
Megan E. Barra

SEE PAGE 327 FOR COMPLETE ANTI-EPILEPTIC DRUG CHART WITH

FURTHER INFORMATION.

FOR STATUS EPILEPTICUS LOADING DOSES AND GUIDANCE, SEE PAGE 259

LEVETIRACETAM

DRUG DOSING PK/PD MONITORING CONSIDERATIONS

Levetiracetam IV loading dose: T1/2: ~6 to 8 h BMP/CBC w/ diff Relatively low drug
(LEV) 60 mg/kg (max Metabolism: interactions/
Agitation/
4500 mg). Enzymatic contraindications
irritability,
hydrolysis
Maintenance somnolence, Up to 50%
(non-CYP) to
dosing: fatigue, asthenia, removed during
inactive metabolite
dizziness, dialysis session.
Unimpaired Elimination: 66%
infection, Supplemental dose
renal function: renally eliminated
depression, 250–500 mg after
PO: 500–2000 mg unchanged
psychotic HD recommended
twice daily Protein binding:
symptoms, ataxia,
<10%
Renal anemia,
Bioavailability:
impairment: leukopenia,
100%
CrCl < 15 mL/min: thrombocytopenia
Volume of
PO: 500 mg once
distribution:
daily or 250 mg
0.5–0.7 L/kg
twice daily
IV:PO conversion:
1:1

Addressing Levetiracetam-Associated Behavioral Changes:

DRUG DOSING NOTES

Pyridoxine Optimal dosing Small case series/case-control trials in pediatric patients
(B6) unknown in adults. Can demonstrated moderate reduction in behavioral symptoms
trial 100 mg TID. within 1–2 weeks [3, 4]. Benefit in adult patients is
unknown; however, B6 is readily available, inexpensive,
Largest case series used
and has a low risk profile.
6–7 mg/kg/day and
were conducted in
children [1, 2].

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141
VALPROATE
DRUG DOSING PK/PD MONITORING CONSIDERATIONS
Valproate IV loading dose: T1/2: 9–19 h LFTs, CBC w/ diff, ~35% of patients on
(VPA) 20–40 mg/kg Metabolism: Hepatic albumin VPA therapy have
(rec max Elimination: <3% hyperammonemia,
Goal level:
3000 mg) renally eliminated as many of which are
50–125 mcg/mL
unchanged drug asymptomatic. See
Maintenance (toxicity may
Protein binding: 95% below for treatment
dosing: 15 occur if >100)
Bioavailability: of encephalopathy.
mg/kg/day CAUTION IN LIVER
90–100%
ER PO QD; other DISEASE. Consider free
Volume of distribution:
PO formulations Hyperammonemia, valproate level in
0.1–0.4 L/kg
dosed BID- hair loss, n/v, patients with
IV: PO conversion: 1:1
QID. Increase weight gain, hypoalbuminemia,
weekly by thrombocytopenia, concurrent phenytoin
Through unclear
5–10 mg/kg/day hypothyroidism, therapy, or s/sx of
mechanisms,
up to PCO, pancreatitis, VPA toxicity
increased VPA serum
60 mg/kg/day parkinsonism.
concentrations
decrease carnitine
IR to ER
serum concentration,
conversion
correlating with
requires a dose
increased ammonia.
increase by
8–20%

Addressing Hyperammonemia:

DRUG DOSING NOTES

Levocarnitine Hyperammonemic L-Levocarnitine, a water-soluble amino acid, may
encephalopathy: be helpful in the management of valproic acid-
IV levocarnitine: 100 mg/kg induced hyperammonemia and hepatic toxicity
IV bolus f/b 15 mg/kg q6h with or without symptoms. Mostly case reports and
until clinical improvement retrospective studies showing clinical improvement
and/or decreased plasma ammonia
Asymptomatic valproic
concentrations with therapy [5, 6]. May cause
acid-induced
nausea and vomiting.
hyperammonemia (e.g.
ammonia >80 μmol/L):
PO levocarnitine: 1000
mg/day divided q6–8h, can
titrate up to 3000 mg/day

142
LACOSAMIDE
DRUG DOSING PK/PD MONITORING CONSIDERATIONS
Lacosamide IV loading T1/2: 13 h EKG, BMP Few drug–drug
(LAC) dose: Metabolism: hepatic interactions. May
Baseline EKG
200–400 mg Elimination: renal require insurance
before initiating
(40% as unchanged prior-authorization.
therapy, watch
Maintenance drug, dose adjust)
for PR interval If CrCl < 30 mL/
dosing: 100 mg Protein binding:
prolongation. Do min: ↓ dose by 75%.
BID PO, may <15%
not use of second HD: ~50% removed.
increase to Bioavailability: 100%
or third degree Add’l dose after HD
200 mg BID Volume of distribution:
AV block or sick session
PO. 0.6 L/kg
sinus syndrome recommended.
IV: PO conversion: 1:1

PHENYTOIN
DRUG DOSING PK/PD MONITORING CONSIDERATIONS
Phenytoin IV loading dose: Michaelis-Menten BMP, CBC w/ diff, Highly protein
(PHT) Use fosphenytoin first-order kinetics at LFTs, albumin, vital bound: low
whenever possible low concentrations, but signs albumin, critical
to load and when zero-order kinetics at illness, uremia, and
Target total level:
phenytoin is being therapeutic drug–drug
10–20 mcg/mL
given IV. concentrations (thus interactions all may
Target free level:
Fosphenytoin at therapeutic affect the
1–2 mcg/mL
results in lower window, slight concentration of
rates of dose changes can active drug.
When loading with
hypotension and cause a dramatic
IV, EKG and BP Calcium and
bradycardia: changes in
monitoring should vitamin D should be
20mg/kg (rec concentration).
be used given risk used in patients on
max 1500mg)
T1/2: 7–42 h of hypotension and chronic therapy.
Correct level for Metabolism: Hepatic bradycardia.
albumin (see Elimination: Nonlinear
Level must be
below). Re-dose hepatic elimination
corrected for low
as needed to (Michaelis-Menten)
albumin.
reach targeted Protein binding: >90%
level (see below). Bioavailability: Variable Long-term usage
(monitor levels when can cause gingival
Daily maintenance
converting from IV to hypertrophy, hair
is ~4–6 mg/kg.
PO) increase, folic acid
100 mg Q8H PO
Volume of distribution: depletion, and
is a reasonable
0.7 L/kg decrease bone
starting dose for
IV: PO conversion: 1:1 density. See AED
most patients.
chart for full side
effect profile
143
Notes on the Dosing of Phenytoin
Correcting for albumin Correct PHT = (Total PHT)/((0.2 × albumin level) + 0.1)
level NOTE: found to be imprecise in critically ill patients
(Winter-Tozer Equation)
Estimating free PHT in Free PHT = 1.69 + 0.139 × (total PHT) − 0.008 (age) − 0.424 (albumin)
critically ill patients + 0.01 (BUN) + 0.288 (critically ill:[yes = 1, no = 0]) [7]
May be more precise in critically ill patients
These equations are NOT valid if the patient is on valproate. Check free levels!

More Tips for PHT:

–– Send a free level when possible, but know it may take longer than a total to
result (lab dependent).
–– If a patient is on tube feeds (TF), the TFs must be held for an hour before and
after dosing for oral phenytoin.

When bolusing to Partial loading dose = weight (kg) × 0.7 × ([target PHT level] − [current
achieve a higher level corrected PHT level])

REFERENCES
1. Marion S, et al. Pyridoxine add-on treatment for the control of behavioral adverse effects
induced by levetiracetam in children: a case-control prospective study. Ann Pharmacother.
2018;52(7):645–9.
2. Major P, et al. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior
side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557–9.
3. Mahmoud A, Tabassum S, Al Enazi S, Lubbad N, Al Wadei A, Al Otaibi A, Jad L, Benini
R. Amelioration of Levetiracetam-Induced Behavioral Side Effects by Pyridoxine. A Randomized
Double Blind Controlled Study. Pediatr Neurol. 2021;119:15–21. PMID: 33823377.
4. Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of
levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav.
2008;13(3):557–9. PMID: 18647662.
5. Mock CM, Schwetschenau KH. Levocarnitine for valproic-acid-induced hyperammonemic
encephalopathy. Am J Health Syst Pharm. 2012;69(1):35–9. PMID: 22180549.
6. Glatstein M, Bonifacio Rino P, de Pinho S, Scolnik D, Pivko-Levi D, Hoyte C. Levocarnitine for
the Treatment of Valproic Acid-Induced Hyperammonemic Encephalopathy in Children: The
Experience of a Large, Tertiary Care Pediatric Hospital and a Poison Center. PMID: 29232283.
7. Barra ME, Phillips KM, Chung DY, et al. A novel correction equation avoids high-magnitude
errors in interpreting therapeutic drug monitoring of phenytoin among critically ill patients. Ther
Drug Monit 2020;42(4):617–25.

144
APPROACH TO INFECTIOUS ENCEPHALITIS AND MENINGITIS
Catherine S. W. Albin and Megan E. Barra

Encephalitis and meningitis should be considered in any patient with altered mental
status and fever; however, note that septic encephalopathy from a non-CNS source
of an infection is more common than encephalitis.
Encephalitis and meningitis are diagnosed when there is evidence of inflammation in
the brain parenchyma or meninges, respectively. This requires evidence of inflamma-
≥
tion in the CSF (pleocytosis 5 cells/mm3) and/or an abnormality on neuroimaging
(as some immunocompromised hosts or certain infections may not result in signifi-
cant pleocytosis).

EXTRINSIC FACTORS
SIGNS THAT INCREASE CONCERN HOST FACTORS THAT THAT MAY INCREASE
FOR MENINGITIS/ENCEPHALITIS INCREASE RISK FOR CNS RISK FOR CNS
INCLUDE: INFECTION: INFECTION
• Fever • Older age (>65 years old) • S eason (increased
• Headache • T ransplant recipient or on risk for mosquito or
• Nuchal rigidity immunosuppression for tick associated illness
• Altered mental status autoimmune condition in summer)
• Photophobia • A
ctive malignancy and/or • Travel
Patients may also present with: cancer treatment • Geographic origin
• Hydrocephalus • H
IV+, or other acquired/
• Seizures inherited immunodeficiency
• Coma • P rior CNS surgical procedure
• Photophobia • CSF leak
• Nausea/vomiting • R ecent traumatic brain injury
Note that elderly and • External ventricular drain
immunosuppressed patients may have
atypical presentations and no fever or
neck rigidity

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145
WORKUP [1]
□□CBC and PT/INR/PTT, anticoagulant-specific anti-Xa, and INR may be particu-
larly useful if patient on baseline anticoagulation to ensure adequate clearance
prior to high-bleed risk procedures such as lumbar punctures
□□ Blood cultures STAT
□□ CT scan should strongly be considered before LP; mandatory for patients who
are immunocompromised, >60 years old, have known CNS lesions, seizure on
presentation or recently, abnormal level of consciousness, focal neurologic
findings, and papilledema.
□□ LP. Test ordering guidance, see page 159. Consider in all patients:
• Cell count, Tube 1 and Tube 4
• Tube 2: Total protein, glucose
• Tube 3: CSF gram stain and culture
• Empiric HSV PCR testing should be considered in all patients as it is common
and treatable
• Biofire® ME Panel can be considered; hospital policies differ on who qualifies
for this test. Shown in a multicenter prospective study to have 84.4% positive
and >99.9% negative agreement between conventional methods [2]. However,
note that cryptococcal antigen is much more sensitive than the Biofire test for
cryptococcus. (See next page for a list of what is included)
• Other studies should be guided by patient’s risk factors, clinical/radiographic
syndrome, and exposures. See page 180.
□□ MRI with and without gadolinium should be obtained urgently, but not before
the patient has been resuscitated and started on broad spectrum
antimicrobials.
• MRI can be used to evaluate for meningeal and brain parenchymal enhance-
ment, indicate patterns of edema (e.g. limbic encephalitis vs. rhombencephali-
tis), or demonstrate other anatomic findings suggestive of a specific disease
pathology (e.g. dilated Virchow-Robin spaces in cryptococcal meningitis see
Fig. 25.1) [3].
□□ Consider continuous EEG monitoring in patients with fluctuating or depressed
consciousness

Although risk of herniation is not precisely known, LP should be deferred in cases

with clinical or radiographic evidence of herniation, shift or compression of
fourth ventricle, midline shift, cerebellar mass, and obstructive hydrocephalus

146
CNS Biofire FilmArray
Bacterial Pathogens
• Escherichia coli K1,
• Haemophilus influenzae
• Listeria monocytogenes
• Neisseria meningitidis
• Streptococcus agalactiae
• Streptococcus pneumoniae

Viral Pathogens
• Cytomegalovirus (CMV),
• Enterovirus (EV),
• Herpes simplex virus 1 (HSV-1),
• HSV-2,
• Human herpesvirus 6 (HHV-6),
• Human parechovirus (HPeV),
• Varicella-zoster virus (VZV).
Yeast
• Cryptococcus neoformans/Cryptococcus gattii.

Fig. 25.1 MRI T2-weighted image demonstrating dilated Virchow-Robins spaces throughout the
basal ganglia and thalamus in a patient with cryptococcal meningitis. Note that traditioanl antigen
detection is more sensitive than the BioFire Assay for this pathogen
147
TYPICAL CSF FINDINGS IN INFECTIOUS MENINGITIS
TOTAL NUCLEATED CELL COUNT PROTEIN GLUCOSE
Bacterial meningitis 1000–3000, neutrophilic Very Very low. Less than
predominance elevated 2/3 serum glucose.
Often <25 mg/dL
Viral meningitis 200 to >1000, lymphocytic Mildly Normal, although
*HSV encephalitis may have although may be neutrophilic early elevated may be low in
increased red blood cells in in disease some cases
CSF
Fungal meningitis 100–500 Very Low
elevated

TREATMENT
Do not delay starting treatment to get neuroimaging/LP. Draw blood cultures and
then start treatment while arranging for imaging and LP. Most antibiotics result in
CSF sterilization within 4 h; however, Neisseria Meningitidis may be sterilized in
30 min after effective antibiotics.

EMPIRIC TREATMENT FOR COMMUNITY-ACQUIRED MENINGITIS/ENCEPHALITIS

NOTE: dose adjustment may be required in patients with renal dysfunction.

• Vancomycin (dosed by weight and renal function)

• Ceftriaxone 2 g IV Q12H (May consider alternative third/fourth-generation
cephalosporin)
• Acyclovir 10 mg/kg IV Q8H
• If patient > 50 yo or immunocompromised, add Ampicillin 2 g IV Q4H for
Listeria monocytogenes
• If high concern for bacterial (particularly Streptococcal pneumoniae meningi-
tis), give Dexamethasone 10 mg IV about 10 min prior to first dose of antibiot-
ics. And continue 48–96 h if proven S. pneumoniae infection

HSV PCR and Treatment:

If moderate suspicion for HSV encephalitis and PCR negative, do not stop
treatment. Per IDSA guidelines, continue treatment, resend CSF HSV PCR in
3–7 days.

148
IF CONCERN ATYPICAL
IF HEALTHCARE-ASSOCIATED INFECTIONS (BRUCELLA,
VENTRICULITIS/MENINGITIS (CNS MYCOPLASMA,
DRAINS, NEUROSURGERY, HEAD RICETTSIOSIS, PATIENTS WITH PENICILLIN
TRAUMA) [4]: EHRLICHIOSIS): ALLERGIES:
Use vancomycin + a pseudomonal- Doxycycline 100 mg PO Vancomycin PLUS
active third or fourth-generation or IV Q12H
IgE-mediated reaction (e.g.
cephalosporin (ceftazidime vs.
anaphylaxis, angioedema, hives/
cefepime) or meropenem; remember
urticara):
that these patients are at higher risk
Aztreonam (+TMP/SMX if listeria
for fungal meningitis and infectious
coverage required)
disease guidance is helpful in
Meropenem (has listeria
determining treatment and explant of
coverage)
potentially infected hardware, as
applicable. Severe penicillin allergy (e.g. SJS/
TENs, DRESS, hemolytic anemia):
Fluroquinolone +
TMP/SMX (if indicated for listeria
coverage)

CNS PENETRATION OF COMMONLY USED ANTIBIOTICS

EMPIRIC DOSING IF CRCL > 50 ML/MIN
CNS % DOSE ADJ MAY BE REQUIRED IF POOR
DRUG PENETRATION RENAL FXN
Penicillin G Moderate 4 million units IV q4h
Ampicillin Moderate 2 g IV q4h
Nafcillin Moderate 2 g IV q6h
Piperacillin/tazobactam Poor Do not use for CNS infections
Cefazolin Low Do not use for CNS infections
Ceftriaxone Moderate 2 g IV q12h
Ceftazidime Moderate 2 g IV q8h
Cefepime Moderate 2 g IV q8h
Meropenem Good 2 g IV q8h
Ciprofloxacin Excellent 400 IV q8h
Levofloxacin Excellent 750 IV 24 h
Doxycycline Moderate Atypical meningitis only
Vancomycin Poor to moderate See vancomycin dosing, below
Linezolid Excellent 600 IV q12h
TMP/SMX Moderate-good 15–20 mg/kg/day divided q6–8h
Metronidazole Good 500 IV q6–8h
Acyclovir Good 10 mg/kg IV q8h

149
Sample Vancomycin Dosing Guidance
CRCL CRCL CRCL <20 ML/
LOADING >80 ML/ 40–80 ML/ CRCL CRCL MIN, AKI, OR
DOSE (ALL MIN AND MIN OR 39–39 20–29 LABILE RENAL
PATIENTS) AGE < 65 AGE > 65 ML/MIN ML/MIN FXN CRRT OR IHD
20–25 15 mg/kg 15 mg/kg 15 mg/kg 15 mg/kg Discuss with Discuss with
mg/kg q8h q12h q24h q24–q48h pharmacy, dose pharmacy, dose
by level by level

Subtherapeutic vancomycin trough before the 4th of 5th dose in patients with stable renal function
First level within 10% of goal Continue same dose with expected accumulation
Level < 5 mcg/mL from goal Increase each dose by 250 mg
Level > 5 mcg/mL lower than Modify dosing interval to next shorter interval (e.g. q12h to q8h)
goal
Supratherapeutic vancomycin trough before the 4th of 5th dose in patients with stable renal function
21–25 mcg/mL Hold next dose until level is expected to be within target then
decrease dose by 250 mg/dose or 500 mg/day
26–30 mcg/mL Hold dose, repeat an interval vancomycin level to inform dosing
>30 mcg/mL Hold dose, re-initiate when an interval level within target range.
Consult Rx for dose recommendations

REFERENCES
1. Venkatesan A, et al. Case definitions, diagnostic algorithms, and priorities in encepha-
litis: consensus statement of the international encephalitis consortium. Clin Infect Dis.
2013;57(8):1114–28.
2. Leber AL, et al. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for
detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol.
2016;54(9):2251–61.
3. Berkefeld J, Enzensberger W, Lanfermann H. Cryptococcus meningoencephalitis in AIDS:
parenchymal and meningeal forms. Neuroradiology. 1999;41(2):129–33.
4. Tunkel AR, et al. 2017 Infectious Diseases Society of America’s clinical practice guidelines for
healthcare-associated ventriculitis and meningitis. Clin Infect Dis. 2017;64(6):e34–65.

150
NON-INFECTIOUS MENINGITIS
Catherine S. W. Albin and Sahar F. Zafar

Below is a framework and suggested workup for patients with symptoms and signs of
meningitis for whom the entire infectious workup is unrevealing. This is conception-
ally different from “aseptic meningitis” – which is a term that is broadly applied to
meningeal irritation when routine bacterial cultures do not grow. Thus, the term
“aseptic meningitis” includes viral, fungal, spirochete and mycobacterial etiologies
(which do not readily grow in culture); this workup is covered in the previous chapter.

CSF Studies Helpful in Non-infectious Meningitis Workup:

□□10 cc of CSF for cytology/flow cytometry evaluation, ×3.
□□Soluble Interleukin-2
□□IgH gene rearrangement (CSF lymphoma)
□□Beta-2-microglobulin (lymphoproliferative disorders)
□□Oligoclonal bands
□□IgG index

For patients in whom the infectious workup is negative or a non-infectious source is

presumed, consider, as indicated by clinical suspicion [1]:
□□ CXR
□□ CT chest, CT abdomen w/ and w/o IV contrast
□□ UA for proteinuria
□□ ANA, anti-SSA/B, ANCA
□□ Dilated slit lamp exam, fundoscopy, Schirmer test
□□ Whole body positron emission tomography-CT (PET/CT), as needed

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151
Systemic Sarcoidosis F > M; young adults. Most commonly affects suprasellar and frontal
diseases basal meninges, as well as cranial nerve palsy(ies). Lymphocytic
predominance of the CSF; high pleocytosis, may cause
hypoglycorrhachia. May cause encephalomyelitis.

Biopsy may be needed for diagnosis (may be of non-CNS site of

inflammation – i.e. lungs, skin).
Systemic lupus F > M. Lymphocytic predominance. Meningitis is relatively
erythematosus uncommon even in patients with neuro-lupus [2].

Diagnosis based on criteria; dsDNA, ANA

Behçets M > F. More prevalence in patients of Mediterranean, Middle
Eastern, or Japanese origin. Rhombencephalitis. Genital and oral
ulcers, skin lesions. Neutrophilic meningitis with high pleocytosis.
May also result in vascular CNS complications.

HLA-B51. Biopsy needed.

Sjögrens F > M. May cause polyneuropathy and cranial nerve palsies and
encephalomyelitis.

Anti-SSA (Ro), anti-SSB (La), salivary gland biopsy

IgG4 Disease IgG4-related disease is a polyclonal lymphoproliferative disorder
and a rare cause of pachymeningitis and hypophysitis. Confirmation
usually involves biopsy which demonstrates marked lymphocyte and
plasmocyte infiltration and IgG-positive plasma cell infiltration [3].
Neoplastic Leptomeningeal Most commonly seen with breast cancer, lung cancer, melanoma,
carcinomatosis and lymphoma. May cause hypoglycorrhachia.

Biopsy often needed (may be of extra-CNS tissue). CSF IgH gene

rearrangement.
Treatment- Reported with immune checkpoint inhibitors, monoclonal antibodies
associated
meningitis
Iatrogenic Associated most commonly with nonsteroidal anti-inflammatory drugs (NSAIDs),
penicillins, sulfamides, intravenous immunoglobulin (IVIG)

CSF may have a neutrophilic predominance with normal cell glucose. Brain imaging
usually normal.

152
Fig. 26.1 Leptomeningeal Fig. 26.2 Leptomeningeal enhancement
carcinomatosis: T cell lymphoma caking on T1 MR post-contrast in a patient with
the thoracic meninges (arrow) in a neurosarcoidosis who presented
post-gadolinium MRI with rhomboencephalitis

REFERENCES
1. Tattevin P, et al. Aseptic meningitis. Rev Neurol. 2019;175(7–8):475–80.
2. Ungprasert P, Crowson CS, Matteson EL. Characteristics and long-term outcome of neurosar-
coidosis: a population-based study from 1976-2013. Neuroepidemiology. 2017;48(3–4):87–94.
3. Michaël L, Mikaël C, Saskia B, CarolineGiordana, Fanny Burel-Vandenbos, Lydiane M,
JacquesSedat, Denys F, Véronique B, Nihal M, ChristineLebrun-Frenay, Immunoglobulin
G4-related hypertrophic pachymeningitis: A case-oriented review. Neurol Neuroimmunol
Neuroinflamm 2019;6(4):e568.

153
INFLAMMATORY AND AUTOIMMUNE ENCEPHALITIS
Catherine S. W. Albin and Sahar F. Zafar

Establish a Syndrome if Possible

–– Acute encephalitis may be accompanied by myelitis and should be thought of as
encephalomyelitis, which may be a finding in multiple sclerosis or an acute
monophasic illness like acute disseminated encephalomyelitis (ADEM).
–– Optic neuritis is also present in particular forms of encephalitis such as the neu-
romyelitis optica (NMO) spectrum disorders, and the presence of this finding
may help narrow the differential diagnosis
–– Acute necrotizing encephalopathy is a rare encephalopathy thought to be para-
infectious with hallmark finding of high-intensity signal symmetrically affecting
the periventricular white matter and deep gray structures (thalamus and brain-
stem) with a fast progression to coma.

MAJOR CATEGORIES OF INFLAMMATORY/AUTOIMMUNE ENCEPHALITIS

Note that these categories overlap and that a clinical syndrome may be caused by
more than one category. For example, ani-NMDA-R encephalitis may be post-
infectious, purely antibody mediated (associated with no cancer), or paraneoplastic
(often associated with an ovarian teratoma).

TYPE EXAMPLE(S)
CNS manifestation Sarcoid, systemic lupus erythematosus
of a systemic disease
Primary autoimmune Steroid responsive encephalitis associated with autoimmune thyroiditis
(STREAT/Hashimoto’s), Miller-Fisher Syndromea, Bickerstaff encephalitis,
Neuromyelitis Optica Spectrum disordersb, multiple sclerosisb, anti-myelin
oligodendrocyte glycoproteinb, Susac’s syndrome
Parainfectious Post-viral cerebellitis, acute demyelinating encephalomyelitis (ADEM)b
Antibody Mediated / See table, page 163
Paraneoplastic
Drug induced Encephalitis associated with interferon-alpha, tumor necrosis factor-alpha,
checkpoint inhibitors and CAR T cells
a
Debated if truly causes encephalitis
b
Primarily demyelinating diseases, covered on 175

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155
WORKUP [1, 3]
1. Establish there is inflammation in the CNS (CSF pleocytosis, elevated protein,
and/or oligoclonal bands; however, note that some syndromes may not have signifi-
cant CSF abnormalities, advanced neurodiagnostic needed)
(a) CT scan may be needed to establish safety of lumbar puncture
(b) SAVE ADDITIONAL CSF
(c) Evaluate for and treat potential infectious etiologies, as indicated, see page 145
(d) Remember that toxic-metabolic and neoplastic causes can result in profound
encephalopathy and abnormal neuroimaging without inflammation. Consider
primary CNS tumors, PRES, hyperammonemia, Wernicke’s encephalopathy,
osmotic demyelination, heroin inhalation, etc., as alternative diagnoses
2. Neuroimaging: MRI Brain w/ and w/o gadolinium. MRI C/T spine should be consid-
ered based on physical exam.
3.
Search for cause of
inflammation

Systemic disease Primary autoimmune Parainfectious Paraneoplastic

ESR/CRP, ANA, Consider patient's

ANCA, cryoglobulin, Autoimmune Autoimmune
encephalopathy exposures! encephalopathy
complement Established
levels, anti-SSA/SSB panel (see page 163) panel (see page 163)
parainfectious
syndromes to Consider CT
Anti-TPO antibodies COVID-19, Chest/Ab/Pelvis,
Consider CT chest (STREAT), anti-MOG mycoplasma, varicella, eye exam, testicular or
(sarcoid), anitbodies, anti-AQP4 influenza, enterovirus, ovarian ultrasound,
comprehensive eye antibodies (NMOSD), EBV,HIV, Zika, others. skin exam, whole body
exam, skin exam anti- GQ1 antibodies IgG/IgM testing. PET/CT
(MIller-
Fisher/BIckerstaff)

4. As mentioned in the chart above, most patients with evidence of inflammation and
a negative infectious workup should be screened with the Autoimmune
Encephalopathy Panel (ARUP/Mayo)
5. Consider utility of advanced neuroimaging and neuro-diagnostics: EEG, Brain
18
FDG-PET, MR Perfusion. These tests may be helpful in establishing CNS inflam-
mation when traditional neuroimaging and CSF sampling fail to demonstrate signifi-
cant inflammation but based on the patient’s clinical symptoms there is still a strong
suspicion of encephalitis.
6. In cases where there is a strong suspicion for an underlying malignancy or primary
inflammatory disorder consider vertex to thigh 18FDG-PET

TREATMENT [3]
For hospitalized patients, immunosuppression may need to begin before a definitive
diagnosis. Ensure that infectious causes of meningitis/encephalitis have been
excluded. To the extent possible, complete imaging and laboratory workup as
156
treatment will impact the yield. This is true of tissue biopsy as well. SAVE
ADDITIONAL CSF AND SERUM PRETREATMENT WHENEVER POSSIBLE.

INDUCTION IMMUNOSUPPRESSION [2]

PLASMA INTRAVENOUS
TREATMENT GLUCOCORTICOIDS EXCHANGE IMMUNOGLOBULIN
Dose 1 g methylprednisolone QD × Five exchanges 0.4 g/kg ideal body weight
3–5 days done QOD × 5 days (2 g/kg IBW total)
Notes/ Psychosis/mania, hyperglycemia, Requires dialysis Hypersensitivity reactions,
side-effects/ insomnia. Long-term use can also catheter. aseptic meningitis,
monitoring result in opportunistic infections, thromboembolic
Hypocalcemia,
osteoporosis, myopathy, adrenal complications, hemolytic
hypotension,
suppression, weight gain, cataracts anemia, neutropenia.
arrhythmias,
Anti-acid medication (H2 blocker coagulopathy. Pretreat with acetaminophen
or proton pump inhibitor). If long and diphenhydramine
Monitor
term, consider PJP prophylaxis,
electrolytes and
vitamin D + calcium
coagulation profile

Maintenance immunosuppression should be guided by the diagnosis. Prior to treat-

ment all patients will need hepatitis B screening, hepatitis C screening, HIV testing,
tuberculosis testing, and a pregnancy test, as applicable. Additional testing may be
needed based on the patient’s exposures and the immunosuppressant agent to
be used.

Fig. 27.1 MRI T1-weighted post gadolinium demonstrating temporal lobe encephalitis in a patient
with post-HSV anti-NMDA-R encephalitis

157
REFERENCES
1. Toledano M, Davies NWS. Infectious encephalitis: mimics and chameleons. Pract Neurol.
2019;19(3):225–37.
2. Rubin DB, et al. Autoimmune encephalitis in critical care: optimizing immunosuppression. Semin
Respir Crit Care Med. 2017;38(06):807–20. Thieme Medical Publishers.
3. Long SS. Encephalitis diagnosis and management in the real world. In: Hot topics in infection
and immunity in children VII, vol. 697. New York: Springer; 2011. p. 153–73.

158
INFECTIOUS WORKUP BY NEUROANATOMICAL
LOCATION: AN ORDERING GUIDE
James Hillis and Catherine S. W. Albin

The terms below apply to the chart on the following pages.

Affects General Population (General): Can be found in the general population,

although may be uncommon. Use clinical judgment when ordering.

Can Affect All Patients, but Specific Risk Factors (Rare): Require specific epide-
miological exposures/clinical history. Do not order unless features of the history sup-
port this test.

Immunocompromised (IC): Should only be considered in patients with severe

immune deficiency: AIDS, bone marrow transplant, significant immunosuppressive
medications.

Note: Cerebellitis is isolated involvement of the cerebellum and rhomb-

encephalitis refers to inflammation of the brainstem and the cerebellum.

Fig. 28.1 FLAIR image demonstrating significant atrophy of the temporal lobe in a patient with HSV
limbic encephalitis

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https://doi.org/10.1007/978-3-030-75732-8_28
159
Infectious diseases consultants and institutional protocols can guide which tests to order.
BASAL GANGLIA/
LIMBIC THALAMUS CEREBELLITIS RHOMBENCEPHALITIS ENCEPHALOMYELITIS OTHER
General HSV-1 (CSF PCR) WNVa (CSF IgG/ VZVb (CSF PCR) Listeria (CSF culture) WNVa (CSF IgG/IgM) Enterovirusd (CSF
Syphilis (CSF VDRL) IgM) Listeria (CSF WNVa (CSF IgG/IgM) VZVb (CSF PCR) PCR) – may also be
–Non-infections- Influenza culture) Enterovirus (CSF PCR) — accompanied by flaccid
NMDA-R, LGI-1, & (nasopharyngeal, — EEEa (CSF IgG/IgM) NMO (serum AQP4/ paralysis
other paraneoplastic influenza A/B & Paraneoplastic TBc (T spot, CSF MOG antibodies) Mycoplasma
encephalitis etiology RSV PCR) (autoimmune mycobacterial culture) ADEM (see page 155) (CSF PCR and IgG/IgM)
(autoimmune encephalopathy — Paraneoplastic —
encephalopathy panel, Mayo) NMO (serum AQP4/ (autoimmune TB (T spot, CSF
panel, Mayo/ARUP) MOG antibodies) encephalopathy panel, mycobacterial culture) -
ADEM (see page 155) Mayo) meningitis, abscesses,
— tuberculomas
Bickerstaff Encephalitis
(anti-GQ1b antibodies)

Rare EEEa (CSF IgG/ Whipple (CSF EV71 (CSF PCR) JEVe Anaplasmosis &
e
IgM) PCR) JEV EV71 (CSF PCR) Ehrlichiosis (serum PCR
JEVe SLEVe Brucella (serum IgG/ Tick-borne encephalitis and smear)
SLEVe Mumpse IgM) viruse (CSF IgM) Histoplasmosisd (CSF
Powassane Powassane Bechet (see page 155) Polio antigen and IgG/IgM,
EBV (CSF PCR, AHL (see page 155) Rabies urinary antigen) –
serum IgG/IgM) meningitis
Coccidioidesd (CSF fungal
culture, antigen and IgG/
IgM, urinary antigen)

160
Immuno- HHV-6 (CSF PCR) EBV (CSF PCR, CMV (CSF PCR) – Cryptococcusd (CSF
compromised serum IgG/IgM) often causes a cryptococcal
JC virus/PML radiculitis antigen) – meningitis
(CSF PCR) JC virus/PML (CSF
PCR) – white matter
disease
Toxoplasmosis (Serum
Toxo IgG)

ADEM acute disseminated encephalomyelitis, AHL acute hemorrhagic leukoencephalitis, EBV Epstein-Barr virus, EEE eastern equine encepha-
litis, EV71 enterovirus 7, HHV human herpes virus, HSV herpes simplex virus, JC virus/PML John Cunningham virus/progressive multifocal
leukoencephalopathy, JEV Japanese encephalitis virus, LGI-1 leucine-rich glioma-inactivated 1, NMDA-R N-methyl-D-aspartate receptor, NMO
neuromyelitis optica, SLEV St Louis encephalitis virus, TB tuberculosis, VZV varicella zoster virus, WNV West Nile virus
a
Arbovirus Antibody Panel. Usually performed by a state’s viral serology lab. Routinely includes WNV/EEE IgG/IgM with the possibility of adding
further studies through the CDC. You will need to fill out the appropriate form with relevant history. Note that WNV PCR is not sensitive
b
VZV PCR is highly specific but not as sensitive as VZV IgG (compared between serum/CSF). Note that VZV cerebellitis is more common in
children than adults
c
TB CSF PCR, if high index of suspicion
d
Usually cause meningitis, but can cause meningoencephalitis
e
Rare viral encephalitis studies can be ordered through the State Viral Serology Lab (and will then be sent to the CDC). You will need to talk with
the State Lab to organize ordering

161
AUTOIMMUNE ENCEPHALITIS TESTING
Juan Carlos Martinez Gutierrez and James Hillis

When testing for autoimmune or paraneoplastic causes of neurologic symptoms, it is

best to send either the autoimmune encephalopathy or paraneoplastic antibody
panel. Typically only one is needed as these panels mostly overlap. The autoim-
mune encephalopathy panel is generally sufficient, unless there are concerns for a
paraneoplastic process in the peripheral nervous system (as the extra tests on the
paraneoplastic antibody panel relate to the peripheral nervous system).
Send both serum and CSF panels (the antibodies can have different sensitivities in
each; notably NMDA-R has greater sensitivity in CSF). Anti-Ma and anti-Ta are not
tested by these panels and should be ordered separately if concerned
(details below).
Tests are performed by immunofluorescence assay (IFE), enzyme immunoassay,
radioimmunoassay (RIA), western blot (WB), cell-binding assay or flow cytometry.
Most are IFE and then reflex tested to confirm by western blot or quantified with an
assay listed above.
The table below is adapted from Linnoila and Pittock [1] and the Mayo Clinic
Laboratories antibody matrix:

ASSOCIATED
ANTIBODY TYPE CANCER(S)A CLINICAL SYMPTOMSB
AChR binding Surface Thymoma Myasthenia gravis
AChR Surface Multiple carcinomas Autonomic dysfunction
ganglionic
AGNA (SOX1) Intracellular Small cell lung cancer Lambert Eaton myasthenic syndrome
AMPA-R Surface Thymoma, lung cancer, Limbic encephalitisc
breast cancer
Amphiphysin Intracellular Breast cancer, small cell Wide clinical spectrum including stiff
lung cancer person syndrome, cerebellar ataxia,
encephalomyelitis
ANNA-1 (Hu) Intracellular Small cell lung cancer, Wide clinical spectrum including sensory
neuroblastoma, thymoma neuropathy, encephalomyelitis, limbic
encephalitis, cerebellar ataxia
ANNA-2 (Ri) Intracellular Small cell lung cancer, Opsoclonus myoclonus, cerebellar ataxia,
breast cancer brainstem encephalitis
ANNA-3 Intracellular Lung cancer Sensory neuropathy, cerebellar ataxia,
encephalomyelitis

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_29
163
ASSOCIATED
ANTIBODY TYPE CANCER(S)A CLINICAL SYMPTOMSB
CASPR2 Surface Thymoma Morvan syndromed
CRMP-5 Intracellular Small cell lung cancer, Wide clinical spectrum including
thymoma cerebellar ataxia, encephalomyelitis,
sensory neuropathy, optic neuritis, chorea
DPPX Surface B-cell cancers Encephalitis with CNS hyperexcitability
GABA-B-R Surface Small cell lung cancer, Limbic encephalitis
neuroendocrine cancer
GAD65 Intracellular Only occasional (lung Wide clinical spectrum including stiff
cancer, thymoma) person syndrome, cerebellar ataxia,
encephalitis
Glycine receptor Surface Infrequent Wide clinical spectrum including stiff
person syndrome, PERMe
LGI-1 Surface Thymoma, small cell lung Limbic encephalitis, faciobrachial dystonic
cancer seizures
Ma1/Ma2 (Ta) Intracellular Ma1 & Ma2: multiple Brainstem and cerebellar dysfunction
carcinomas
Ma2 (only): testicular
cancer
mGluR1 Surface Hodgkin lymphoma Cerebellar ataxia
NMDA-R Surface Ovarian teratoma Progressive symptoms. Psychiatric
symptoms → seizures and autonomic
dysfunction → catatonia and coma
PCA-1 (Yo) Intracellular Gynecologic cancer Cerebellar ataxia
(especially ovarian),
breast cancer
PCA-2 Intracellular Small cell lung cancer Encephalomyelitis, cerebellar ataxia
PCA-Tr Surface Hodgkin lymphoma Cerebellar ataxia
Striational Intracellular Thymoma Myasthenia gravis
VGCC (P/Q and Surface Lung, breast, gynecologic Lambert Eaton myasthenic syndrome,
N-type) cancer cerebellar ataxia
VGKC complex Surface Mostly due to associated LGI-1/CASPR2 antibodies (see those
antibodies)
a
Many antibodies may be associated with future cancers (or no cancer); the cancers listed are
considered the “classic” associations
b
Many antibodies may have clinical symptoms beyond the key symptoms listed
c
Symptoms of limbic encephalitis include short-term memory loss, focal seizures, irritability,
depression, and cognitive issues
d
Morvan syndrome involves neuromyotonia (muscle twitching) alongside autonomic and central
nervous system dysfunction
e
Progressive encephalomyelitis with rigidity and myoclonus

164
REFERENCE
1. Linnoila J, Pittock SJ. Autoantibody-associated central nervous system neurologic disorders.
Semin Neurol. 2016;36(04):382–96. Thieme Medical Publishers.

165
APPROACH TO NEW ONSET WEAKNESS
Catherine S. W. Albin and Sahar F. Zafar

The differential diagnosis for a patient with new onset weakness is extremely exten-
sive, but can be significantly narrowed by localizing the weakness and generating a
localization-based differential, which can further be narrowed by the time-course,
patient’s exposures/risk factors, and diagnostic tests [1].

Brain

Myelopathy

Plexopathy
Anterior Horn cells
(“Acute flaccid
myelitis”)

Neuropathy

NMJ

Myopathy

Fig. 30.1 Anatomical locations of potential injury in the neuro-axis

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_30
167
Hyperreflexia.*
Brain Commonly associated with cortical signs or atered mental status.
UMN pattern weakness.

Hyperreflexia.*
Spinal cord
Commonly presents with sensory and motor symptoms.
(Myelopathy)
Look for sensory level.
Physical findings / symptoms suggestive of

No sensory involvement. May be asymmetric. Patient may have

Anterior horn cells
UMN and LMN symptoms in the same limb.
this localization

Nerve roots Hyporeflexia/areflexia if the nerve root supplies a reflex. LMN fndings.
(Radiculopathy) Radiating pain common.

Hyporeflexia/areflexia. LMN findings

Mononeuropathy (multiplex): Asymmetric. Pain in effected nerve(s)' distribution.
Nerve
Polyneuropathy: Axonal = Length depdentent; Demyelinating=non-length
(Neuropathy)
dependent. Often symmetric weakness + sensory symptoms. Parestheisa
common.

Weakness is fluctuating and fatiguing (MG), or gets better with repititive

NJM
stimuation (LEM). Ptosis or bulbar weakness common.

Muscle No upper or lower motor signs. No sensory changes. Characteristic

(Myopathy) patterns: proximal myopathies, limb-girdle, and distal myopathies

*In hyperacute setting, the patient may have spinal shock and the reflexes are absent

UPPER MOTOR NEURON FINDINGS LOWER MOTOR NEURON FINDINGS

Hyperreflexia, clonus, +Babinski sign, +jaw jerk, Atrophy, hyporeflexia, fasciculations
Hoffman’s sign

EVALUATION
Patients with upper motor findings require screening with MRI brain and, as appropri-
ate, C/T spine. The approach to demyelinating diseases is covered on page 175.
Acute onset unilateral pure motor weakness involving face arm and leg is a classi-
cally described lacunar syndrome, and stroke evaluation should proceed (see page
61). Many infectious, inflammatory, neoplastic, and autoimmune causes of encephali-
tis can also cause transverse myelitis. More common causes of myelitis are reviewed
here, but the workup of an unknown lesion in the spinal cord should be undertaken
with the same framework as new brain lesion (see page 133).

168
ELECTED SCREENING EVALUATION FOR INFRATENTORIAL CAUSES OF ACUTE
S
WEAKNESS BY ANATOMICAL SYNDROME
Note that this is not an all-inclusive list of all things that may result in weakness, but a
framework for screening for some of the more common or treatable causes of
weakness that progress quickly enough to warrant hospitalization.
Many etiologies of peripheral weakness progress slowly and are evaluated in the
outpatient setting and are not the focus of this chapter.
Etiologies organized in their category by “VITAMIN” Mnemonic: Vascular, Infectious,
Traumatic, Autoimmune, Metabolic, Iatrogenic, Neoplastic

ANTERIOR HORN
MYELOPATHY [2] CELLS [3] RADICULOPATHY PLEXOPATHY
Causes − Dural AVF Described often as − Lyme disease − Vasculitis
− Stroke “acute flaccid − Acute nerve root − Trauma
− VDRL, VZV, myelitis” compression/trauma − Parsonage-
CMV, EBV, HIV, Infections: − Guillain-Barre (GBS or
−
Turner
Polio
− West Nile Virus
mycoplasma, AIDP) syndrome

− Enterovirus D68 − Leptomeningeal

TB, HTLV-1 (polyradiculoneuropathy) (idiopathic
− Trauma/ brachial
compression (other entero-/ carcinomatosis plexopathy)
− MS, anti-MOG, rhio-/corona-virus) − Diabetic
NMOSD − SARS-CoV2 amyotrophy
− Sarcoid, SLE, (COVID19) [4]
− Tetanus
(lumbosacral
Sjogren’s plexopathy)
disease (accompanied by
− CRMP-5, hypersympathetic
ampiphysin, Hu state)
− B12, copper, E Other:
− Anti-Hu syndrome
− ALS (slowly
deficiencies
− Tumor
progressive)

For suggested workup of each, see next page.

169
ANTERIOR HORN
MYELOPATHY [2] CELLS [3] RADICULOPATHY PLEXOPATHY
Possible − MRI C/T spine − MRI C/T spine w/ − MRI C or L spine − Vasculitis
workup w/ and w/o and w/o (localized by exam) w/ screen: ESR/
− dAVF requires − CSF studies (see and w/o; nerve root CRP, ANCA,
MRA-TOFTR page 159 for enhancement commonly C3/C4,
− Demyelinating guidance), seen in GBS hepatitis B/C
workup: see consider Biofire® − CSF routine – look for − Rheumatologic
page 175 − Paraneoplastic albumin-cytologic screen: ANA,
− Viral studies panel from CSF dissociation, consider dsDNA,
from CSF & and serum Biofire®
anti-Ro/La, RF
serum (see − Consider − CSF cytometry and flow − HgbA1c
page 159 for Enterovirus D86 cytology
guidance) testing from − Consider EMG/NCS
− CSF routine respiratory − Lyme (CSF and serum
studies, OCB, specimen, can IgG/IgM)
consider CSF screen with a − Paraneoplastic panel
Biofire® respiratory Biofire® from CSF and serum
− CSF cytology panel for occult − Consider workup for
and flow infections if occult malignancy if
cytometry available high concern for
− Paraneoplastic − Paraneoplastic leptomeningeal
panel from CSF panel (anti-Hu) carcinomatosis
and seruma
− ESR/CRP,
Anti-Ro/La,
ANA/dsDN
− Elements and
Vitamin screen:
B12, vitamin E,
copper, zinc

170
MONONEURITIS NEUROMUSCULAR
MULTIPLEX [8] POLYNEUROPATHY JUNCTION MYOPATHY [6]
Causes − Vasculitis − Vasculitis − Botulism − Crush injury/
(eosinophilic − Lyme disease, HIV, − Myasthenia rhabdomyolysis
granulomatosis leprosy, hepatitis gravis (MG) − Inflammatory
with polyangiitis, C − Lambert Eaton myositis
polyarteritis − Cryoglobulinemia myasthenic (dermatomyositis
nodosa, − Guillain-Barre syndrome and polymyositis)
microscopic Syndrome (AIDP) − Inclusion body
polyangiitis) − AL amyloidosis myositis
− Multiple − Acute intermittent − Necrotizing
compressive lesions porphyria myositis (often
− Systemic − Nutritional/ associated with
rheumatologic diabetic (much HMG-CoA
disease (SLE, more likely to Reductase)
rheumatoid cause sensory − Dystrophies,
arthritis, Sjogren’s neuropathies) metabolic and
most commonly) − Heavy metals mitochondrial
− Diabetes − Critical illness myopathies (not
− Lymphoma, neuropathy covered in workup
Waldenström − Paraneoplastic below as often
macroglobulinemia (anti-Hu/anti-MAG require special
IgM) [5] genetic tests)
− Metabolic, vitamin
deficiency, and
endocrinopathies
− Critical illness
myopathy
− Medication
induced (steroids,
statins,
amiodarone,
colchicine others)
− Cushing syndrome

171
MONONEURITIS NEUROMUSCULAR
MULTIPLEX [8] POLYNEUROPATHY JUNCTION MYOPATHY [6]
Possible − Vasculitis screen: − CSF studies − Anti-AChR − Creatinine kinase
workup ESR/CRP, ANCA, (routine) antibody (CK)
C3/C4, hepatitis − Serum anti-GQ1b − Anti-MuSK − Parathyroid
B/C IgG antibody antibody hormone, TSH
− Rheumatologic (Miller Fisher − Anti-striated − iCal, phosphorous
screen: ANA, variant, see muscle antibody level and basic
dsDNA, anti-Ro/ below) − Paraneoplastic metabolic panel
La, RF − Paraneoplastic panel (VGCC for for hypokalemia
− SPEP/UPEP/IFE panel (anti-Hu) LEMS) − Myositis panel b

− Consider workup − SPEP/UPEP, IFE − EMG/NCS with − ANA

for occult − Anti-MAG IgM repetitive nerve − HMG-CoA
malignancy (serum stimulation reductase IgG
cryoglobulin) − Screen for Antibody (not
− Cryoglobulins thymoma if new included in Mayo
− C3/C4, ESR, CRP onset myasthenia MyoMarker 3 Plus
− HbA1c, TSH gravis panel)
− Screen medication − Screen medication
list/alcohol intake list
− B12, HgbA1c
a
When testing for weakness, the Mayo’s Paraneoplastic Serum and CSF panel should be used
which includes anti-striation antibody
b
The Mayo’s MyoMarker Panel 3 Plus can be used to evaluate for polymyositis, dermatomyosi-
tis, and anti-synthetase syndrome and includes Anti-Jo-1 Ab, Anti-TIF-1gamma Ab, Anti-MDA-
5-Ab (CADM-140), Anti-NXP-2 (P140) Ab, Anti-SAE1 Ab IgG, Anti-PM/Scl-100 Ab, Anti-SS-A
52kD Ab IgG, Anti-U1-RNP Ab

172
Selected Variants of Guilain-Barré [7]
Guillain-Barre syndrome = AIDP = Acute inflammatory demyelinating polyneuropathy.
It is actually a polyradiculoneuropathy. There are multiple variants to be aware of
when assessing a patient with weakness.

SYNDROME CLASSIC FINDINGS

Classic GBS Acroparesthesia which may or may not be associated with radicular or
neuropathic pain → “Ascending” symmetric progressive weakness. However
descending weakness has been described. Areflexia may be delayed up to
a week. Half of GBS cases may have a normal CSF protein in the
first week. It is critically important not to rule out GBS in a patient
with vague acroparesthesias and back pain because their reflexes
are preserved and CSF protein is normal or only mildly abnormal
Usually demyelinating, but axonal variant happens ~5% of cases, usually
associated with Campylobacter jejuni. These variants may be pure motor (acute
motor axonal neuropathy [AMAN]), and associated with anti-GD1a and GM1
antibodies or acute motor and sensory axonal neuropathy [AMSAN]
Miller-Fisher Ophthalmoplegia, ataxia, and areflexia. Associated with anti-GQ1b and/or
variant (MFS) GT1a antibodies in the serum
Bickerstaff Very rare. May be a variant of MFS with alterations of consciousness,
brainstem hyperreflexia, ataxia, and ophthalmoparesis. Also associated with anti-GQ1b
encephalitis antibodies. MRI changes only found in 30% of patients
Pharyngeal- Ptosis, facial, pharyngeal, and neck flexor weakness that spreads to arms but
cervical-brachial spares the legs. Sensation and reflexes are not affected. Mimics botulism.
motor variant

Treatment is vastly different based on the etiology of weakness.

–– Guillain-Barre and myasthenia gravis are two of the most common peripheral
causes of weakness and as such, their acute management (including when to
transfer to the ICU) is covered on page 269.

REFERENCES
1. Berkowitz AL. Clinical neurology and neuroanatomy: a localization-based approach. New York:
The McGraw-Hill Companies; 2017.
2. Kitley JL, et al. The differential diagnosis of longitudinally extensive transverse myelitis. Mult
Scler J. 2012;18(3):271–85.
3. Messacar K, et al. Acute flaccid myelitis: a clinical review of US cases 2012–2015. Ann Neurol.
2016;80(3):326–38.
4. Abdelhady M, Elsotouhy A, Vattoth S. Acute flaccid myelitis in COVID-19. BJR Case Rep.
2020;6(3):20200098.
5. Antoine J-C, Camdessanché J-P. Paraneoplastic neuropathies. Curr Opin Neurol.
2017;30(5):513–20.
6. Katzberg HD, Kassardjian CD. Toxic and endocrine myopathies. Continuum.
2016;22(6):1815–28.
173
7. Dimachkie MM, Barohn RJ. Guillain-Barré syndrome and variants. Neurol Clin.
2013;31(2):491–510.
8. Samson M, et al. Mononeuritis multiplex predicts the need for immunosuppressive or immuno-
modulatory drugs for EGPA, PAN and MPA patients without poor-prognosis factors. Autoimmun
Rev. 2014;13(9):945–53.

174
WORKUP OF NEW DEMYELINATING LESION
Kathryn Holroyd and Kristin Galetta

OVERVIEW
• Demyelinating diseases are autoimmune diseases that damage myelin
in the CNS
• Most present between ages 15–50 years old and are more common in women
• Symptoms include episodes of weakness,
numbness or tingling, monocular vision Clues to multiple sclerosis
loss, and double vision. Cortical symptoms (MS) include that symptoms
such as aphasia or neglect (as seen in worsen in heat (Uhthoff phe-
stroke) are usually not present. nomenon) and patients may
• Symptoms present over hours to days and report episodes of electric
improve in days to months, even resolving shocks down the back of the
completely neck (L’Hermitte sign).
• Neurologic exam findings include asymmet-
ric weakness, sensory loss, eye movement
abnormalities (specifically internuclear ophthalmoplegia), and hyperreflexia
• Most MS is relapse-remitting. However, patients can also present with constant
decline in function over time, indicative of progressive MS (ongoing
neurodegeneration).
• When the primary presenting symptom is severe or bilateral vision loss, a severe
spinal cord syndrome, or intractable nausea/vomiting and hiccups (area postrema
syndrome), neuromyelitis optica (NMO) or anti-myelin oligodendrocyte glycoprotein
(MOG) disease should be considered
• Severe, multifocal deficits with encephalopathy should raise concern for acute
demyelinating encephalomyelitis (ADEM).

DIAGNOSTIC WORKUP
• MRI brain, cervical spine, and thoracic spine
should be ordered w/ and w/out gadolinium. 2017 McDonald Criteria
• If visual loss is concerning for optic neuritis for MS [1]
(ON), MRI orbits w/ gadolinium should also 1. Dissemination in space =
be obtained. evidence of ≥2 lesions in
• Gadolinium enhancement on MRI indicates two separate regions:
active inflammation in a lesion. periventricular, juxtacorti-
• If McDonald criteria are met via imaging and cal, infratentorial, spinal
symptoms, no further testing is needed; MS cord (not optic nerve)
is diagnosed.

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_31
175
• If McDonald criteria for dissemination in time
are not met, or the presentation or imaging 2. Dissemination in time =

are atypical for MS, a lumbar puncture simultaneous enhancing
should be performed. and non-enhancing lesions
• If MRI is atypical or shows a spinal lesion >3 OR non-enhancing lesion +
segments, optic neuritis that is bilateral, >2/3 OCBs on lumbar puncture
of the tract or involves the optic chiasm, or OR new lesion on follow-up
an area postrema lesion, serum antibody MRI OR new clinical attack
testing with anti-aquaporin 4 and anti-MOG
should be sent.

ACUTE MANAGEMENT
• If evidence of acute demyelination based on
exam or enhancing lesion on MRI, high-dose Studies to send from CSF:
steroids (1000 mg IV methylprednisolone) –– Total protein
should be administered for 3–5 days. –– Glucose
• Patients with MS exacerbations generally –– White cell count
respond well to IV steroids alone –– Red cell count
• When NMO is suspected based on the –– Gram stain and culture
clinical presentation and imaging, early –– Oligoclonal bands (OCBs)
plasma exchange (PLEX) should be consid- –– IgG Index
ered as limited data indicate this may
improve outcomes [2] Serum studies:
• For patients with ADEM or other demyelinat- –– Anti-aquaporin 4 antibody
ing lesions who do not demonstrate a –– Anti-MOG antibody
clinical response to high-dose steroids, a
treatment course with IVIG (2 g/kg) or
plasma exchange (five sessions) should be
considered, though data is limited [3]

176
DEMYELINATING SYNDROMES
ACUTE
MULTIPLE NEUROMYELITIS ANTI-MOG DEMYELINATING
SCLEROSIS OPTICA SYNDROME ENCEPHALOMYELITIS
Demographics Mean age 28–31 Mean age 31–42 Onset 20–30s More common in
2.3:1 F:M ratio 5:1 F:M ratio Equal M:F ratio children
Low vit D is risk May be ⇑ Considered Often preceded by
factor incidence in those “NMO spectrum infection
⇑ incidence in of African, Latin disorder,” though
northern latitudes American, East may be unique
Asian descent disease
Suggestive Subacute unilateral Severe binocular No findings Acute
exam sensory loss or vision loss specific to encephalopathy with
findings weakness Severe spine anti-MOG focal neurologic
Unilateral vision loss symptoms Can mimic NMO deficits
Double vision Intractable nausea or ADEM
Ataxia or hiccups
Suggestive Ovoid lesions Central spinal No specific Diffuse, bilateral,
imaging Lesions lesions >3 segments findings, but may asymmetric lesions in
findings [4] perpendicular to Bilateral ON have increased white matter of brain
ventricles ON affecting proportion of Multi-segment spine
(“Dawson’s fingers”) chiasm brainstem lesions lesions can be seen
Dorsal spinal lesions Area postrema Can mimic NMO
<2 segments lesion or ADEM

Laboratory ⇑ protein in CSF ⇑ protein in CSF ⇑ protein in CSF ⇑ protein in CSF

findings <50 WBCs in CSF <100 WBCs in <100 WBCs in <100 WBCs in CSF
+ OCBs in CSF CSF CSF May have CSF OCBs
⇑ IgG index in CSF OCBs rare in CSF OCBs rare in CSF May be anti-MOG +
Serum anti-AQ4 Serum anti-MOG
Ab + Ab +
Treatment High-dose IV High-dose IV High-dose IV High-dose IV steroids,
and steroids steroids and early steroids, consider consider PLEX, IVIG
prognosis >15 disease PLEX PLEX, IVIG Usually monophasic,
modifying therapies Disease modifying Disease no need for long-term
approved and can therapy to prevent modifying immune suppression
reduce relapses by relapse therapy to
>80% prevent relapses

177
REFERENCES
1. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revi-
sions of the McDonald criteria. Lancet Neurol. 2018;17(2):162–73. https://doi.org/10.1016/
S1474-4422(17)30470-2.
2. Bonnan M, Valentino R, Debeugny S, et al. Short delay to initiate plasma exchange is the stron-
gest predictor of outcome in severe attacks of NMO spectrum disorders. J Neurol Neurosurg
Psychiatry. 2018;89(4):346–51. https://doi.org/10.1136/jnnp-2017-316286.
3. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Weinshenker BG. Plasma
exchange for severe attacks of CNS demyelination: predictors of response. Neurology.
2002;58(1):143–6. https://doi.org/10.1212/wnl.58.1.143.
4. Tillema JM, Pirko I. Neuroradiological evaluation of demyelinating disease. Ther Adv Neurol
Disord. 2013;6(4):249–68. https://doi.org/10.1177/1756285613478870.

178
APPROACH TO THE “DIZZY” PATIENT
Eric C. Lawson

• A consult for a dizzy patient is one of the most common a neurologist will encounter
• It is important to approach and triage each dizziness consult based on symptom
quality, vascular risk factors, and other common culprits

STEP 1: DEFINE THE DIZZINESS

Vertigo False sense of motion, can be rotation, tilting, or dropping of environment
Imbalance Unsteadiness or sensation of being off-balance
Near-faint Feeling of impending loss of consciousness
Lightheadedness/woozy Overall vague description, often described as feeling “off”
Out of body/floating No sensation of environment moving, commonly psychogenic

STEP 2: EXAMINING THE DIZZINESS: THE TiTraTE METHOD [1]

Timing
• Onset: Acute or
Gradual?
• Episodic, Constant
or Chronic?

TiTraTE
Method
Triggers Targeted
• Positional
• Sound
Exam
• HINTS Exam
• Valsalva
• Cerebellar Signs
• Complex visual
• Dix-Hallpike
stimulation
• Orthostatic Vitals

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_32
179
• HINTS Exam: Best utilized in patients with acute onset constant symptoms
° Components:
° Head Impulse:
• Normal (no correctional saccade) – concern for central etiology
• Abnormal (correctional saccade) – suggests peripheral etiology
° Nystagmus:
• Direction changing – concern for central etiology
• Vertical – concern for central etiology
° Test of Skew:
• Vertical misalignment – concern for central etiology
• Dix-Hallpike Maneuver:
° Best utilized in patients with episodic triggered symptoms suggestive of BPPV
° (a) Examiner rotates patient head 45° to right to align posterior semicircu-
lar canal with sagittal plane of body
° (b) Examiner moves patient with eyes open from seated position to supine,
right-ear-down position with slight neck extension. Examiner observes for
latency, duration, and direction of nystagmus

a plane
l body
Sagitta
45˚
Gravity

At rest there should be

no nystagmus

Vantage
point
Superior
canal

Posterior
osterior
canal Utriculus
U
Ut

Po
Posterior-canal
P
Gravity aampulla
am

Particles

b
Gravityy

ch eyes for torsional and

Watch
p-beating nystagmus
up-beating

Utriculus
Posterior-canal
ampulla
Superior
canal
Posterior
canal
Vantage
point
Gravity
Particles

The nystagmus is a result of the particles

oving with in the semi-circular canal
moving

Dix-Hallpike Testing for BPPV [2]

180
STEP 3: DIAGNOSING, LOCALIZING, AND TREATING THE CAUSE [3]
DISORDER DURATION TRIGGERS DIAGNOSIS TREATMENT
Benign Acute onset; Turning in bed, Upbeating-torsional Epley Maneuver
paroxysmal duration is reaching upward nystagmus on (see below)
positional seconds Dix-Hallpike
vertigo (BPPV)
Stroke Acute onset; Spontaneous Central nystagmus, Stroke
symptoms last negative head thrust, management (See
days to weeks other neurologic signs page 61)
Posterior Acute onset; Spontaneous Other neurologic TIA management
circulation TIA minutes symptoms
Orthostatic Acute onset; Standing from Postural drop in Hydration,
hypotension seconds sitting or lying blood pressure medication
management
Vasovagal Acute onset; Prolonged Positive tilt table test Hydration
seconds- standing, heat,
minutes stress
Cardiogenic Acute onset; Exertion, heart Arrhythmia, valvular Cardiology
seconds- failure disease Management
minutes
Anxiety Acute or Stress, complex Associated anxiety Anxiety disorder
disorders gradual onset; visual surroundings, and other somatic management
minutes-days crowds symptoms
Vestibular Subacute Spontaneous Unidirectional Consider
neuritis onset; days to horizontal nystagmus. corticosteroids
weeks +Head thrust test
Meniere Subacute Sodium intake Fluctuating hearing Diuretics, restrict
syndrome onset; hours loss sodium intake
Migraine- Gradual onset; Stress, lack of Personal or family hx migraine
associated minutes-days sleep, diet of migraine, other prophylaxis
associated symptoms
Adapted from: Kerber [3]

STEP 4: FURTHER MANAGEMENT DETAILS

In any patient with acute onset vertigo and a HINTS exam that suggests a central
etiology a stat noncontrast head CT and CT angiogram should be obtained. See
page 61 for suspected acute stroke management.

181
For patients with BPPV, the Epley Maneuver can be tried in which the patients head
is rotated in stages (A) -> (B) -> (C) and then the patient is helped to sit up while
keeping their head facing the downward shoulder until they are completely upright
and then head can be turned midline, as seen in (D). Patients can do these move-
ments at home once trained.
a
Superior Posterior-canal
canal Utriculus ampulla

Gravity

Vantage
point

b
Superior Posterior
canal canal

Vantage
point

Gravity

Particles

Posterior
c canal

Vantage
point
Particles

Gravity

Superior
canal

182
d Superior
Posterior canal
canal

Utriculus

Particles

Posterior-canal
ampulla

Epley Maneuver [2]

REFERENCES
1. Newman-Toker DE, Edlow JA. TiTrATE: a novel, evidence-based approach to diagnosing
acute dizziness and vertigo. Neurol Clin. 2015;33(3):577–99, viii. https://doi.org/10.1016/j.
ncl.2015.04.011. PMID: 26231273; PMCID: PMC4522574.
2. Furman JM, Cass SP. Benign paroxysmal positional vertigo. N Engl J Med. 1999;341(21):
1590–96.
3. Kerber KA, Baloh RW. The evaluation of a patient with dizziness. Neurol Clin Pract.
2011;1(1):24–33. https://doi.org/10.1212/CPJ.0b013e31823d07b6.

183
PART IV

NEUROICU
INTRACRANIAL PRESSURE: THEORY AND MANAGEMENT
STRATEGIES
Melissa Bentley and Catherine S. W. Albin

THEORY AND FORMULAS CENTRAL TO NEUROCRITICAL CARE

Monro-Kellie Doctrine
The sum of the volume of brain parenchyma, cerebral spinal fluid, and intracra-
nial blood is constant. An increase in one should cause a decrease in one or
both of the remaining two.

When pathology leads to an increase in one of these components (for example, a

space occupying lesions such as a brain tumor), there must be a decrease in the
others. When autoregulatory mechanism fails – chiefly, the ability for CSF to move
into the spinal column – intracranial pressure increases, and if not controlled, sec-
ondary brain injury and, ultimately, herniation results.

ICP is considered pathologically elevated when >20 mmHg1 for >5 min

Much of neurocritical care is focused on lowering intracranial pressure to prevent

herniation and also secondary ischemic damage to healthy brain issue. Ischemic injury
can result from increased ICP because cerebral perfusion pressure is related to ICP.

Cerebral perfusion pressure (CPP) = mean arterial blood pressure (MAP) –

intracranial pressure (ICP)

Despite this strong relationship, under normal circumstances, cerebral blood flow
(CBF) can be kept constant over a wide range of cerebral perfusion pressures, and
thus over wide variations in MAPs due to cerebrovascular resistance regulation
(CVR). CVR is an ATP-dependent process that allows the arterioles to vasocon-
strict/dilate.

Cerebral blood flow (CBF) = cerebral perfusion pressure (CPP)/cerebrovascular

resistance (CVR)

Note that the Brain Trauma Foundation uses 22 mmHg as its threshold for pathologically elevated ICP.
1

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_33
187
For example, as the MAP increases CPP also increases. But, through autoregulatory
mechanisms, CVR also increases, and CBF is kept constant. The brain tissue
continues to receive necessary oxygen. This regulatory mechanism breaks down at
the extreme of perfusion pressures.

100

80
CBF (mL/100g/min)

0
0 40 80 120 160 200
CPP (mmHg)

Because of these relationships, by targeting an adequate/normal CPP (by controlling

ICP and MAP, variables we can measure at the bedside), CBF should theoretically
be stable and secondary injury due to ischemia or hyperemia avoided.

The Brain Trauma Foundation Guidelines recommend target CPP values of

60–70 mmHg for survival and favorable outcomes [8].

However, in vivo, these relationships are more complex. The reasons are multifacto-
rial, but two important concepts need to be considered:
1. Chronically high (or low) MAP resets the “set point” for autoregulation.
(a) For example: chronically hypertensive patients may be able to tolerate much
higher perfusion pressures without hyperemia. But, may have tissue ischemia
even with a CPP of 60–70 mmHg.

188
2. CVR is ATP-dependent. In damaged/ischemic tissue regulation of a constant CBF
for a wide range of CPP is not possible and the relationship between CPP and CBF
becomes more linear.
(a) This means that in some tissues where a CPP of 60 mmHg would have been
adequate for optimal CBF under normal vasoregulation, the vasculature cannot
lower CVR enough to optimize CBF and tissue ischemia results
(b) Or, conversely, a CPP of 120 mmHg, which would be well within most normal
autoregulation capabilities, in damaged brain may result in hyperemia and
reperfusion injury, because of the inability to raise CVR.

100

80
CBF (mL/100g/min)

0
0 40 80 120 160 200
CPP (mmHg)

Recognizing the personalized and dynamic nature of cerebrovascular autoregulation,

the pressure reactivity index is being used in some institutions to more precisely
direct the goal for a patient’s CPP.
The pressure reactivity index (PRx) is a correlation coefficient between ICP and MAP
using 10 s-averaged samples. Although it does not directly assess cerebrovascular
autoregulation, the PRx is strongly related to it, and by collecting the collecting
arterial blood pressure and ICP, an automated mathematical algorithm will fit these
variables to an optimal CPP (CPPopt) curve, which aims to optimize the CPP for the
individual patient. This is being investigated in clinical decision-making [1–3].

189
TRATEGIES FOR MONITORING ICP
S
Noninvasive ICP Monitoring

Symptoms/signs of significantly elevated ICPs Physiologic parameters

Abducens palsy Bradycardia
Restricted upgaze Hypertension
Decreased consciousness Irregular breathing patterns
Severe headache Diabetes insipidus – resulting
Vomiting in large volume of very dilute
Sluggish pupils to light confrontation testing urine (see page 307 for
Anisocoria or dilated or fixed pupil(s) management)
Bedside testing Radiology
Pupillometry: rapid, objective, and noninvasive tool to indirectly Head CT should be obtained
assess ICP. Device is held up to eye and uses a light flash to measure in any patient with clinical and
the constriction velocity (CV), which is then used to calculate the physiologic signs of elevated
Neurological Pupil Index ICPs.
NPi 3–5: Briskly reactive, normal See page 29 for examples of
NPi <3: Sluggish, abnormal herniation on CT scan
Brisker CVs and higher NPis correlated with ICPs w/in desired limits See page 29 for examples of
[4]. Abnormal NPis may precede significant elevation of ICP or hydrocephalus
worsening head CT by hours [5]. Can be used as a bedside screen TCDs can also be used as a
for worsening ICPs as well as to monitor response to hyperosmolar screen for ICP elevation using
therapy [6] the pulsatility index, although
Optic nerve diameter by ultrasound can be considered with this is not well validated. See
a ONSD ≥0.48 predicting an ICP >20 mmHg [7] page 49

Invasive ICP Monitoring

Subarachnoid Externalized
bolt ventricular drain
(EVD)

Fig. 33.1 Positions of invasive neuro-monitors

190
The most common ways of measuring intracranial pressure are with a bolt placed in
the subarachnoid space, an intraparenchymal fiberoptic sensor, or an externalized
ventricular drain (EVD) placed at the intraventricular foramina. Unlike other pressure
sensors, an EVD has the benefit of being able to drain CSF and therefore is not just
a monitoring device but can be used to also treat elevated ICP. For practical tips on
EVD management, see page 197.

When to Monitor
IF TBI [8]: IF NOT TBI [9]:
GCS score ≤8 and CT scan No strict management guidelines.
showing evidence of mass effect In general patients with conditions that would put them at high
risk for developing elevated ICP should be considered for
OR monitoring:
• IVH, especially with early signs of hydrocephalus
When normal CT if:
• Acute hydrocephalus
• Age >40 years
• High-grade (Hunt Hess3–5) subarachnoid hemorrhage
• Motor posturing
• Evidence of shift, herniation, or effacement of basilar cisterns
• Systolic BP <90 mmHg
• Those with clinical signs of increased ICP, see above
• Meningitis/encephalitis when concerned for communicating
hydrocephalus resulting from meningitis and/or or significant
cerebral edema

WAVEFORM INTERPRETATION
Sustained ICPs greater than 20 mmHg are associated with poor outcomes and
should trigger treatment (see page 187). The waveform of the ICP curve is also
helpful in determining brain compliance.
Normal waveform: Waveform when compliance is diminished

P2
20 mmHg 20 mmHg
P1
P3
15 mmHg P1 15 mmHg
P2

P3
1- 4 mmHg
10 mmHg 10 mmHg

5 mmHg
5 mmHg
1 second 1 second

191
P1 = The percussion wave, representing arterial pulsations that are transmitted to
the CSF from the arteries and choroid plexus
P2 = The tidal wave, representing the compliance in the ventricles, thought of as
a rebound of the arterial pulsation
P3 = The dicrotic wave, representing aortic valve closure

When the brain’s compliance is decreased, the P2 wave will be higher than P1. At
this point, very small fluctuations in volume can lead to dramatic increases in
pressure. An intervention to lower ICP can be considered (see page 187).
In addition to beat-to-beat variation, which causes a change of about 1–4 mmHg per
cardiac cycle, there may also be more dramatic changes in the ICP captured by
monitoring. These classic changes were described first by Lunderg in the 1950s and
1960s [10]. The three main categories of ICP variations have been named Lundberg
A, B, and C waves.

Lundberg A Waves
A rapid rise in ICP, continuation on a high level, and then a rapid fall. Also termed
“Plateau Waves.” Clinically may result in changes in consciousness, headache, and
tonic posturing. ICP is dramatically elevated to 50–100 mmHg for 5–20 min before
returning to baseline. Clinically, these waves are driven by a failure of compliance: as
ICP rises, CPP decreases, triggering vasodilation which worsens ICP and edema.
The continued elevation of ICP results in ischemia and failure of cerebral flow to
ischemic territories, ending the positive feedback cycle.

Lundberg B Waves
Variations in the ICP occurring 1/3 to 3 cycles per minute. These fluctuations are on
the order of 5–20 mmHg. Although the phenomenon that causes B waves is complex
and incompletely understood, they likely represent cerebral autoregulation to blood
pressure fluctuations and changes in arterial CO2. These may be seen in normal
individuals as well as those with brain injuries.

Lundberg C Waves
Oscillations 4–8 waves/min associated with variations in the ICP with the respira-
tory cycle.

192
MANAGEMENT OF INCREASED INTRACRANIAL PRESSURE
The most recent editions of the Brain Trauma Foundation (BTF) Guidelines for
Management of Severe Traumatic Brain Injury (sTBI) have removed the algorithms
by which to manage sTBIs due to the lack of evidence of their effectiveness. As a
result, in 2019, 42 physicians gathered together to create the Seattle Severe
Traumatic Brain Injury Consensus Conference (SIBICC) algorithm which provides
three tiers whereby to manage elevated ICPs in severe TBI [8].
Careful consideration should be given when advancing tiers, as higher risk is associ-
ated with the treatment modalities included in the higher tier.
These recommendations were created for severe TBI; however, the principles are
often widely applied to elevated ICP for any cause and guided by Society of
Neurocritical Care Guidelines [11, 12]. Below is an adaptation of sTBI treatment
guidelines that can be applied to all patients with concern for elevated ICP or docu-
mented elevated/refractory ICPs. For further guidance in the management of TBI,
see page 245.

Tier Zero

• Admission to ICU • Serial evaluation of neurological status and

•E
ndotracheal intubation and pupillary reactivity (most hospitals implement
mechanical ventilation for any patient Q1H or Q2H neurochecks)
with GCS ≤8 • Maintain Hgb >7 g/dL
• Elevate HOB 30–45 • Analgesia to manage signs of pain (not ICP
• Optimize venous return from head directed)
(e.g.: Keep head midline, ensure • Avoid hyponatremia
cervical collars are not too tight) • Sedation to prevent agitation, ventilator
• Arterial line continuous blood pressure asynchrony, etc. (not ICP directed)
monitoring • Temperature management to prevent fever
• Goal to maintain SpO2 ≥ 94% (measure core temperature & treat core
temperature >37.5C)

193
Tier One

• ICP monitoring if meets criteria described above, EVD provides additional ability to drain CSF
• Maintain CPP 60–70 mmHg
For ICP >20 mmHg for 5 min, perform one or more:
• Mannitol or hypertonic saline (HTS) by intermittent bolus for symptoms documented ICP, not
for goal Na/serum Osm goals.
• Increase analgesia & sedation
• Maintain PaCO2 at lower end of normal (35–38 mmHg)
• CSF drainage, if EVD available.
Steroids should NOT be used in any cases other than elevated ICP from vasogenic edema
secondary to tumor or meningitis

Tier Two

• Perform MAP challenge to assess cerebral autoregulation & guide MAP &
CPP goals
• Mild hypocapnia (32–35 mmHg). This is usually only done if there is a plan
for surgical intervention as a prolonged period of hyperventilation may result
in tissue ischemia due to vasocontriction
• Paralytics in adequately sedated patients only if a trial dose is efficacious

Tier Three

• Secondary decompressive craniectomy (see page 200 for data in stroke and
251 for data in TBI)
• Pentobarbital coma, but note significant GI complications and prolonged
sedation with this medication
• Mild hypothermia (35–38 °C)

The Theory of Hyperosmolar Therapy:

By providing an osmotic gradient, tissue with an intact blood brain barrier (BBB) will
efflux water. Thereby shrinking the intact tissue, to make more room for the cerebral
edema/blood products in the injured part of the brain. In drawing fluid into the blood,
hyperosmolars also decrease blood viscosity, which can promote cerebro-
vasconstriction and lower ICP.

194
Which Hyperosmolar Therapy to Use?
Both Hypertonic Saline (HTS) and mannitol have benefits and risks. Some compara-
tive studies have found no difference in their effect [13], while a meta-analysis of
small trials found that hypertonic saline is more effective than mannitol in the treat-
ment of elevated ICP [14]. The NCS recommends HTS as first line for
SAH. Generally, the use of which solutions is often an institutional preference and
should be guided by the patient’s personal comorbidities. Both can be used; note with
this strategy careful monitoring of I/Os and electrolyte balance is critically important.

MANNITOL HYPERTONIC SALINE

Practically: Practically:
− 500 mL bag; 1 g/kg dosing (100 g max) − Any concentration >3% requires central
− Majority excreted within 3 h access, although a one-time dose in
− Should have a foley to manage Ins and Outs emergencies can be considered
− Administer through a filtered IV − 30 mL/bag for 23.4% NaCl
− A dose = 30 ml for 23.4% NaCl or 250 ml
for 3% NaCl
Goals: Goals:
− Most institutions stop administration for serum − Most intuitions stop administration for serum
osmolarity >320 mOsm/L or osmolar gap Na > 155–160, although there is no strong
20 mOsm/L. evidence in support of one target and the BTF
did not feel there was sufficient evidence to
make a recommendation [8]
PROS: PROS:
− Able to be administered peripherally − Effects can be seen up to 12 h post
− May improve brain circulation through administration
possible improvement in blood rheology − Positive inotropic effects can result in increased
− The reflection coefficient is 0.9 cardiac output, MAP, & CPP
− Faster onset of action (<5 min)
CONS: CONS:
− Osmotic diuresis can result in hypotension, − Small volume but can result in volume overload
hyponatremia, and potentially decreased CPP and pulmonary edema in patients with heart
if volume is not replaced failure, as the intravascular load is not
− May increase risk of acute kidney injury counterbalanced with the diuretic effect seen
− Needs to be rewarmed if crystals form with mannitol.
− May result in rebound increase in intracranial − Can result in metabolic acidosis secondary to
pressure hyperchloremia and result in acute kidney
− Not recommended for use in ESRD/anuric injury.
patients
Both require close monitoring of electrolytes, serum osmolarity, and kidney function

195
Practical Tips for Fever/Shivering Management
Avoid hyperthermia: Avoid shivering:
• Arctic sun or blanketrol for target temp of •S
urface counter-warming w/ Bair Hugger
37.5 °C • Dexmedetomidine infusion
• Central fever management: bromocriptine or • Buspirone 30 mg Q8H
scheduled acetaminophen ×72 h (check LFTs) • Magnesium infusion
• Occasional NSAID administration if bleeding risk • Increase sedation
is low and patient is several days from bleed •P
aralytics (should be tried only when other
(always clear with neurosurgery team). interventions fail)

REFERENCES
1. Aries MJ, Wesselink R, Elting JW, Donnelly J, Czosnyka M, Ercole A, Maurits NM, Smielewski
P. Enhanced visualization of optimal cerebral perfusion pressure over time to support clinical
decision making. Crit Care Med 2016;44(10):e996–9.
2. Sorrentino E, Diedler J, Kasprowicz M, Budohoski KP, Haubrich C, Smielewski P, Outtrim JG,
Manktelow A, Hutchinson PJ, Pickard JD, Menon DK, Czosnyka M. Critical thresholds for cere-
brovascular reactivity after traumatic brain injury. Neurocrit Care. 2012;16(2):258–66.
3. Aries MJ, Czosnyka M, Budohoski KP, Steiner LA, Lavinio A, Kolias AG, Hutchinson PJ, Brady
KM, Menon DK, Pickard JD, Smielewski P. Continuous determination of optimal cerebral perfu-
sion pressure in traumatic brain injury. Crit Care Med. 2012;40(8):2456–63.
4. McNett M, et al. Correlations between hourly pupillometer readings and intracranial pressure
values. J Neurosci Nurs. 2017;49(4):229–34.
5. Chen JW, et al. Pupillary reactivity as an early indicator of increased intracranial pressure: the
introduction of the Neurological Pupil index. Surg Neurol Int. 2011;2:82.
6. Ong C, et al. Effects of osmotic therapy on pupil reactivity: quantification using pupillometry in
critically ill neurologic patients. Neurocrit Care. 2019;30(2):307–15.
7. Rajajee V, et al. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit
Care. 2011;15(3):506–15.
8. Carney N, et al. Guidelines for the management of severe traumatic brain injury. Neurosurgery.
2017;80(1):6–15.
9. Helbok R, Olson DM, Le Roux PD, et al. Intracranial pressure and cerebral perfusion pressure
monitoring in non-TBI patients: special considerations. Neurocrit Care. 2014;21:85–94.
10. Lundberg N, Troupp H, Lorin H. Continuous recording of the ventricular-fluid pressure in patients
with severe acute traumatic brain injury: a preliminary report. J Neurosurg. 1965;22(6):581–90.
11. Cook AM, et al. Guidelines for the acute treatment of cerebral edema in neurocritical care patients.
Neurocrit Care. 2020;32(3):647–66.
12. Stevens RD, Shoykhet M, Cadena R. Emergency neurological life support: intracranial hyperten-
sion and herniation. Neurocrit Care. 2015;23(Suppl 2):S76–82. PMID: 26438459.
13. Francony G, et al. Equimolar doses of mannitol and hypertonic saline in the treatment of increased
intracranial pressure. Crit Care Med. 2008;36(3):795–800.
14. Kamel H, et al. Hypertonic saline versus mannitol for the treatment of elevated intracranial pres-
sure: a meta-analysis of randomized clinical trials. Crit Care Med. 2011;39(3):554–9.

196
MANAGEMENT OF EXTERNAL VENTRICULAR CATHETERS
Catherine S. W. Albin and Sahar F. Zafar

External ventricular drains (EVDs) offer an ability to measure ICP in real time and
also allow for treatment of elevated ICP by drainage of CSF.
EVDs or lumbar drains (LDs) may also be used to treat an active CSF leak post-CNS
procedure or craniofacial trauma, or to prevent a CSF leak after a skull-based
procedure.

EVD SETUP
Often placed at the bedside. The catheter is advanced through a drilled hole in the
skull, preferably through the right frontal lobe and ipsilateral lateral ventricle to the
Foramen of Monro (intraventricular foramen). The catheter has holes for CSF
drainage through the last several centimeters. These holes can be visualized in CT
scans when windowed to the bone window (red arrows).

Fig. 34.1 EVD on head CT Brain window and bone window

An opening pressure will be obtained on placement.

Once placed, the EVD pressure transducer
must be leveled by placing it at the level of It is critically important to
the Foramen of Monro, which is approxi- never raise or lower the bed in
mated by the external auditory canal. The a patient with an open EVD as
drip chamber is then set to the prescribed changing the bed in
height, often between 0 and 20 cmH2O relationship to the collecting
determined by the indication. system will effectively lower or
raise the EVD, respectively.
Note: In many hospitals, although the drip
chamber height is set in cmH2O, the sensor
will read in mmHg.
20 cmH2O = 15 mmHg (approximately)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_34
197
CSF will drain whenever the ICP is higher than the prescribed chamber height
pressure. Thus, if the chamber is set at 20 cmH2O, then when the pressure in the
brain is higher than about ~15 mmHg, CSF will flow from the brain into the chamber.
For most EVDs, ICP is only accurately obtained when the EVD is clamped and
the system is opened to the transducer. If there is a number displayed on the
monitor when the EVD is open, it is not an accurate measure of ICP if a standard
EVD is being used.
For waveform interpretation see page 191

FOR PATIENTS WITH EVDS, THINGS TO MONITOR AND REPORT

□□ICP value range
□□ICP waveform
□□Any change in CSF color (blood may signal rebleed, cloudiness could mean
infection, etc.)
□□Daily output from the drain and range of hourly outputs.
° About 400–600ccs of CSF are produced daily. That is about 15–25cc an hour.
As such, if the EVD drains >20cc/hour for multiple hours, there is a risk of
overdrainage. See “Selected Complications” below.
□□ Coagulation status – some hospitals have a formalized protocol for measuring
the PTT or anti-Xa level when patients with an EVD are being treated with DVT
prophylaxis or treatment dose anticoagulation.

SELECTED COMPLICATIONS
□□On placement: tract hemorrhage or placement into brain parenchyma
° Most institutions will use a CT scan to confirm placement and rule out
hemorrhage
□□ Ventriculitis
° May be monitored for by routinely sending CSF for glucose/total protein +/-
culture. A dramatic drop in glucose should raise concern for the development
of bacterial infection.
□□ Over-drainage: Can result in subdural hemorrhage, hygromas, upward hernia-
tion, intracranial hypotension, and pneumocephalus
° In most cases, CSF should not be drained more than 20cc/h to prevent this
complication.

198
MALIGNANT MIDDLE CEREBRAL ARTERY INFARCTION
Catherine S. W. Albin and Sahar F. Zafar

Malignant edema is life-threatening, space occupying edema after massive MCA

infarction. Cerebral edema manifests within the 2 to 7 days and results in herniation
in up to 80% of patients with conservative treatment alone [1].

CT scan in a young patient with MRI DWI in the same patient CT scan of the same patient
a near-full territory MCA infarct. approximately 30 h post stroke shortly after a post-decompressive
Image approximately 24 h from ictus hemicraniectomy (about 34 h
stroke ictus. after ictus) demonstrating
significant extracranial herniation
from severe cerebral edema.
DHC successfully prevented
transtentorial herniation.

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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199
AJOR TRIALS EVALUATING SURGICAL DECOMPRESSION AND DURAPLASTY VS
M
CONSERVATIVE TREATMENT
MAJOR INCLUSIONS/
TRIAL EXCLUSIONS AND METHODS RESULTS DISCUSSION
DESTINY I Sequential design. Enrolled Survival at 6 and Decompressive
[2] (Stroke within 36 h from stroke ictus. 12 months was hemicraniectomy had a
2007) Age 18–60. Baseline mRS 0–1. At 82% in the surgical significant mortality
least 2/3 MCA territory ischemia + group vs. 47% in benefit.
part of basal ganglia. NIHSS >18 the conservative
Trial ended early before
(non-dominant), >20 (dominant). group.
meeting the primary end
Decreased consciousness.
48% of the points because of the joint
Conservative treatment included surgical group analysis of the three
osmotherapy, mechanical ventilation vs. 27% in European trials.
for GCS ≤ 8, ICP monitoring, conservative
sedation, maintenance of treatment group
normothermia, normoglycemia, reached an mRS
normovolemia. score 2–3.

32 patients. 17 in surgery group, The surgical group

15 in the conservative group. Mean had a higher
age 44.6 (range 29–60). Surgical percentage of mRS
group with lower NIHSS (21 vs. 4 & 5 (35% vs.
24). Average time to surgery 20%)
after symptom onset: 24 h, up
to 36 allowed.

200
MAJOR INCLUSIONS/
TRIAL EXCLUSIONS AND METHODS RESULTS DISCUSSION
HAMLET Enrolled within 96 h from stroke Survival at 91% of patients in the
[3] ictus. Age 18–60. Baseline mRS 12 months was surgical group were
(Lancet 0–1. At least 2/3 territory of MCA 78% in the surgical admitted to the ICU vs.
Neurology territory stroke within 96 h prior to group vs. 41% in 16% in the medical
2009) enrollment. NIHSS ≥ 16 the conservative management group.
nondominant, ≥21 dominant. group.
Attempted to analyze
Gradual decrease in consciousness
25% of both groups quality of life. In the
without confounding factors.
had an mRS 2–3. surgical group 78% of
Conservative treatment included patients had symptoms of
The surgical
osmotherapy, mechanical ventilation mild depression on
group had a
for GCS ≤ 8, ICP monitoring, MADRS metric vs. 58% in
larger portion of
sedation, maintenance of medical group (P = 0.22).
patients with
normothermia, normoglycemia,
mRS of 4–5 In both groups, both
normovolemia.
(53% vs. 15%). patients and caregivers
64 patients. 32 surgical, 32 had very low rates of
conservative treatment. Mean age being dissatisfied with
was 50 (surgical) vs. 47 (medical). treatment ≤10% in all
The mean time from symptom groups. 22 of the 38
onset to randomization was survivors had an mRS
41 (surgical) vs. 45 (medical). score of 4 or 5 at 1 year,
NIHSS was not statistically different and all but one was
(23 vs. 24). happy with the treatment
they received.a

201
MAJOR INCLUSIONS/
TRIAL EXCLUSIONS AND METHODS RESULTS DISCUSSION
DECIMAL Enrolled within 24 h. Age 18–55. Survival at In the craniectomy group,
[4] NIHSS >15. Decreased level of 12 months was 67% of survivors were
(Stroke consciousness. >50% of MCA 75% in surgery vs. home 1 year after
2007) territory. DWI volume >145 cm3. 22% in no surgery. treatment. Age was
Baseline mRS 0–1. Patients could Most patients in the significantly correlated
not have received no surgery group with better outcome in the
tPA. Hemicraniectomy had to be died early (within craniectomy group.
done no more than 6 h after 3.1 ± 1.9 days).
randomization (no more than 30 h
50% of patients in
post-stroke)
the surgical group
Conservative treatment mannitol or achieved an mRS of
furosemide only recommended in 2–3 vs. 22%
hernation, ICP monitoring was not achieving an mRS
recommended; sedation, intubation, of 3 in the
maintenance of normothermia, conservative
normoglycemia, normovolemia were treatment group.
at the discretion of treating
physician.

38 patients. 20 surgical, 18
conservative. Mean age/NIHSS
was 43.5/22.5 (surgical) vs.
43.3/23.4 (medical).

202
MAJOR INCLUSIONS/
TRIAL EXCLUSIONS AND METHODS RESULTS DISCUSSION
DESTINY II Enrollees were >60 years old. Survival at After 12 months, 6% of
[5] Enrolled within 48 h of stroke ictus. 12 months was patients >60 had an mRS
(NEJM All were treated in the ICU. NIHSS 57% in the surgical of 3, compared to 43% of
2014) >14 (nondominant), >19 group vs. 24% in younger patients.
(dominant). Decreased level of the medical group.
Early hemicraniectomy
conscionssness. >2/3 of the MCA
6% surgical and 5% significantly increased
territory and at least a portion of
medical achieved an probability of survival but
basal ganglia. Baseline mRS 0–1.
mRS 3. None <3. most survivors had
Conservative treatment: ICU substantial disability.
The surgical
treatment for all patients. At
group had a
physicians’ discretion: osmotherapy,
larger portion of
mechanical ventilation for GCS ≤ 8,
patients with an
ICP monitoring, sedation,
mRS 4–5 (51%
maintenance of normothermia,
vs. 19%). mRS 5
normoglycemia, normovolemia.
was more than
112 patients included. Mean age 2× more
was 70 (range 61–82). Average common in the
NIHSS 20 (surgical) vs. 21 surgery group
(conservative). Mean time from (28% vs. 13%)
onset of symptoms to
hemicraniectomy = 28 h.
a
This is an interesting finding, but as noted in the trial, should be interpreted with caution as the
patient feeling compelled to give the desired answer cannot be excluded as the question was
not predefined

Notes:
The pooled analysis [6] of DESTINY I, HAMLET, and DECIMAL demonstrated that
early hemicraniectomy (w/in 48 h):
–– Increased 1 year survival from 29% to 78%
–– Resulted in a low rate of severe disability (mRS 5): 4%
–– Resulted in a moderate percentage of patients with a good outcome (mRS 2–3):
43% vs. 21%
–– Number needed to treat to obtain a survival of mRS ≤ 3: 4
A recent meta-analysis reviewing seven trials [7] found that there was no evidence of
heterogeneity of treatment outcome based on the presence of aphasia, stroke
severity, age, and involvement of other vascular territories in addition to the MCA. In
regard to age, the positive effect of surgery was smaller and the Confidence Interval
crossed 1. In this meta-analysis, there was a slight favoring of medical treatment for
patients being treated after 48 h.
203
REFERENCES
1. Hacke W, et al. Malignant middle cerebral artery territory infarction: clinical course and prognos-
tic signs. Arch Neurol. 1996;53(4):309–15.
2. Jüttler E, et al. Decompressive surgery for the treatment of malignant infarction of the middle
cerebral artery (DESTINY) a randomized, controlled trial. Stroke. 2007;38(9):2518–25.
3. Hofmeijer J, et al. Surgical decompression for space-occupying cerebral infarction (the
Hemicraniectomy After Middle Cerebral Artery infarction with Life-threatening Edema Trial
[HAMLET]): a multicentre, open, randomised trial. Lancet Neurol. 2009;8(4):326–33.
4. Vahedi K, et al. Sequential-design, multicenter, randomized, controlled trial of early decom-
pressive craniectomy in malignant middle cerebral artery infarction (DECIMAL trial). Stroke.
2007;38(9):2506–17.
5. Jüttler E, et al. Hemicraniectomy in older patients with extensive middle-cerebral-artery stroke. N
Engl J Med. 2014;370(12):1091–100.
6. Vahedi K, Hofmeijer J, Juettler E, et al. Early decompressive surgery in malignant middle
cerebral artery infarction: a pooled analysis of three randomised controlled trials. Lancet Neurol.
2007;6:215–22.
7. Reinink H, et al. Surgical decompression for space-occupying hemispheric infarction: a sys-
tematic review and individual patient meta-analysis of randomized clinical trials. JAMA Neurol.
2021;78(2):208–16.

204
INTRAPARENCHYMAL HEMORRHAGE
Catherine S. W. Albin and Sahar F. Zafar

OMMON ETIOLOGIES OF NON-TRAUMATIC INTRAPARENCHYMAL HEMORRHAGE

C
BY LOCATION

Note that bleeding related to vascular malformations and hemorrhagic conversion of

ischemic strokes can occur at all sites.

Intraacerebral hemorrhage

“Deep” (basal ganglia, “Lobar” (cortical and

Cerebellar Brainstem
internal capsule) subcortical)

CAA (much more likely

Hypertension Hypertension Hypertension
with increasing age)

Hemorrhagic metastasis
Hemorrhagic
(frequently @ gray-white
metastasis
junction)

Venous sinus thrombosis

Endocarditis (septic
emboli)

Hypertension

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_36
205
IMAGING EXAMPLES

CT scan demonstrating a basal SWI MRI demonstrating multiple CT scan of patient with cortical
ganglia hemorrhage secondary features of cerebral amyloid venous sinus thrombosis. Note
to long-standing poorly angiopathy: cortical bleeds, the cortical location with
controlled hypertension microhemorrhages, and surrounding hypodensity
superficial siderosis (representing a combination of
vasogenic and cytogenic edema)

CT scan in patient with mitral MRI T2 FLAIR of hemorrhagic CT scan demonstrating pontine
valve endocarditis and multiple cerebellar metastasis hemorrhage secondary to
mycotic aneurysms. Bleed likely long-standing poorly controlled
due to hemorrhagic hypertension
transformation of septic embolic
infarct

206
EARLY MANAGEMENT [1]
□□Somnolence common, assess need for
intubation (GCS ≦8) For tPA-Related Bleeding:
□□ Consider need for external ventricular
□□
Hold tPA
drain, hemicraniectomy, or other
surgical intervention in discussion with
□□
STAT CBC, PT, PTT,
fibrinogen, and D-dimer
□□
neurosurgery – see Trials, page 211
Confirm SBP < 140 vs 1601 – see
□□
Type and Screen and if
systemic bleeding,
Trials, page 211
□□ Confirm received reversal of anticoagu-
cross match
□□
Once ICH confirmed,
lation, if applicable (see page 215)
□□ Review head CT
see page 215 for
□□ Review or order CT angiogram based
reversal strategies
on potential etiology, review images to
look for a “spot sign” (Fig. 36.1) or a vascular malformation
□□ Confirm that the patient is ordered for stability imaging2
□□ Consider if a conventional angiogram should be pursued (young/atypical
pattern/unexplained bleed)
□□ Consider need for CT venogram vs MRI w/ and w/o + MR venogram if high
concern for venous sinus thrombosis
□□ Review EKG

LABS TO REVIEW OR ORDER

□□Coagulants, CBC, BMP, LFTs, type and Who Should Get an
screen, urine toxicology/serum toxicology External Ventricular Drain?
□□Review glucose, aim for <180 No trials, consider in:
• Significant IVH, espe-
DMISSION CHECKLIST: CONFIRM PATIENT
A
cially in the third and/or
ORDERED FOR
fourth ventricle
□□Repeat stability scan, if not completed yet • Evidence of hydrocephalus
□□Anti-hypertensive (infusion medication
preferred)
□□No chemical DVT ppx for at least 24–48 h
□□PRNs for hyperglycemia, fevers, constipation,
sedation, ventilation as appropriate
□□PT/OT/SLP
ONGOING MANAGEMENT
□□Consider MRI w/ and w/o gadolinium for further etiology evaluation
□□Consider utility of IT tPA in patients with significant IVH, see Trials, Page 211
1
Threshold institution-dependent, see INTERACT/ATACH (page 211).
2
Institutional preference varies, from 6 to 24 h reasonable given clinical concern for bleed expansion.

207
SCORING SYSTEMS [3–5]

ICH Score FUNC Score

GCS score: ICH volume:
3–4: 2 points <30 cm3: 4 points
5–12: 1 point 30–60 cm3: 2 points
13–15: 0 points >60 cm3: 0 points

ICH volume: Age:

≥ 30 cm3: 1 point <70: 2 points
<30 cm3: 0 points 70–79: 1 point
>79: 0 points
IVH:
Yes: 1 point ICH location:
No: 0 points Lobar: 2 points
Deep: 1 point
Infratentorial origin of ICH: Infratentorial: 0 points
Yes: 1 point
No: 0 points GCS score:
≥ 9: 2 points
Age: <9: 0 points
Age ≧ 80: 1 point
Age < 80: 0 points Pre-ICH Cognitive Impairment
No: 1 point
ICH scores & Mortality Risk: Yes: 0 points
0 points: 0%
1 point: 13% % Func. Indep. @ 90 Days (all/survivors):
2 points: 26% Score: % (all) % (survivors)
3 points: 72% 0–4: 0 0
5–7: 13 29
4 points: 97%
8: 42 48
5 points: 100% 9–10: 66 75
6 points: 100% (estimated) 11: 82 95

208
Boston Criteria for Cerebral Amyloid Angiopathy:
Definite cerebral amyloid angiopathy:
Full post-mortem examination reveals lobar, cortical, or cortical/subcortical
hemorrhage and pathological evidence of severe CAA
Probable cerebral amyloid angiopathy (w/ pathological evidence):
Clinical data and pathological tissue demonstrate a hemorrhage and some
degree of vascular amyloid deposition. Does not have to be post-mortem.
Probable cerebral amyloid angiopathy:
Pathological confirmation not required
• Patient older than 55 years
• Appropriate clinical history
• MRI findings demonstrate multiple hemorrhages of varying sizes/ages with no
other explanation
Possible cerebral amyloid angiopathy:
• Patient older than 55 years
• Appropriate clinical history
• MRI findings reveal a single lobar, cortical, or cortical/subcortical hemor-
rhage w/o another cause, multiple hemorrhages with a possible other cause,
or some hemorrhage in an atypical location

NOTES ON SCORING SYSTEMS

Volume is calculated with A (length) × B (width) × [(#number of slices bleed is seen
on CT)/4 (if CT scan slices are 0.5 cm)]
The prognostic variables for the ICH score were derived in patient population in
whom withdrawal of life support was allowed, which raises concern for a self-fulfilling
prophecy in patients who were felt likely to have a poor prognosis. Subsequent
studies have raised the possibility that when maximally aggressive care is pursued,
in patients with a very poor predicted outcome (GCS ≦8 and hematoma >60 cm3),
they may survive hospitalization and be discharged to rehabilitation facilities [6].

209
Fig. 36.1 A “Spot Sign” – the appearance of contrast density within the hematoma bed which is a
concern for ongoing active extravasation of contrast – is seen here in a patient with a large basal
ganglia hemorrhage

REFERENCES
1. Hemphill JC III, et al. Guidelines for the management of spontaneous intracerebral hemorrhage:
a guideline for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2015;46(7):2032–60.
2. Wada R, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral
hemorrhage. Stroke. 2007;38(4):1257–62.
3. Hemphill JC, et al. The ICH score. Stroke. 2001;32(4):891–7.
4. Rost NS, et al. Prediction of functional outcome in patients with primary intracerebral hemor-
rhage: the FUNC score. Stroke. 2008;39(8):2304–9.
5. Knudsen KA, et al. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston
criteria. Neurology. 2001;56(4):537–9.
6. Becker KJ, Baxter AB, Cohen WA, Bybee HM, Tirschwell DL, Newell DW, Winn HR, Longstreth
WT Jr. Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies.
Neurology. 2001;56(6):766–72. https://doi.org/10.1212/wnl.56.6.766. PMID: 11274312.

210
INTRACRANIAL HEMORRHAGE – LANDMARK TRIALS
Catherine S. W. Albin and Sahar F. Zafar

TRIAL TRIAL DESIGN MAJOR FINDINGS

INTERACT-2 Patients with ICH with SBP between 150– The rate of death or disability in
(NEJM 2015) 220 within 6 h of symptom onset were aggressively managed BP group was
[1] randomized to intensive BP control (goal nonsignificantly lower than pts with
SBP < 140 within 1 h) or SBP < 180 target SBP < 180.

Goal was reduction in death or disability At 1 h, the mean systolic blood
(mRS 3–6) at 90 days. 2839 patients, 1403 pressure was 150mmHg in the
to early intensive treatment, 1436 to usual intensive treatment group. (33%
care. The mean interval between symptom achieved the target <140) vs.
onset and randomization was ~4 h. 164mmHg in the standard treatment
group. Primary treatment failure was
seen in 66% of the participants within
1 h after randomization.

>50% of patients in both groups had

a poor outcome of either death or
mRS 3–5.
ATACH-2 Patients with ICH < 60 cm3 and GCS > 5 No significant difference in death or
(NEJM 2016) with SBP ≥ 180 within 4.5 h of symptom disability.
[2] onset were randomized to intensive BP
Note that >50% of patients had
control (SBP 110–139) or SBP140–179.
favorable clinical characteristics
Goal was reduction in death or disability (initial GCS of 15). Treatment failure
(mRS 4–5) at 3 months. 1000 patients, 500 was seen in 12.2% patients at 2 h.
to the intensive treatment group. The mean The mean minimum BP in the
interval between symptom onset and treatment group for the first 2 h was
randomization was ~3 h. 129 vs. 141 in the standard care
group. Post hoc comparison showed
a higher rate of renal adverse events
within 1 week after randomization in
the intensive treatment group

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_37
211
TRIAL TRIAL DESIGN MAJOR FINDINGS
STICH II Parallel-group trial. Patients with 10–100 cc No significant difference in GOSE at
(Lancet 2012) ICH not due to vascular malformation or 6 months in patients treated with
[3] tumor, bleeds ≤1 cm from cortex, GCS ≥ 8, early surgery vs. patients treated with
no IVH, and <48 h from ictus were initial conservative treatment. 57% of
randomized to early clot evacuation (w/in surgical patients vs. 51% medical
12 h of randomization) + med tx or patients attained a mRS < 4. Only
conservative med tx (w/ option for late subgroup to show possible benefit
surgery). were patients with a predicted “poor
prognosis” based on GCS and
Primary outcome was GOSE at 6 months.
hemorrhage characteristics but yet
601 patients in 27 countries. Median age
still met inclusion criteria.
was 65 (17–94). Method of evacuation was
craniotomy in 98% of cases. Most patients Note, significant (21%) crossover
had small (~30 cc) hemorrhages and 50% from the conservative treatment group
had a GCS of 14–15 at randomization to receive delayed surgery, which
may have diluted the mortality
benefit.
MISTIE III Open-label, blinded endpoint, international. No improvement in functional
(Lancet 2019) Patients >18 with spontaneous supratentorial outcome but >40% of patients
[4] ICH (either deep or lobar) >30 cc achieved a good functional outcome,
randomized to minimally invasive surgery 80% were at home or in active
with thrombolytic irrigation of catheterized rehabilitation centers, which was
ICH clot vs usual care. The irrigation catheter higher than expected. Hypothesis for
was left in the clot postoperatively and as this better-than-predicted recovery
early as 6 h later 1 mg alteplase was included low withdrawal of care, ICU
administered q8H for up to 9 doses. 24 h CT care, stability in hematoma growth.
scans were completed
Analysis suggested that clot reduction
Goal was functional outcome improvement at to ≤15 cc was associated with better
1 year and safety assessment. 506 adults mRS at 1 year. Number of CNS
(median age 62) were randomized once the infections and symptomatic bleeds
hematoma had stabilized (median time 47 h) was 2% vs. 1%.

212
TRIAL TRIAL DESIGN MAJOR FINDINGS
CLEAR Randomized, multicenter, double-blind, At 180 days the treatment group had
IVH-III placebo-controlled. Patients with ICH <30 cc lower mortality 18% vs 29%;
(Lancet 2017) with IVH obstructing the third or fourth however more patients with severe
[5] ventricle. Patients were screened for EVD disability (17% vs. 9%). Rates of
tract hemorrhage and if none present at symptomatic bleeding, ventriculitis
6–12 h post-placement, patients were and serious adverse events were not
randomized to received rtPA vs. normal statistically different.
saline infusions. Excluded if coagulopathy or
Failed to improved outcomes to the
confirmed/suspicion of aneurysm, AVM,
cutoff of mRS 3 at 180 days, but rtPA
other vasc malformation.
did not have appear to have
Treatment was up to 12 doses of 1 mg significant adverse events.
alteplase q8h. CT scans were obtained every
Subgroup analysis failed to show any
24 h.
treatment benefit in patients with
Goal was improved outcome (mRS < 4) at thalamic hemorrhage or those with
180 days. 500 patients included. 249 IVH < 20 cc
alteplase vs. 251 saline.

CT scan on day 1 from a patient who was then CT scan of the same patient on day 5 which
treated with eight doses of intrathecal tPA per demonstrates significant reduction in IVH and
CLEAR trial guidelines (Q8H doses after hydrocephalus.
stabilization of bleeding and no evidence of EVD
tract hemorrhage).

213
REFERENCES
1. Anderson CS, et al. Rapid blood-pressure lowering in patients with acute intracerebral hemor-
rhage. N Engl J Med. 2015;368(25):2355–65.
2. Qureshi AI, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage.
N Engl J Med. 2016;375(11):1033–43.
3. Mendelow AD, et al. Early surgery versus initial conservative treatment in patients with spon-
taneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. Lancet.
2013;382(9890):397–408.
4. Hanley DF, et al. Efficacy and safety of minimally invasive surgery with thrombolysis in intra-
cerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded
endpoint phase 3 trial. Lancet. 2019;393(10175):1021–32.
5. Hanley DF, et al. Thrombolytic removal of intraventricular haemorrhage in treatment of severe
stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial.
Lancet. 2017;389(10069):603–11.

214
REVERSAL OF SELECTED ANTITHROMBOTICS
Catherine S. W. Albin and Megan E. Barra

Anti-platelet agents [1]

Aspirin Desmopressin: Can consider A recently published matched cohort study
ADP- 0.4mcg/kg IV x1 for aspirin or showed that DDAVP for antiplatelet-
inhibitors ADP-inhibitor related bleed. This associated ICH was not associated with a
(Clopidogrel, can be given in addition to reduction in poor outcomes or hematoma
Ticagrelor, platelets, if being used. expansion. Use appeared to be safe [2].
Prasugrel)
Platelet transfusion: One unit PATCH trial (Lancet 2016): twofold increase
can be considered if patient in odds of death or dependence at
undergoing neurosurgical 3-months in the PLT transfusion group.
procedure (craniotomy/EVD). If Patients on ADP-inhibitors were
possible, obtain platelet function underrepresented (~2.6% of all patients).
testing before transfusion and only Platelet transfusions are not recommended
transfuse those without normal for routine use [3].
function

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_38
215
Oral anticoagulants [1, 4–8]
Warfarin Vitamin K: 10 mg IV Peak effect not observed for up to 12–24 h.
if INR ≥ 1.4 Should be co-administered with 4F-PCC if
immediate reversal required

Daily INRs should be checked as one dose

may not be enough to create a durable the
risk decrease in INR and a second dose
may be warranted
4F-PCC (KCentra): Baseline STAT INR at time of administration.
Weight-based protocol: Repeat STAT INR 30-min after
Baseline INR 2–3.9: 25 IU/kg administration.
(maximum 2500 units) Duration of action is 6–8 h, must
Baseline INR 4–6: 35 IU/kg coadminister with vitamin K if sustained
(maximum 3500 units) reversal required.
Baseline INR > 6: 50 IU/kg
Kcentra contains heparin. Do not give if
(maximum 5000 units)
history of heparin-induced
*4F contains factor VII in addition
thrombocytopenia.
to II, IX, X
Fixed dose protocols of 1500–2000 IU
Fixed dose protocol: have been shown to be effective for INR
1500–2000 IU ×1 correction and allowed for more rapid
*If a fixed dosing strategy is used, administration by eliminating need for dose
check a repeat STAT INR 30-min calculations and product selection [9–14].
after administration and if not at
4F-PCC, compared to FFP, was found to
goal ≤1.4, may give remainder of
have faster time to INR correction, 7× faster
calculated weight-based regimen
administration, and ~85% less volume
patient would have otherwise
required for administration, with equal
received based on baseline INR
hemostatic efficacy in the Acute Major
Bleeding Trial and superior hemostatic
efficacy in the Urgent Surgery/Invasive
Procedures Trial [15, 16].
Or, if 4F-PCC unavailable: Downside of this therapy includes larger
Fresh Frozen Plasma: volume of transfusion and longer time to
INR 2–3.9: 10 cc/kg correction. Transfusion-related
INR 4–6: 12 cc/kg complications (TRALI/TACO).
INR >6: 15 cc/kg
Must coadminister with vitamin K if
sustained reversal required.

216
Dabigatran First line: Idaracizumab Baseline STAT aPTT, 2–4 h, and 12–24 h
(Praxbind): 5 g IV administered post administration dTT or TT may be
as two sequential 2.5 g IV infusions helpful in quantifying presence of clinically
no more than 15 min apart significant dabigatran levels in patients with
unknown last administration time or
If Idaracizumab unavailable
ongoing hemorrhage, if readily available
4F-PCC or aPCC: 50 IU/kg (max
dose 5000 IU) In clinical trials, a small proportion of
patients were found to have rebound of
Reversal should be done if the last
dabigatran levels ≥12 h after
dose was administered within 3–5
administration, which was associated with
half-lives (e.g. past 2–4 days).
recurrent or continuous bleeding. This is
Longer if moderate-severe renal
due to re-distribution from adipose tissue
insufficiency. Elevated TT or dTT
after reversal of dabigatran. Patients with
can signify presence of clinically
renal dysfunction at highest risk for
significant dabigatran levels if
phenomenon. May consider re-dosing
unknown last administration
idarucizumab if ongoing hemorrhage or
need for emergent procedures with
abnormal coagulation labs [17].
Apixaban, Andexanet alfa: Baseline anti-Xa for UFH and LMWH may
rivaroxaban Indicated for reversal of apixaban be helpful in ruling out presence of
or rivaroxaban if last dose within clinically significant rivaroxaban- or
previous 18 h: apixaban-levels if undetectable in patients
with unknown last administration time.
Time since last dose
FXa inhibitor Last dose
<8 h or
Or, baseline DOAC-specific anti-Xa levels if
8 –18 h

<10 mg
unknown
Low dosea
readily available
Rivaroxaban >10 mg or
High doseb
unknown
Low dosea Andexanet alfa:
<5 mg Low dosea
Apixaban >5 mg or
High doseb
Short duration of action. Rebound
unknown
a
Andexanet alfa low dose regimen: initial IV bolus 400 mg anticoagulation observed within 2-h of
infused at a target rate of 30 mg/min followed by a 4 mg/min
continuous intravenous infusion for up to 120 min cessation of IV infusion to levels observed in
b
Andexanet alfa high dose regimen: initial IV bolus 800 mg
infused at a target rate of 30 mg/min followed by a 8 mg/min patients not reversed with andexanet alfa.
continuous intravenous infusion for up to 120 min
Best used in patients with acute
hemorrhages at high risk for hematoma
Alternative: 4F-PCC 25–50
expansion.
IU/kg (max dose 5000 IU)
4F-PCC:
No standardized dosing available, most
guidelines recommend 50 IU/kg, though
lower dose regimens (25–37.5 IU/kg) have
been increasingly reported with similar
hemostatic effectiveness rates

217
Edoxaban Andexanet alfa: High-dose Baseline anti-Xa for UFH and LMWH may
regimen (off-label) be helpful in ruling out presence of
Initial IV bolus 800 mg infused at a clinically significant rivaroxaban or
target rate of 30 mg/min followed apixabanlevels if undetectable in patients
by a 8 mg/min continuous with unknown last administration time.
intravenous infusion for up to 120
Edoxaban underrepresented in studies
Alternative: 4F-PCC 25–50 evaluating safety and efficacy of andexanet
IU/kg alfa. High-dose regimen is recommended.
Parenteral anticoagulants [1]
Unfractionated Protamine 1 mg/100 units of Re-check STAT aPTT 15 min after protamine
heparin heparin administered in past 3 h, administration, if aPTT remains elevated,
max single dose 50 mg repeat 0.5 mg/100 units of heparin
administered in previous 3 h.
Reversal for prophylactic dosing not
recommended
Enoxaparin Last enoxaparin Re-check STAT aPTT 2–4 h after protamine
administration Protamine Dose

1 mg protamine per 1 mg
administration. If aPTT remains elevated or
<8 h
enoxaparin*
ongoing significant bleeding, repeat
0.5 mg protamine per 1 mg
>8 h
enoxaparin* 0.5 mg/1 mg enoxaparin.
*Max single dose 50 mg
Protamine does not completely neutralize
anti-Xa activity (maximum neutralization
60–75%).
Reversal for prophylactic dosing not
recommended
Fondaparinux aPCC: 20 IU/kg Reversal for prophylactic dosing not
If unavailable: rFVIIa: 90 mcg/kg recommended
×1

218
Fibrinolytics [18]
Recombinant Stop infusion immediately. Reverse Baseline STAT Fibrinogen *do not wait for
tissue if within 24 h of rtPA infusion. lab to result to administer cryoprecipitate*
plasminogen Repeat fibrinogen 30 min- 1 h after
Cryoprecipitate: Potential benefit
activator (rtPA) administration and every 2 h until bleeding
in all patients
controlled
• Empiric administration of
10 units in all patients
• Repeat dose until fibrinogen
≥150 mg/dL

Antifibrinolytic agents: May

be considered in all patients; can
be of benefit in patients with
contraindications or religious
exemptions to blood products
• Tranexamic acid 10 mg/kg
IV, may repeat q8h for ongoing
bleeding
• Aminocaproic acid 4–5 g IV
bolus followed by 1 g/h for 8 h

Platelets: May consider if

PLT < 100,000/mcL

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in patients on antiplatelet therapy. Journal of the Neurological Sciences. 2022:120142.
3. Baharoglu MI, Cordonnier C, Salman RA, et al. Platelet transfusion versus standard care after
acute stroke due to spontaneous cerebral hemorrhage associated with antiplatelet therapy
(PATCH): a randomised, open-label, phase 3 trial. Lancet. 2016;387(10038):2605–13.
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line and expert panel report. Chest. 2018;154(5):1121–201.
5. Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for man-
agement of venous thromboembolism: optimal management of anticoagulation therapy. Blood
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6. Tomaselli GF, Mahaffey KW, Cuker A, et al. 2020 ACC expert consensus decision pathway on
management of bleeding in patients on oral anticoagulants: a report of the American College of
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2019;140(2):e125–51.
8. Christensen H, Cordonnier C, Kõrv J, et al. European Stroke Organisation guideline on reversal
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9. Varga C, Al-Touri S, Papadoukakis S, Caplan S, Kahn S, Blostein M. The effectiveness and safety
of fixed low-dose prothrombin complex concentrates in patients requiring urgent reversal of war-
farin. Transfusion. 2013;53(7):1451–8.
10. Klein L, Peters J, Miner J, Gorlin J. Evaluation of fixed dose 4-factor prothrombin complex. con-
centrate for emergent warfarin reversal. Am J Emerg Med. 2015;33(9):1213–8.
11. Hirri HM, Green PJ. Audit of warfarin reversal using a new Octaplex reduced dose protocol.
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12. Khorsand N, Veeger NJ, van Hest RM, Ypma PF, Heidt J, Meijer K. An observational, prospec-
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2012;97(10):1501–6.
13. Khorsand N, Veeger NJ, Muller M, et al. Fixed versus variable dose of prothrombin complex con-
centrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21(2):116–23.
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15. Goldstein JN, Refaai MA, Milling TJ, et al. Four-factor prothrombin complex concentrate ver-
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16. Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex
concentrate in patients on vitamin K antagonists presenting with major bleeding: a randomized,
plasma-controlled, phase IIIb study. Circulation. 2013;128(11):1234–43.
17. Pollack CV, Reilly PA, van Ryn J, et al. Idarucizumab for dabigatran reversal—full cohort analysis.
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18. Yaghi S, Willey JZ, Cucchiara B, et al. Treatment and outcome of hemorrhagic transformation
after intravenous alteplase in acute stroke: a scientific statement for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke. 2017;48:e343–61.

220
AN IN-DEPTH REVIEW OF REVERSING DIRECT FACTOR
XA-INHIBITOR-RELATED HEMORRHAGES
Megan E. Barra

Indications for Factor-Xa inhibitor reversal: Life-threatening hemorrhage

defined as:
• Critical site bleeding (ICH or other CNS hemorrhage, pericardial tamponade,
airway or posterior epistaxis, hemothorax, intraabdominal, retroperitoneal, intra-
muscular, and intraarticular hemorrhage).
• Major bleeding that is nonresponsive to supportive care measures.

BACKGROUND
• In landmark clinical trials for DOAC therapy, incidence of ICH was 0.51% and
ICH-mortality ranged from 45.3% (apixaban) to 48% (rivaroxaban) before reversal
agents were available [1, 2].
• Withholding reversal in DOAC-associated ICH has been associated with 1.5-fold
increased risk of death and worse functional outcomes [3].

FACTOR-XA INHIBITOR REVERSAL THERAPY USED IN CLINICAL PRACTICE

Andexanet Alfa (FDA-Approved for Rivaroxaban and Apixaban Reversal)

• Mechanism of action: binds to and sequesters Factor-Xa inhibitors with high affinity.
Also found to inhibit activity of tissue factor pathway inhibitor (TFPI) resulting in an
increase in tissue factor-initiated thrombin generation.

ANNEXA-4 TRIAL [4]

Inclusion Patients with major bleeding within 18 hours of last known administration of oral
factor-Xa inhibitor, ICH patients represented 64% of enrollment
Laboratory 92% reduction in anti-factor Xa activity
normalization Rebound anticoagulation after cessation of continuous infusion
Hemostatic 80% patients with ICH had good or excellent hemostatic effectiveness (≤ 35%
effectiveness expansion)
Thromboembolic 10% 30-day thromboembolic event rate
events
Mortality 14% 30-day mortality across all patients

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C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_39
221
ANNEXA-4 TRIAL [4]
Comments • Major criticisms of this trial include lack of a comparator arm and exclusion of
patients with severe intracranial hemorrhages (GCS score <7, hematoma
volume >60 cc), expected survival <1-month, thromboembolic events within
previous 2 weeks, or were going to have surgery within 12 hours that may
have bias the results towards a better outcome.
• Short duration of action only provides ~4 hours of factor Xa
inhibitor reversal.
• Associated with significantly high costs ($33,000 – $60,000/therapy) with
unclear benefit over PCC in clinical outcomes.

PCC (Off-Label Use)

• Mechanism of action: replenishment of coagulation factors resulting in increased
thrombin generation.
• In vitro data suggest dose-dependent partial to complete reversal on coagulation
parameters [5, 6].
• Observational data of variable dosing schemes most commonly between 25–50 IU/
kg report ICH hemostatic effectiveness ranging from 60–100% [7–12].
• Largest observational study to date on PCC:

FIX-ICH OBSERVATIONAL STUDY [13]

Inclusion 433 patients with spontaneous or traumatic ICH were assessed for hemostatic
efficacy and 663 for safety of PCC administration
Laboratory Not assessed
normalization
Hemostatic 81.8% good or excellent hemostatic effectiveness (≤35% hematoma expansion)
effectiveness
Thromboembolic 3.8% thromboembolic events
events
Mortality 12.2% in-hospital mortality
Comments • Major critiques of this study include its observational study design, baseline
hematoma volume not reported, time since last rivaroxaban or apixaban
administration not available.
• Variable dosing of PCC (median 4F-PCC dose 43.8 IU/kg [IQR 25.6–49.8]
and aPCC 26.7 IU/kg [IQR 23.8–48.3]).
• ~1/3 patients excluded for not having at least 1-follow up image within first
24 hours after PCC administration

• Major criticisms of PCC data include majority observational retrospective studies,

lack of a comparator arm, variability in definitions of hemostatic effectiveness,
variation in dosing, and reported baseline risk factors or presentation severity
between observational studies.
• Lower cost comparatively (~$5000 – $15,000).

222
The decision about which agent (andexanet alfa vs PCC) for Factor Xa inhibitor
reversal is often guided by which agent is available on hospital formulary.

REFERENCES
1. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with
major bleeding in patients with atrial fibrillation treated with apixaban or warfarin: insights from the
ARISTOTLE trial. Eur Heart J. 2015;36(20):1264–72.
2. Piccini JP, Garg J, Patel MR, ROCKET AF Investigators, et al. Management of major bleeding
events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur
Heart J. 2014;35(28):1873–80.
3. Apostolaki-Hansson T, Ullberg T, Pihlsgard M, Norrving B, Petersson J. Reversal treatment
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4. Connolly SJ, Crowther M, Eikelboom JW, et al. ANNEXA-4 investigators. Full study report of andex-
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5. Barco S, Whitney CY, Coppen M, et al. In vivo reversal of the anticoagulant effect of rivaroxaban
with four-factor prothrombin complex concentrate. Br J Haematol. 2016;172(2):255–61.
6. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by
prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy
subjects. Circulation. 2011;124(14):1573–9.
7. Majeed A, Ågren A, Holmström M, et al. Management of rivaroxaban- or Apixaban-
associated major bleeding with prothrombin complex concentrates: a cohort study. Blood.
2017;130(15):1706–12.
8. Gerner ST, Kuramatsu JB, Sembill JA, et al. Association of prothrombin complex concentrate
administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related
intracerebral hemorrhage. Ann Neurol. 2018;83(1):186–96.
9. Schulman S, Gross PL, Ritchie B, et al. Prothrombin complex concentrate for major bleeding on
factor Xa inhibitors: a prospective cohort study. Thromb Haemost. 2018;118(5):842–51.
10. Wilsey HA, Bailey AM, Schadler A, et al. Comparison of low- versus high-dose four-factor pro-
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11. Castillo R, Chan A, Atallah S, et al. Treatment of adults with intracranial hemorrhage on apixa-
ban or rivaroxaban with prothrombin complex concentrate products. J Thromb Thrombolysis.
2021;51(1):151–8.
12. Lipari L, Yang S, Milligan B, et al. Emergent reversal of oral factor Xa inhibitors with four-factor
prothrombin complex concentrate. Am J Emerg Med. 2020;38(12):2641–5.
13. Panos NG, Cook AM, John S, et al. Factor Xa inhibitor-related intracranial hemorrhage: results
from a multicenter, observational cohort receiving prothrombin complex concentrates. Circulation.
2020;141(21):1681–9.

223
INTRACRANIAL HEMORRHAGE – MANAGEMENT
OF ANTICOAGULATION
Juan Carlos Martinez Gutierrez

EARLY MANAGEMENT
Hematoma expansions occur in 14–38%, most happen in first hour (26%) and first
day (12%) and rarely in subsequent 2 weeks (<2%).
Factors associated with expansion [1].
–– Liver dysfunction (18.3% higher incidence).
–– Spot sign (77% expand when present, 96% do not expand when absent) [2].
–– Hematoma volume <20 cc (8.2%) vs. >20 cc (31.5%).
–– Irregular shape (13.2% higher incidence).
–– Antithrombotics.
All antithrombotics should be held and reversed (if applicable) in the first
24 hrs (see page 215 for reversal agents).
DVT Prevention:
□□
Start pneumoboots on admission. DVTs can occur in 17–40.4% of ICH patients
without prophylaxis and only 6.7% with boots [3, 4].
□□Chemical DVT prophylaxis can be started 24–48 after bleed stability is con-
firmed, if there are no other contraindications (elevated INR, low plts, etc.).

SUBACUTE AND LATE MANAGEMENT

Overall, the risk of rebleed depends on the etiology of the index event, location
of the bleed, and MRI findings (microbleeds, superficial siderosis, and leukoara-
iosis). Although there are multiple etiologies for IPH, the risk of rebleed after two most
common primary etiologies – CAA (lobar) and HTN (deep) – will be reviewed here.
Secondary ICHs – those due to vascular malformations, trauma, VST, etc. – have
different risks of recurrence.
Hypertensive Hemorrhage (Deep, Brainstem, Cerebellar):
–– Without anticoagulation use, the annual risk of recurrence is 2–4% (most hap-
pen within 2 years), a second recurrence is rare [5, 6]. Optimizing BP is crucial
to lower the long-term risk.
–– In multivariate analysis [7], anticoagulation resumption after non-lobar ICH was
associated with decreased mortality (hazard ratio [HR] = 0.25; 95%
CI = 0.14–0.44, p < 0.0001) and improved functional outcome (HR = 4.22; 95%
CI = 2.57–6.94, p < 0.0001).
–– The ASA Stroke Guidelines support resumption of anticoagulation on a case-by-
case basis [8].

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

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225
Cerebral Amyloid Angiopathy (Lobar, See Boston Criteria Page 209):
–– Without anticoagulation use the annual risk of recurrence ~15% [9].
–– Cortical superficial siderosis (cSS) is present in 60.5% of CAA patients [10] and
implies increased risk of lobar ICH over a 4-year period [11].
–– In a decision analysis “Do not anti-coagulate” optimized Quality Adjusted Life
Years among patients with atrial fibrillation [9].
–– Traditionally anticoagulation is NOT resumed in these patients.
Microbleeds
–– Meta-analysis data suggests infarct risk is higher than bleed risk after a stroke/
TIA in pts with microbleeds [12].
° Stroke/TIA pts with lobar cortical microbleeds (CMB) had incidence of 9.3% of
infarct vs. 3.6% (absolute event rate) for ICH.
° However, note that the risk of ICH increases with the amount of cortical
microbleeds.

DATA ABOUT RISK OF RECURRENT ICH WITH DIFFERENT ANTITHROMBOTICS

DRUG DATA ABOUT RISK OF ICH
Warfarin CHIRONE study of warfarin use after ICH showed rebleed rate of 7.5% with high
fatality rate in bleeders (25%) [13].
Aspirin Safe monotherapy. There is a presumed risk of ICH with any blood thinner - including
aspirin, but for aspirin the risk appears to be the same in patients with or without a
prior ICH [14, 15]. When added to warfarin, increases the bleeding risk.
DOACS Moderate risk (limited data). Large non-ICH meta-analysis [16] showed
lower ICH rate in the DOAC vs. warfarin (RR 0.48). In RE-LY, warfarin vs.
dabigatran, the ICH risk was 0.36%/year vs. 0.09%/year, but mortality from ICH
was the same [17].

TIMING OF RESUMPTION
Still undefined. In one study of 59 patients that restarted anticoagulation after ICH,
the combined risk of recurrent intracranial hemorrhage or ischemic stroke reached a
nadir if warfarin was resumed after approximately 10–30 weeks [18].
Clinical practice varies though, and many experts would resume anticoagulation at
1–2 months post-bleed depending on the reason to need anticoagulation.

226
Take Away Recommendations for Management
–– Whenever possible, obtain MRI to assess for CMB, cSS, and leukoaraiosis
to help risk-stratify.
–– Whenever possible, consider devices that would limit the need for life-long
pharmacologic anticoagulation such as a WATCHMAN device (AF) or IVC
filter (VTE).
–– For hypertensive/deep hemorrhages, restarting anticoagulation when nec-
essary can be considered; DOACs are preferable.
–– In patients with suspected CAA, anticoagulation is usually not resumed for
atrial fibrillation; PE and DVTs must be evaluated on a case-by-case sce-
nario. If needed DOAC use is likely preferable.

REFERENCES
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2009;80:51–7.
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hemorrhage. Stroke. 2007;38:1257–62.
3. Ogata T, et al. Deep venous thrombosis after acute intracerebral hemorrhage. J Neurol Sci.
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4. Dennis M. Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein
thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled
trial. Lancet. 2013;382:516–24.
5. Bae H, et al. Recurrence of bleeding in patients with hypertensive intracerebral hemorrhage.
Cerebrovasc Dis. 1999;9:102–8.
6. Vermeer SE, Algra A, Franke CL, Koudstaal PJ, Rinkel GJE. Long-term prognosis after recovery
from primary intracerebral hemorrhage. Neurology. 2002;59:205–9.
7. Biffi A, et al. Oral anticoagulation and functional outcome after intracerebral hemorrhage. Ann
Neurol. 2017;82:755–65.
8. Hemphill JC III, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontane-
ous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2015;46:2032–60.
9. Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated
after intracerebral haemorrhage? A decision analysis. Stroke. 2003;34:1710–6.
10. Zhang H, et al. Prevalence of superficial Siderosis in patients with cerebral amyloid Angiopathy.
Neurology. 2010;74:1346–50.
11. Charidimou A, et al. Cortical superficial siderosis and intracerebral hemorrhage risk in cerebral
amyloid angiopathy. Neurology. 2013;81:1666–73.
12. Wilson D, et al. Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and
TIA. Neurology. 2016;87(14):1501–10.
13. Poli D, et al. Recurrence of ICH after resumption of anticoagulation with VK antagonists:
CHIRONE Study. Neurology. 2014;82:1020–6.
14. Gorelick PB, Weisman SM. Risk of hemorrhagic stroke with aspirin use: an update. Stroke.
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5. Viswanathan A, et al. Antiplatelet use after intracerebral hemorrhage. Neurology. 2006;66:206–9.
1
16. Ruff CT, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in
patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–62.
17. Hart RG, et al. Intracranial hemorrhage in atrial fibrillation patients during anticoagulation with
warfarin or dabigatran: the RE-LY trial. Stroke. 2012;43:1511–7.
18. Majeed A, Kim Y-K, Roberts RS, Holmström M, Schulman S. Optimal timing of resumption of
warfarin after intracranial hemorrhage. Stroke. 2010;41:2860–6.

228
SUBARACHNOID HEMORRHAGE – DIFFERENTIAL
Catherine S. W. Albin and Sahar F. Zafar

While aneurysm rupture is the classic and most feared etiology of subarachnoid
hemorrhage (SAH), trauma is the most common. However, there are many other
additional etiologies of SAH. In addition to evaluating for aneurysm and trauma,
the following etiologies should also be considered:
□□ Coagulopathy – can result in spontaneous SAH.
□□ Reversible cerebral vasoconstriction syndrome (RCVS) – commonly results in
convexity SAH, see page 123.
□□ Venous sinus thrombosis – may be associated with both SAH and parenchy-
mal hemorrhage.
□□ Endocarditis – may be the result of mycotic aneurysm rupture or hemorrhagic
ischemia from septic emboli.
□□ Intracranial dissection – See page 89.
□□ Cerebral amyloid angiopathy (CAA) – mechanism likely overlaps with process
causing superficial siderosis.
□□ Pituitary apoplexy.
□□ Bleeding from other vascular malformations – including arteriovenous malfor-
mations and dural arteriovenous fistulas.
Perimesencephalic Non-Aneurysm SAH Subarachnoid blood in the interpeducu-
lar, crural, ambient, and quadrigeminal cisterns, typically located immediately anterior
to the midbrain or in the prepontine cistern. These patients tend to be younger and
less hypertensive than patients with aneurysmal hemorrhage. They have a more
benign clinical course than angio-confirmed aneurysmal SAH with a subsequent
rebleed rate of 2–5%, as well as lower rates of hydrocephalus and of significant
vasospasm. However, they may still develop significant hyponatremia and cardiac
abnormalities [1].

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229
EXAMPLES OF ANGIO-NEGATIVE SUBARACHNOID HEMORRHAGE

Perimesencephalic blood in the prepontine and Convexity SAH, in this case from reversible
intrapeduncular cisterns. cerebral vasoconstriction syndrome.

MANAGEMENT AND WORKUP OF ANGIONEGATIVE SAH

Institutions differ in the management of these patients. For patients with blood in the
basal cisterns, a repeat vessel imaging study (DSA vs. CTA) should be considered at
7 days. Patients should have an MRI w/ and w/o gadolinium. Screening TCDs and
nimodipine treatment may be considered in patients with cisternal blood but should
be case-specific in patients with convexity SAH.

REFERENCE
1. Kapadia A, et al. Nonaneurysmal perimesencephalic subarachnoid hemorrhage: diagno-
sis, pathophysiology, clinical characteristics, and long-term outcome. World Neurosurg.
2014;82(6):1131–43.

230
ANEURYSMAL SAH – ADMISSION AND EARLY
MANAGEMENT
Christopher Reeves and Catherine S. W. Albin

The care of aneurysmal SAH is generally a two-staged approach. The first stage
occurs when the patient is “unsecured” meaning there has been no neurosurgical
intervention on the aneurysm. The objective of this stage is to prevent herniation
from hydrocephalus and cerebral edema and then to identify and intervene upon
the source of bleeding. It is critical to prevent re-rupture of the suspected aneu-
rysm; outcomes following rebleed events are markedly worse.

ED management (or any location prior to transfer to an SAH referral center):

□□ ≤
ABCs, Assess the need for intubation (GCS 8 or rapidly worsening exam).
□□
Obtain STAT coags, CBC, BMP, troponin.
□□
Reverse any anticoagulation, see page 215.
□□
Ensure SBP < 160 mmHg (ASA guidelines) [1].
□□
Seizure prophylaxis with levetiracetam (or alternative widely available AED),
not recommended beyond the immediate post-hemorrhage period
□□
If potential delays in access to definitive aneurysm treatment and the patient
has a low risk for ischemic/thrombotic complication (MI, PE, significant CAD),
they may be considered for tranexamic acid 1 g (or, if TXA unavailable, amino-
caproic acid 5 g). Continue Q6H until aneurysm is secured (but no longer than
72 hours) [2].
□□
If concern for elevated ICP (low GCS, vomiting, pupil abnormalities, etc.),
consider hyperosmolar treatment. Foley placement to monitor I/Os: goal
euvolemia
□□
CT angiogram (CTA), but do not delay transfer to an SAH-capable facility for
vessel imaging.
Immediate Management on Arrival to Neuro ICU
□□
ABCs, assess the need for intubation.
□□
Obtain and document a baseline neurologic exam.
□□
If any concern for elevated ICP/herniation, administer hypersomolar treatment
–– Remember the patient will be flat during angiography, which may increase ICP.
□□
Review CT/CTA for evidence of hydrocephalus, cerebral edema, and aneu-
rysm location. If CTA not yet completed, stabilize patient and then obtain.

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□□Clearly define Hunt/Hess (HH) and modified Fisher scores (mFS) of the bleed
which are determined by the patient’s presentation to hospital, see page 233.
□□Early collaboration with neuroendovascular and neurosurgery to establish the
plan for four-vessel angiography and possible placement of external ventricu-
lar drain
–– EVDs should be considered for all HH Grade 3 and higher but may also be
considered in lower grades if there is significant ventricular/cisternal blood or
radiographic evidence of hydrocephalus.
–– EVD should be either clamped or set to 20 cmH2O prior to aneurysmal secur-
ing (prevents over-draining and potential re-rupture).
□□ Review medications/history/labs for any anticoagulation, aspirin,
thrombocytopenia.
□□ SBP <160 mmHg (exact threshold institution specific, 160 mmHg per ASA
guidelines) prior to aneurysm being secured.
□□ Order a prophylactic anti-epileptic drug until aneurysm secured or for the first
3–7 days (institution specific). Note that phenytoin is not recommended [3].
□□ Order daily transcranial dopplers (see page 47 for interpretation tips)
□□ Review EKG.
□□ Echocardiogram ASAP as at risk for stress cardiomyopathy (Takotsubo’s).
□□ Hold all chemical DVT prophylaxis.

REFERENCES
1. Connolly J, Sander E, et al. Guidelines for the management of aneurysmal subarachnoid hemor-
rhage: a guideline for healthcare professionals from the American Heart Association/American
Stroke Association. Stroke. 2012;43(6):1711–37.
2. Hillman J, et al. Immediate administration of tranexamic acid and reduced incidence of early
rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J
Neurosurg. 2002;97(4):771–8.
3. Diringer MN, Bleck TP, Claude Hemphill J 3rd, et al. Critical care management of patients fol-
lowing aneurysmal subarachnoid hemorrhage: recommendations from the Neurocritical Care
Society’s Multidisciplinary Consensus Conference. Neurocrit Care. 2011;15(2):211–40.

232
SUBARACHNOID HEMORRHAGE – SCORING SYSTEMS
Catherine S. W. Albin and Sahar F. Zafar

HUNT AND HESS GRADE [1]

1 Asymptomatic or mild headache, slight nuchal rigidity
2 Moderate to severe headache, nuchal rigidity, no neurologic deficit other than cranial nerve
palsy (often cranial nerve 3 due to compression from a PComm Aneurysm)
3 Drowsiness, confusion, mild focal neurologic deficit
4 Stupor, moderate-severe hemiparesis, or other moderate focal disability
5 Coma, decerebrate posturing

MODIFIED FISHER SCALE (IMAGING APPEARANCE) [2]

PROBABILITY OF
SCORING SYMPTOMATIC VASOSPASM
0 No blood detected 0%
1 Diffuse deposition or thin layer with all vertical layers of blood (in 24%
interhemispheric fissure, insular cistern, or ambient cistern) less
than 1 mm thick (thin); no IVH
2 Diffuse deposition or thin layer with all vertical layers of blood (in 33%
interhemispheric fissure, insular cistern, or ambient cistern) less
than 1 mm thick (thin); IVH present
3 1 mm or more in thickness; no IVH 33%
4 1 mm or more in thickness; IVH present 40%

WORLD FEDERATION OF NEUROSURGEONS (WFNS) CLASSIFICATION [3]

GRADE GCS MOTOR DEFICITS
1 15 Absent
2 13–14 Absent
3 13–14 Present
4 7–12 Present or absent
5 <7 Present or absent

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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233
REFERENCES
1. Hunt WE, Hess RM. Surgical risk as related to time of intervention in the repair of intracranial
aneurysms. J Neurosurg. 1968;28(1):14–20.
2. Frontera JA, et al. Prediction of symptomatic vasospasm after subarachnoid hemorrhage: the
modified fisher scale. Neurosurgery. 2006;59(1):21–7.
3. Teasdale GM, Drake CG, Hunt W, et al. A universal subarachnoid hemorrhage scale: report of
a committee of the world federation neurosurgical societies. J Neurol Neurosurg Psychiatry.
1988;51(11):1457–63.

234
ANEURYSMAL SAH – DAILY MANAGEMENT PRINCIPLES
Christopher Reeves and Catherine S. W. Albin

The second stage of care focuses on

close neurologic monitoring for and DDx for Worsening Exam in
management of common sequelae of Aneurysmal SAH
the bleed. These sequelae include, Each possibility is discussed in
but are not limited to: detail below:
–– Hydrocephalus. □□ Aneurysm re-rupture.
–– Delayed cerebral ischemia □□ DCI/vasospasm.
(DCI) and vasospasm. □□ Worsening hydrocephalus.
–– Cardiac and pulmonary compli‑ □□ Nonconvulsive seizures or status
cations. epilepticus.
–– SIADH/cerebral salt wasting. □□ Rapid shifts in electrolytes.
–– Pain. □□ Infection (patients are at risk for
ventriculitis, CLABSIs, and
DAILY MANAGEMENT PRINCIPLES CAUTIs).
• Maintain euvolemia, normothermia, □□ Delirium (diagnosis of exclusion,
normoglycemia. but extremely common as this
• Goal for eunatremia (see SIADH/ population undergoes prolonged
Cerebral Salt Wasting, below), periods of frequent
higher sodium goals may be sought neuromonitoring).
in patients with cerebral edema. Alert neurosurgery/endovascular team.
• Thorough neuromonitoring for
complications, as below.

MONITORING FOR AND TREATMENT OF HYDROCEPHALUS

• Consider EVD in any patient with IVH and altered mental status, especially
GCS ≦ 8 or Hunt Hess 3+.
• Once the aneurysm is secured, the EVD can remain open. The initial EVD level is
determined by the patient’s degree of hydrocephalus in collaboration with
neurosurgery.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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235
• Keep in mind that EVDs have complications including bleeding, longer length of
stay in ICU, ventriculitis, and eventual need for a ventricular peritoneal
shunt (VPS).
○ Some ICUs institute infectious screening with regular CSF sampling for hypo‑
glycorrhachia and up-trending nucleated cell count.
○ DVT prophylaxis can be used in patients with an EVD but therapeutic monitor‑
ing of enoxaparin levels may be required, institution specific.
• Institutions differ in when the EVD should be removed. Generally, radiographic
hydrocephalus should be improved, and there are no ongoing concerns for DCI/
symptomatic vasospam.
○ The EVD may either be “weaned” (taken 5 cm H2O higher, i.e. from 5 to 10
cmH2O every 24 hours until 20 cmH2O is reached) and then clamped or a clamp
trial with intermittent opening to drain CSF as needed can be trialed. This is
institution specific.
○ Clamp trials have been shown to be safe and can result in shorter length of stay
and fewer complications when compared to a slow wean [1].
○ Radiographic monitoring with head CT is often obtained after 24 hours of clamp‑
ing prior to EVD removal. A longer clamp trial may be sought if there is a con‑
cern for slow-developing hydrocephalus.
○ During a clamp trial, the EVD is unclamped for sustained ICP elevations, e.g.
ICP >20–22 mmHg for >5 mins.
○ DVT prophylaxis should be held the night before EVD removal.

CT angiography axial MIPs day 1. Distal CT angiography axial MIPS day 9. Flow-diverting stent
ICA aneurysm is one CT slice below. noted with arrow. Significant vasospasm throughout the
Image demonstrates no vasospasm or anterior and posterior circulations, but most prominent
baseline intracranial atherosclerosis in the bilateral MCAs in this projection (arrow heads).

MONITORING FOR DELAYED CEREBRAL ISCHEMIA (DCI)

• Document a thorough initial neurologic exam evaluating all vascular territories to
establish a clear baseline.
○ Remember to test orientation, memory, language, calculation, sequenc-
ing, and logic as these can be more subtle changes heralding DCI (a
result of ACA territory/ frontal lobe DCI).

236
• Close neurologic monitoring with very frequent neuro-checks.
• Institutions vary in what DCI monitoring is performed which may include some
combination of CT angiography (CTA), CT perfusion (CTP), brain tissue oxygen
monitoring, or Near Infared Spectroscopy (NIRS).
• Many institutions rely on daily or near daily transcranial dopplers (TCDs) as a key
component of vasospasm detection (see
page 47 for interpretation).
• Consider cvEEG for Hunt Hess 3–5 patients Percent Alpha Variability:
as a component of DCI monitoring or where A qualitative analysis of the
there is suspicion for non-convulsive seizures. change in Alpha variability. 4
○ Trend the relative alpha variability (rAV) is excellent, 3 is good, 2 is
and alpha–delta ratio (ADR), worsening fair, and 1 is poor. Any
focal slowing, and new epileptiform abnor‑ decrease in the score
malities. Late appearing epileptiform should heighten concern
abnormalities had the highest predictive for DCI.
valve for DCI [2]. Alpha–Delta Ratio:
○ Changes in TCDs and EEG may not cor‑ Concerning when there is a
relate with exam changes, but should decrement in the alpha
heighten vigilance about impending DCI. percentage (i.e. more
slowing) especially when
the difference is lateralized.
TREATMENT AND PREVENTION OF DELAYED
CEREBRAL ISCHEMIA
• At the time of admission, begin nimodipine
60 mg q4h for 21 days.
○ May change to 30 mg q2h if larger dose results in hypotension.
• If clinical decline, urgently communicate with neurosurgery and initiate rescue
therapies:
○ Position patient flat or reverse Trendelenburg for brain perfusion as respiratory
status allows.
○ Ensure euvolemia – bolus as needed. (Hypervolemia – part of the now aban‑
doned “triple-H therapy” – has had questionable benefit and may cause cardio‑
pulmonary complications) [7].
○ Consider induced hypertension with vasopressors.
○ CT/CTA/CTP may be pursued to evaluate for vasospasm and infarction prior to
DSA; if there is a high concern, however, the patient may go directly to DSA for
intra-arterial therapies. Notify neuroendovascular/neurosurgery immediately.
• Intra-arterial therapies include IA-milrinone or IA-verapamil and angioplasty.

237
• There are no large, randomized trials that address the management of vasospasm
discovered by TCDs or CT angiography with only a questionable clinical exam
correlate. However, emerging therapies and protocols have suggested some
benefit in the prevention and treatment of vasospasm, and may be considered
prior to or in addition to intra-arterial therapy.

Milrinone [3] 0.125–1.25 mcg/kg/min Watch for tachyarrhythmias, hypotension

Intrathecal 4–5 mg intrathecally every Infusion related headache, nausea, transient
nicardipine [4, 5] 8–12 hours increase in ICP
Cilostazol [6] 100 mg BID for 14 days Bleeding (anti-platelet effect, delay start until
48 hours after surgery), tachyarrhythmias

CEREBRAL EDEMA
• May be seen early or late in the course, with 8–67% of patients demonstrating
early global cerebral edema and 12% of patients developing edema in a delayed
fashion [8].
• Mechanisms include early ischemic injury at the time of aneurysm rupture, dysfunc‑
tion of autoregulation, reaction to toxic degrading blood products, neuroinflamma‑
tion, and hyponatremia [9].
• Management should include ICP monitoring and treatment of cerebral edema in a
stepwise fashion, see page 187, hypertonic saline is the preferred hyperosmolar
agent in SAH.

SYSTEMIC COMPLICATION

Fever
• Extremely common in aSAH patients, associated with poor outcomes, but unclear
if treatment improves outcomes.
• Infectious and DVT screening should occur routinely in all febrile patients, but also
consider drug withdrawal, neuroleptic malignant syndrome, and serotonin syn‑
drome in appropriate patients.
• Treat with acetaminophen, bromocriptine, and, if needed, consider surface cooling
or intravascular devices.
• Treat shivering which can raise ICP.

SIADH/Cerebral Salt Wasting

Hyponatremia is common in aSAH patients and may be the result of SIADH or
cerebral salt wasting (CSW)
• Use urine output and urine sodium and urine osmolarity to clarify exact etiology.
• See page 311 for more details.

238
• In general, AVOID free water restrictions, as the goal is euvolemia, given the risk of
vasospasm/DCI.
• With SIADH use salt tabs or 3% sodium chloride infusion.
• With CSW can use salt tabs, 3% sodium chloride infusion, and/or mineralocorti‑
coids if needed to ensure euvolemia.

Other Complications
Hyperglycemia, pulmonary edema, cardiomyopathy and EKG changes, hypotha‑
lamic, pituitary disruption, and anemia are all common in subarachnoid hemorrhage
patients and need to be monitored for. The specific management is beyond the
scope of this chapter.

REFERENCES
1. Chung DY, Mayer SA, Rordorf GA. External ventricular drains after subarachnoid hemorrhage: is
less more? Neurocrit Care. 2018;28(2):157–61.
2. Rosenthal ES, et al. Continuous electroencephalography predicts delayed cerebral ischemia
after subarachnoid hemorrhage: a prospective study of diagnostic accuracy. Ann Neurol.
2018;83(5):958–69.
3. Lannes M, et al. Milrinone and homeostasis to treat cerebral vasospasm associated with
subarachnoid hemorrhage: the Montreal Neurological Hospital protocol. Neurocrit Care.
2012;16(3):354–62.
4. Webb A, Kolenda J, Martin K, Wright W, Samuels O. The effect of intraventricular administra‑
tion of nicardipine on mean cerebral blood flow velocity measured by transcranial Doppler in
the treatment of vasospasm following aneurysmal subarachnoid hemorrhage. Neurocrit Care.
2010;12(2):159–64.
5. Suzuki M, Mamoru D, Yasunari O, Ogasawara K, Ogawa A. Intrathecal administration of
nicardipine hydrochloride to prevent vasospasm in patients with subarachnoid hemorrhage.
Neurosurg Rev. 2001;24:180–4.
6. Senbokya, N et al. “Effects of cilostazol on cerebral vasospasm after aneurysm subarachnoid
hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial.”
J Neurosurg. 2013;118(1):121–30.
7. Rinkel GJ, Feigin VL, Algra A, van Gijn J. Circulatory volume expansion therapy for aneurysmal
subarachnoid haemorrhage. Cochrane Database Syst Rev. 2004;2004:CD000483.
8. Claassen J, Carhuapoma JR, Kreiter KT, Du EY, Connolly ES, Mayer SA. Global cerebral
edema after subarachnoid hemorrhage: frequency, predictors, and impact on outcome. Stroke.
2002;33:1225–32.
9. Hayman EG, et al. Mechanisms of global cerebral edema formation in aneurysmal subarachnoid
hemorrhage. Neurocrit Care. 2017;26(2):301–10.

239
SUBARACHNOID HEMORRHAGE – NOTABLE TRIALS
Catherine S. W. Albin and Sahar F. Zafar

THEME TRIAL NAME TRIAL DESIGN MAJOR FINDINGS

Clipping vs. International 2143 patients with ruptured 23.7% patients in
coiling Subaranoid Aneurysm aneurysms randomly endovascular treatment had
Trial (ISAT) of assigned to clipping or a poor outcome at 1 year
neurosurgical clipping coiling. Primary outcome vs. 30.6% of those allocated
vs. endovascular was mRS between 3 and 6. to clipping (P = 0.0019).
coiling (Lancet 2002) Rebleed rates were low in
[1] each group, but slightly
higher in the endovascular
group.
Tranexamic Immediate Multicenter and 27 rebleeds occurred in the
acid (TXA) administration of prospective. 505 patients control group (10.8%) and
tranexamic acid and CT verified SAH at local 13 died vs. 6 rebleeds in the
reduced incidence of hospital randomized to TXA group (2.4%) and 2
early rebleeding after either usual care (n = 251) died. The trial showed a
aneurysmal or received 1 g of TXA significant decrease in
subarachnoid Q6H starting at transferring rebleed, but was not
hemorrhage: a hospital until aneurysm was powered to show a
prospective secured (no more than difference in functional
randomized study 72 hours) (n = 254) outcomes. No increase in
(J Nsgy 2002) [2] ischemic conditions or
vasospasm noted in the TXA
group.
Ultra-early tranexamic Multicenter, randomized, TXA was administered @ an
acid after prospective, open-label average of 185 min after
subarachnoid trial. CT confirmed SAH, ictus of subarachnoid. Trend
hemorrhage (ULTRA): then TXA 1 g given on towards a reduction in
a randomized arrival to hospital and excellent clinical outcomes
controlled trial (Lancet continued 1 g/8 hour (mRS 0–2) in the control
2020) [3] infusion until aneurysm group, no difference in the
secured (but no more rate of achieved a good
than 24 hours if delay clinical outcome (mRS 0–3).
in treatment) vs. usual 10.2% reruptured in the TXA
care. group vs. 14% in control
group. Aneurysms coiled at
an average of 14 hr after
ictus.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_45
241
THEME TRIAL NAME TRIAL DESIGN MAJOR FINDINGS
Nimodipine/ Cerebral arterial Original trial of nimodipine. An unresolved neurologic
Calcium spasm–a controlled 125 neurologically normal deficit or death occured in 8
Channel trial of nimodipine in patients randomized to of 60 patients in the placebo
blockers patients with placebo or nimodipine and arm compared to 1 of 56
subarachnoid followed for new neurologic patients in the nimodipine
hemorrhage. (NEJM deficits or death for group (p = 0.03). No side
1983) [4] 21 days. effects of nimodipine
reported.
Cochrane Review of Reviewed 8 trials including Nimodipine reduced the risk
Calcium Channel 1574 patients treated with of poor outcome: RR 0.7
Blockers [5] nimodipine. (0.58–0.84). “The evidence
for nimodipine is not beyond
every doubt, but given the
potential benefits and
modest risk…oral
nimodipine is currently
indicated.”
“Triple-H Multiple trials. Systemic Reviewed 4 prospective, Triple-H therapy was
therapy” review of the comparative studies. 488 associated with reduced risk
(hypertension, prevention of delayed patients. of symptomatic vasospasm
hypervolemia, ischemic neurologic (RR 0.45, CI 0.32–0.65)
hemodilution) deficits with but not delayed neurologic
hypertension, deficits and the risk of death
hypervolemia, and was higher. Emphasized the
hemodilution therapy need for randomized
following SAH controlled trial.
(J Neurosurg 1998) [6]
Statins STASH Trial (Lancet International, multicenter, 271 pts in the simvastatin
2014) [7] randomized, double-blind. group vs. 289 pts in the
803 patients with verified placebo group achieved
aSAH less than 96 h from mRS 0–2. Rate of death was
ictus were allocated to 10% in the simvastatin
simvastatin 40 mg group and 9% in placebo
(n = 391) or placebo group (p = 0.592). No
(n = 412). difference in adverse events.
No benefit detected in the
use of simvastatin.

242
THEME TRIAL NAME TRIAL DESIGN MAJOR FINDINGS
Magnesium MASH-2 Trial [8] Phase 3. Internal, 158 patients (26.2%) in the
(Lancet 2012) multicenter, randomized. magnesium group had a
1204 patients randomized poor outcome versus 151
to same treatment, but (25.3%) in the placebo
primary outcome was poor group. Nonsignificant
outcome (mRS 4–6) difference by treatment
3 months after SAH. category.
Intravenous The Montreal Protocol Large case series. Milrinone Large case series, thus no
Milrinone (Neurocritical Care was used as part of a control. However, no
2012) [9] larger protocol focused on significant side effects and
maintaining fluid and the infusion duration was on
electrolyte homeostasis. average 9.8 days; 68% of
Patients who developed patients required
new neurologic deficits norepinephrine. 48.9% of
were treated with patients were able to return
crystalloids to a CVP ≧ 6, to previous activities and
electrolytes were corrected 75% of patients had a good
and a milrinone 0.1–0.2 outcome (mRS ≦ 2).
mg/kg bolus was given; an
infusion was then initiated
at 0.75 mcg/kg/min and
increased if tolerated to 1
mcg/kg/hour.
Dedicated Impact of a dedicated 703 patients with aSAH Patients treated by a
NeuroICU neurocritical care team retrospectively reviewed for neurocritical care team
care in treating patients discharge outcomes before were significantly more
with aSAH [10] and after the development likely to be discharged
(Neurocrit Care 2012) of a multidisciplinary home (36.5% vs. 25.2%)
neurocritical care team. and were more likely to
receive definitive aneurysm
treatment.

REFERENCES
1. Molyneux A, Kerr R, Stratton I, et al. International Subarachnoid Aneurysm Trial (ISAT) of neu-
rosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneu-
rysms: a randomised trial. Lancet. 2002;360:1267–74.
2. Hillman J, Fridriksson S, Nilsson O, Yu Z, Saveland H, Jakobsson KE. Immediate administration
of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid
hemorrhage: a prospective randomized study. J Neurosurg. 2002;97:771–8.
3. Post R, et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a ran-
domised controlled trial. Lancet. 2020;397(10269):112–8.

243
4. Allen GS, et al. Cerebral arterial spasm–a controlled trial of nimodipine in patients with subarach-
noid hemorrhage. N Engl J Med. 1983;308(11):619–24.
5. Dorhout Mees SM, Rinkel GJ, Feigin VL, et al. Calcium antagonists for aneurysmal subarachnoid
haemorrhage. Cochrane Database Syst Rev. 2007;3:CD000277.
6. Treggiari MM, et al. Systematic review of the prevention of delayed ischemic neurological deficits
with hypertension, hypervolemia, and hemodilution therapy following subarachnoid hemorrhage.
J Neurosurg. 2003;98(5):978–84.
7. Kirkpatrick PJ, et al. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicen-
tre randomised phase 3 trial. Lancet Neurol. 2014;13(7):666–75.
8. Mees SMD, Algra A, Vandertop WP, et al. Magnesium for aneurysmal subarachnoid haemor-
rhage (MASH-2): a randomised placebo-controlled trial. Lancet. 2012;380(9836):44–9.
9. Lannes M, et al. Milrinone and homeostasis to treat cerebral vasospasm associated with
subarachnoid hemorrhage: the Montreal Neurological Hospital protocol. Neurocrit Care.
2012;16(3):354–62.
10. Samuels O, Webb A, Culler S, Martin K, Barrow D. Impact of a dedicated neurocritical care team
in treating patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2011;14:334–40.

244
TRAUMATIC BRAIN INJURY
Catherine S. W. Albin and Sahar F. Zafar

FRAMEWORK FOR TRAUMATIC BRAIN INJURY

FOCAL INJURY SEVERITY

• Subdural Hematoma
• Epidural Hematoma Mild: GCS 13-15
Moderate: GCS 9-13
DIFFUSE INJURY Severe: GCS 3-8
• Multicompartmental Injury
• Diffuse Axonal Injury

The Glasgow Coma Scale (GCS)

Eye opening response Eyes open spontaneously 4 points

Eyes open to verbal command, speech, or 3 points
shouting
Eyes open to pain (not applied to face) 2 points
No eye opening 1 point
Verbal response Oriented 5 points
Confused conversation, but able to answer 4 points
questions
Inappropriate response, words discernible 3 points
Incomprehensible sounds or speech 2 points
No verbal response 1 point
Motor response Obeys commands for movement 6 points
Localizes to painful stimulus 5 points
Withdraws from pain 4 points
Abnormal (spastic) flexion, decorticate 3 points
posture
Extensor (rigid) response, decerebrate posture 2 points
No motor response 1 point

EMERGENT MANAGEMENT

□□Airway, breathing, circulation (ABCs).

□□Avoid hypoxia, preference for early intubation for the goal of
PaO2 > 60 mmHg. Low PEEP is preferable; if high PEEP is needed,
consider concurrent ICP monitoring.

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□□Neurologic evaluation focusing on Glasgow Coma Scale (GCS) and signs that
suggest impending herniation:
–– Asymmetric, dilated, or fixed pupils
–– Decorticate/decerebrate posturing
–– Hypertension, bradycardia, irregular respirations
□□ Management of clinical signs of elevated ICP with HOB elevation and hyperos-
molar therapies (see page 187)
–– Per the fourth edition of the Brain Trauma Foundation, there is no sufficient
evidence to support a hyperosmolar treatment strategy, but mannitol use
should be considered in patients without ICP monitoring with severe neuro-
logic worsening and evidence of transtentorial herniation [1].
□□ Goal normocapnia (PaCO2 35–45), hyperventilation is only appropriate for
short durations in herniating patients, often while temporizing for surgery.
□□ Determine the need for ICP monitoring (see below).
□□ Ensure c-spine stability and evaluation (see page 273).
□□ Reverse anticoagulation (see page 215). Can consider DDAVP 0.4ug/kg IV for
patients on aspirin or P2Y12 inhibitors [2].
□□ STAT noncontrast HCT and consider CTA neck to r/o dissection if concerning
mechanism.
□□ Optimize cerebral perfusion pressure (CPP): Goal 60–70 mmHg per BTF,
“whether 60 or 70 mmHg is minimum optimal CPP threshold is unclear and
may depend on the autoregulatory status of the patient.” [1]
–– If no ICP monitor, SBP should be >100 in most patients, and >110 in patients
50–69 [1].

WHEN TO MONITOR ICP [1]

≤
GCS score 8 and CT scan showing Special Considerations in the
evidence of mass effect Management of Trauma Patients
Or if normal CT if: □□ Syncope? Need telemetry
and ECHO.
Age > 40 years
Motor posturing
□□ Alcohol intoxication and depen-
dence? Thiamine, folate, and
Systolic BP <90 mmHg
multivitamin. Review if cirrhosis
may affect medication dosing.
Consider the need for with-
drawal monitoring.
□□ Found down? Check CK; watch
for rhabdomyolysis.
□□ Fever? High risk for aspiration,
low threshold for antibiotics.

246
PRINCIPLES OF ICU MANAGEMENT

□□Repeat imaging. Obtain a stability scan between 6 hours and 24 hours. It

should be dictated by the severity of injury and potential for expansion. Short
duration should be sought in patients on anticoagulation, with epidural hemato-
mas or with a poor neurologic exam.
□□Optimize blood pressure to support cerebral perfusion pressure, goal
60–70 mmHg [1].
–– Bolus fluids PRN, but avoid dextrose containing fluids or hypotonic fluids (no
D5W or lactated ringers).
–– There is currently not strong evidence to support the use of a specific pressor.
□□Aggressive management of elevated ICP. See page 187 for strategies.
–– In TBI, EVD with continuous drainage superior to lower ICP than intermittent
drainage. The use of CSF drainage to lower ICP in patients with initial GCS
<6 can be considered [1].
□□Prophylactic anticonvulsants should be considered: levetiracetam 500 mg–1 g
q12 hour × 7 days, although there is insufficient evidence to clearly recommend
over phenytoin.
□□Consider MRI at 72 hours, beneficial for diagnosing diffuse axonal injury [3].
□□Low threshold for continuous EEG, high risk for nonconvulsive status
epilepticus.

247
SURGICAL MANAGEMENT IN TBI
Traumatic brain injury patients should be co-managed with neurosurgeons.

Focal Lesions
SUBDURAL HEMATOMA [4] EPIDURAL HEMATOMA
Guidance for evacuation − Epidural blood >30 cc
− SDH >1 cm or midline shift >5 mm − Acute epidural hematoma poor neurologic
− GCS ≦ 8 exam or anisocoria
− GCS decreased by two or more points
between injury and hospital admission
− Asymmetric or fixed pupils

In diffuse traumatic brain injury, decompressive hemicraniectomy can be consid-

ered in patients with elevated intracranial pressure that is refractory to medical
management. See trials (page 251) that cover outcomes with decompressive
hemicraniectomy.

FURTHER MANAGEMENT GUIDANCE FOR CHRONIC SUBDURAL HEMATOMAS

Dexamethasone: Recent RCT of dexamethasone [5] for a 14-day tapering course
(starting at 8 mg BID within 72 hours of admission to a neurosurgical unit) compared
to placebo demonstrated fewer favorable outcomes in patients treated with dexa-
methasone and more complications (diabetes, hyperglycemia, psychosis, and
infections), but fewer surgeries for reoccurrence (7.1% vs 1.7%).
Middle meningeal artery embolization: The MMA gives rise to capillary feeders;
embolizing inhibits blood flow into pathologic structures formed during the chronic
phase and has been explored as an alternative or adjunct to open surgical treat-
ments [6].

248
It should be sought in patients with chronic subdural hematomas. A meta-analysis
demonstrated that hematoma recurrence rate was significantly lower in the emboliza-
tion group (2.1% vs 27.7%) [7].

REFERENCES
1. Carney N, et al. Guidelines for the management of severe traumatic brain injury. Neurosurgery.
2017;80(1):6–15.
2. Al-Mufti F, Mayer SA. Neurocritical care of acute subdural hemorrhage. Neurosurg Clin.
2017;28(2):267–78.
3. Haghbayan H, et al. The prognostic value of MRI in moderate and severe traumatic brain injury:
a systematic review and meta-analysis. Crit Care Med. 2017;45(12):e1280–8.
4. Bullock MR, et al. Surgical management of acute subdural hematomas. Neurosurgery.
2006;58(suppl_3):S2–16.
5. Hutchinson PJ, et al. Trial of dexamethasone for chronic subdural hematoma. N Engl J Med.
2020;383(27):2616–27.
6. Ban SP, et al. Middle meningeal artery embolization for chronic subdural hematoma. Radiology.
2018;286(3):992–9.
7. Srivatsan A, et al. Middle meningeal artery embolization for chronic subdural hematoma: meta-
analysis and systematic review. World Neurosurg. 2019;122:613–9.

249
TRIALS IN TBI
Catherine S. W. Albin and Sahar F. Zafar

TRIAL DESIGN MAJOR FINDINGS

DECRA (NEJM Pts who had an ICP > 20 mmHg At 6 months, the extended GOSE was
2011) [1] for >15 mins after treatment with worse in the craniectomy group than in
tier 1 and 2 measures (including the standard-care group. Unfavorable
hyperosmolar therapy and EVD outcomes occurred in 51 patients (70%)
were randomized to bifrontal in the craniectomy group and in 42
decompressive craniectomy+ patients (51%) in the standard-care
medical treatment vs. medical group. Difference disappeared when
treatment alone (barbituates and/ baseline pupil reactivity was adjusted for
or hypothermia). in a post-hoc analysis.
RESCUEicp Pts with ICP > 25 mmHg for 42.8% of the patients in the surgical
(NEJM 2016) [2] >1 hour despite medical group and in 34.6% of those in the
intervention were randomized to medical group (p = 0.12) had favorable
decompressive craniectomy + outcomes. Craniectomy did reduce
medical therapy or medical mortality and resulted in better control of
therapy alone with the option of refractory elevation in ICP, but in this trial
adding barbiturates. there was no significant improvement in
GOSE at 6 Mos.
MRC CRASH >10 k adults with head injury and The risk of both death and disability was
(Lancet 2005) a GCS ≤14 within 8 h of injury higher in the steroid group compared to
[3] were randomized to 48 h infusion placebo group (25.7% vs. 22.3%,
of methylprednisolone or placebo p < 0.0001)
BEST:TRIP (NEJM To determine if monitoring ICP in No major difference in mortality at
2012) [4] pts with severe TBI improved 14 days, 6 months of GOSE at 6 months.
outcomes. 324 pts w/GCS 3–8 The 14-day mortality was 30% in the
randomized to ICP monitor or imaging–clinical examination group and
clinical exam/imaging. 21% in the pressure-monitoring group
(P = 0.18). The 6-month mortality was
41% and 39% (P = 0.60). Note there
was greater use of hypertonic saline,
mannitol, and hyperventilation in the
imaging–clinical examination group, but
the ICP-monitored group had a higher
rate of barbiturates and neuromuscular
blockade.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_47
251
TRIAL DESIGN MAJOR FINDINGS
CRASH-3 (Lancet To determine if TXA reduces There was no significant difference in
2019) [5] death, disability or increases head-injury related death within 28 days.
vaso-occlusive events in adult However, in the subgroup analysis, there
patients with a CGS ≦12 or any was a significant reduction in death in the
intracranial bleeding if group with mild-to-moderate head injury
administered within 3 hours of (GCS 9–15) with a NNT of 59 in this
injury. 9202 patients enrolled. group to prevent 1 death. There was no
significant increase in vaso-occlusive
events.

REFERENCES
1. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain
injury. N Engl J Med. 2011;364:1493–502.
2. Hutchinson PJ, et al. Trial of decompressive Craniectomy for traumatic intracranial hypertension.
N Engl J Med. 2016;375(12):1119–30.
3. CRASH Trial Collaborators. Effect of intravenous corticosteroids on death within 14 days in
10 008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-
controlled trial. Lancet. 2004;364(9442):1321–8.
4. Chesnut RM, et al. A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J
Med. 2012;367(26):2471–81.
5. CRASH, The. Effects of tranexamic acid on death, disability, vascular occlusive events and other
morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-
controlled trial. Lancet. 2019;394(10210):1713–23.

252
NEUROPROGNOSIS AND INDUCED NORMOTHERMIA
AFTER CARDIAC ARREST
Priya Srikanth and Catherine S. W. Albin

The optimal degree of temperature control after cardiac arrest is still unknown. Prior
evidence from small studies had suggested that for out of hospital VT/VF arrest that
33°C was superior to no TTM [1, 2]. In 2013, TTM1 (Targeted temperature
management at 33°C versus 36°C after cardiac arrest [3]) compared 950 patients
with out of hospital arrest and found that 36°C was equivalent to 33°C. Thus, there
was evidence to support a less severe degree of hypothermia.

However, in 2021 the TTM2 Trial (Target hypothermia versus targeted normothermia
after out-of-hospital cardiac arrest, NEJM) [4] was published which compared 2000
patients randomized to 36°C to fever control (the patients only were temperature-
managed if they developed a temperature >37.8°C and the target was set to 37.5°C).
In this trial, neuroprognostication was delayed for 96 hours and the clinicians
performing the neuroprognostication were blinded. Unexpectedly, there was no
mortality benefit of 36°C and there was no difference in disability at 6 months and
there was a signal of harm for hypothermia (more arrhythmias and longer ventilation
times). The lack of benefit in hypothermia held true across subgroup analysis.

At this point, literature supports aggressive fever prevention in all brain injured
patients and there may be a subset of patients for whom hypothermia could have
benefit. Some clinicians may still opt to perform mild hypothermia to 36°C and fever
prevention remains critically important, pending TTM3.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_48
253
GUIDANCE TO MAINTAIN NEUROPROTECTION:
□□Follow core temperature with a bladder or esophageal probe
□□Choose fever prevention (Temp< 37.5°C) or hypothermia (Temp= 36°C)
based on institutional protocols and preference
□□Provide standing acetaminophen to help with prevention of fever in all
patients without a contraindication
□□If the patient develops shivering, paralytics should be used as the last resort
for shivering control. Alternatives include:
–– Surface counter-warming
–– Buspirone 30 Q8H
–– Dexmedetomidine or analgesic dose ketamine infusion
–– Magnesium, to target slightly higher than physiologic levels (3–4 mmols/dL)
□□If the patient is not paralyzed, provide analgesia and sedation at the lowest
dose possible to prevent and treat discomfort. Ketamine, dexmedetomidine
and PRN fentanyl are preferred to more sedating infusions
□□For patients who require paralysis, neurologic prognostication will need to
be delayed to allow for the clearance of paralytics and sedatives

MONITORING FOR NEUROLOGIC COMPLICATIONS AND

NEUROPROGNOSTICATION
□□Obtain a noncontrast head CT when the patient is hemodynamically stabi-
lized (to rule out bleed or evidence of extensive ischemia)
□□Assess pupils Q1H until rewarmed & then at least Q2H (to detect impending
herniation), pupillometry can be used, as available

The following tests are helpful in informing neuro-prognosis*:

□□ Application of continuous video EEG. This should be used whenever pos-
sible to detect seizure and as a component of neuroprognostication
□□ Somatosensory Evoked Potentials (SSEPs) (complete on day 1–3)
□□ Neuron-Specific Enolate (NSE) (send on day 2–3)
□□ MRI (complete on day 3–7)
*See below for further details about the prognostic implication of each test

254
HISTORY IMPORTANT IN NEUROPROGNOSIS:
□□ Time of arrest
□□ Time from arrest to CPR
□□ Initial recorded rhythm
□□ Minutes without a pulse
□□ Time of ROSC
□□ Suspected etiology
□□ Medications given during arrest

PERSPECTIVE IN NEUROPROGNOSTICATION
Current guidelines recommend against withdrawal of life-sustaining because
of perceived poor neurologic prognosis (WLST-N) before 72 hours, and neuro-
prognostication should not be done until after that time.
However, a multicenter trial of OHCA subjects found that 1/3 of patients who died in
the hospital died because of WLST-N before 72 hours. By propensity matching and
the use of logistic regression models, this study estimated that 16% of patients in
whom life support was withdrawn may have had a functionally favorable survival [5].
It is critically important to take time and collect all possible variables for this
matter of life and death.

FOR PATIENT IN WHOM HYPOTHERMIA IS PURSUED

Note that hypothemia affects the following:
–– Alters cellular metabolism
–– Delays clearance of sedatives and paralytics
–– Delays clinical signs of recovery

FINDINGS ASSOCIATED WITH POOR PROGNOSIS

Note that none of these findings should be applied to indicate poor prognosis
in isolation. Compiling data from multiple sources is helpful to best understand a
patient’s likely outcome.
The false prediction rates for each prognostic modality are higher in patients who
undergo therapeutic hypothermia than they were in the pre-TTM cohort and thus
returning to aggressive normothermia may have an advantage in prognosis clarity.
The table reports FPRs in TTM-treated patients. Note that all studies have been
marred by the bias of the self-fulfilling prophecy and that exam findings must be
interpreted in the context of potentially lingering sedation, which is a major
confounder.
Non-neurologic factors also influence the probability of a good recovery.

255
PREDICTOR FPR FOR POOR PROGNOSIS IN TTM
Non-VF cardiac arrest 15% (6–30%)
ROSC >25 mins 24% (13–40%)

MODALITY TIME TO INTERPRET POOR PROGNOSIS FINDINGS PROGNOSTIC VALUE

CT Completed on day 1 Diffuse hypodensity FPR for poor
prognosis effectively
0% [6, 7]
Clinical exam At least 72 hours after No pupillary light reflex FPR for poor
ROSC. No earlier than prognosis 6%
24 hours after [1–20%] [8]
rewarming.
Myoclonus May start at any time Myoclonic status epilepticus begins Pattern 1: very poor
post arrest <48 hours after ROSC prognosis (in series
Two EEG patterns: (1) burst- no patient had
suppressed background with favorable outcome)
polyspike and high-amplitude spikes Pattern 2: less poor,
locked with myoclonus and (2) 50% had meaningful
continual background with narrow recovery [9]
spikes locked with myoclonus
EEG [10] Start cvEEG as early as Diffuse low-voltage pattern FPR 5% (2–14%)
possible and continue Burst suppression (suppression FPR 7% (2–23%)
for 72 hours periods >50%)
Epileptiform activity FPR 9% (2–21%)
Unreactive background FPR 7% (1–18%)
Electrographic status epilepticus or FPR 7% (0–11%)
generalized periodic epileptiform
discharges
Somatic Days 1–3. Prognostic Bilateral absent N20 wave Up to 100% specific
sensory- value is not influenced for permanent coma
evoked by TTM [11] (CI 92–100) [11]
potential
(SSEP)
MRI Within 3–7 days of Threshold of 10% of brain with low FPR 6% (0.3–29%)
arrest ADC [12]
Neuron- TTM does not Higher numbers (40–60 ug/L) [13] NSE values with
specific significantly affect NSE and uptrending serial measurements FPR 5%
enolase (NSE) values [13] in the first 72 hours [14] At 24 h: 49–76
Recommended at 48 ng/ml
and 72 hours At 48 h: 42–68
ng/ml
At 72 h: 33–45
ng/ml [13]

256
REFERENCES
1. Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neu-
rologic outcome after cardiac arrest. NEJM. 2002;346(8):549–56.
2. Bernard SA, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced
hypothermia. NEJM. 2002;346(8):557–63.
3. Nielsen N, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest.
NEJM. 2013;369(23):2197–206.
4. Dankiewicz J, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl
J Med. 2021;384(24):2283–94.
5. Elmer J, et al. Association of early withdrawal of life-sustaining therapy for perceived neurological
prognosis with mortality after cardiac arrest. Resuscitation. 2016;102:127–35.
6. Zhou SE, et al. Distinct predictive values of current Neuroprognostic guidelines in post- cardiac
arrest patients. Resuscitation. 2019;139:343–50.
7. Wu O, et al. Predicting clinical outcome in comatose cardiac arrest patients using early noncon-
trast computed tomography. Stroke. 2011;42(4):985–92.
8. Oddo M, Sandroni C, Citerio G, et al. Quantitative versus standard pupillary light reflex for early
prognostication in comatose cardiac arrest patients: an international prospective multicenter
double-blinded study. Intensive Care Med. 2018;44(12):2102–11.
9. Elmer J, Rittenberger JC, Faro J, Molyneaux BJ, Popescu A, Callaway CW, Baldwin M, Pittsburgh
Post-Cardiac Arrest Service. Clinically distinct electroencephalographic phenotypes of early
myoclonus after cardiac arrest. Ann Neurol. 2016;80:175–84.
10. Westover MB, Edlow BL, Greer DM. Coma after cardiac arrest: management and neurological
prognostication. London: MGH Cardiology Board Review. Springer; 2014. p. 471–85.
11. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked
potentials in cardiac arrest patients treated with hypothermia. Crit Care Med. 2005;33(8):1736–40.
12. Hirsch KG, et al. Prognostic value of diffusion-weighted MRI for post-cardiac arrest coma.
Neurology. 2020;94(16):e1684–92.
13. Stammet P, Collignon O, Hassager C, Wise MP, Hovdenes J, Åneman A, et al. Neuron-specific
enolase as a predictor of death or poor neurological outcome after out-of-hospital cardiac arrest
and targeted temperature management at 33 degrees C and 36 degrees C. J Am Coll Cardiol.
2015;65(19):2104–14.
14. Gillick K, Rooney K. Serial NSE measurement identifies non-survivors following out of hospital
cardiac arrest. Resuscitation. 2018;128:24–30.

257
STATUS EPILEPTICUS
Catherine S. W. Albin and Sahar F. Zafar

DEFINITIONS
Convulsive status epilepticus: >5 mins of convulsive seizures or ≧2 seizures
without return to baseline.
Nonconvulsive status epilepticus (NCSE): Multiple definitions exist using electro-
graphic and electroclinical data. Generally, NCSE is defined as rhythmic/periodic
EEG activity with evolution and with clear correlation between the EEG and clinical
symptoms. A benzodiazepine trial may be helpful to determine the correlation
between clinical and EEG findings (see page 263 for more information on the
interictal continuum and nonconvulsive status epilepticus).
Refractory status epilepticus (RSE): Status that continues despite stages I and II
treatment (see below).
Superrefractory status epilepticus (SRSE): Status that continues despite treat-
ment with anesthetics for >24 hours.

A GUIDE TO STATUS EPILEPTICUS TREATMENT

The following recommendations are based on the American Epilepsy Society (AES)
Guidelines [1], but note that hospital policies differ and that this should be used only
as a guide; treatment should be tailored to the individual patient.
As preparing for treatment, at onset of seizure:
□□Ensure stability of airway, breathing, and circulation, and provide supple-
mental O2.
□□Monitor vitals: HR, BP, O2, and EKG.
□□EKG monitoring and if possible obtain IV access (if not done already).
□□Fingerstick blood sugar. If <60 mg/gL and concern for thiamine deficiency ➔
100–500 mg thiamine and then 50 cc D50 IV.
□□Labs: CBC, BMP, Ca, Mg, Phos, LFT, troponin, ABG, urine and serum toxicol-
ogy, AED levels (if on AEDs), HCG (female) and blood cultures (if febrile), UA.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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259
Phase I (5 mins)
Meets Criteria for • Lorazepam 0.1mg/kg, max 4mg/dose
convulsive SE or • Can repeat dose x1 @ 5 minute if no response (up to 8 mg total)
NCSE

• IV Valproate (VPA) 20-40mg/kg (Max 3000 mg/dose) - Caution if liver disease

Phase II (20-40 mins) • IV Levetiracetam (LEV) 60mg/kg (Max 4500mg/dose)
To prevent further • IV Fosphenytoin (fos-PHT) 20 PE/Kg (Max 1500mg/dose) - May cause hypotension/
events and treat bradycardia
ongoing seizures • [IV Lacosamide (LAC) 400mg IV - Obtain EKG. Do not use if PR interval> 200msec]*
• [Phenobarbital 20mg/kg - long half life; has slow clearance]

Phase III (40-60 mins)

Seizures despite Stage • Continuous EEG monitoring recommended
I/II Treatment • Propofol- Load 2mg/kg IV, then 1-10 mcg/kg/hr
(Intubation Required) • Midazolam- Load up to 0.2mg/kg, then gtt 0.1-2 mg/kghr

• Ketamine: Load 1-2mg/kg, then 1.2-

7.5 mg/kg/hr consider early if patient is
Phase IV refractory to a gaba-ergic drug
Super Refractory
• Pentobarbital: Load 5-15mg/kg, then
Status Epilepticus
0.5-5mcg/kg/hour
• Immunomodulation, surgery if lesion,
other treatments. See below.

NOTES ON MEDICATIONS FOR STATUS EPILEPTICUS

Phase I: If no IV access: IM midazolam 10 mg if the patient is >40 kg
Phase II: ESETT trial [2] demonstrated that VPA, fos-PHT, and LEV treatment resulted in no
differences in efficacy or primary safety outcome in adults. All can be considered
first-choice for benzodiazepine–refractory status epilepticus

For all treatment groups, the success rate – the absence of clinically apparent
seizures with improving responsiveness at 60 mins after the start of the infusion –
was <50%

Takeaway: Stage III treatment may be needed, and given the

equivalent efficacy, pick a drug based on patient comorbidities and
availability. Do not underdose!

*In the TRENDS trial [3], lacosamide was non-inferior to fosphenytoin in controlling
nonconvulsive seizures. Given the favorable side-effect profile and low drug-drug
interaction, it has gained popularity but was not part of ESETT
Practical pearls for the dosing, dose-adjustment, and commonly
encountered side effects for levetiracetam, valproate, and
fosphenytoin can be found on page 141
− For VPA, PHT, and PHB, check level 1 hour after the load (free PHT level is
preferable, but send total if that will result more quickly)
− For fos-PHT send level 2 hours after load (free PHT level is preferable, but
send total if that will result more quickly)

260
Phase III: Anti-seizure doses of anesthetics will be higher than what is needed for general
sedation

Midazolam: GABAergic. It can accumulate especially in patients with low CrCl

and result in a prolonged “wake-up” and may also cause hypotension

Propofol: GABAergic. It frequently causes hypotension and can cause cardiac

depression. Monitor for hypertriglyceridemia and pancreatitis. Note that the
infusion has high calories and that tube feeds should be adjusted. Rarely,
prolonged, and high-concentration (>4 mg/kg/hour) infusion raises the risk of
propofol infusion syndrome (PRIS): bradycardia, severe metabolic acidosis,
rhabdomyolysis, hyperlipidemia, renal failure, and cardiovascular collapse

For IV anesthetics, bolus at the initiation of treatment and consider re-bolusing for
breakthrough seizures before increasing the maintenance dose
Fourth-line Ketamine: Gaspard et al. [4] in a multicenter study found permanent control of
treatments: RSE in 57% of episodes; ketamine appeared to have contributed to the control in
32% of patients. Alkhachroum et al. [5] found that seizure burden decreased by
50% within 24 hours of ketamine infusion in 81% (55 of 68) of patients
retrospectively studied. It may cause hypertension and tachycardia and also
cardiac depression at high doses

Immunomodulation therapies: High-dose steroids, IVIG, plasma exchange

(particularly for new-onset refractory status epilepticus (NORSE)) [6]
Ketogenic diet [7]
Surgery, if lesional

Investigational/case report evidence

Neurosteroids: Allopregnanolone, ganaxolone
Interleukin antagonists: Anakinra, tocilizumab

ADJUNCTIVE WORKUP IN STATUS

Once stabilized – either seizures controlled or definitive airway in place:
□□MRI with and without gadolinium, thin-cuts through temporal lobe (epilepsy
protocol) if possible.
□□Lumbar puncture including autoimmune studies, infectious studies, and flow
cytometry/cytology as indicated (see below).
□□Other history to collect – alcohol use (associated with subacute encephalopa-
thy with seizures in alcoholic patients (SESA)) [8], immunosuppression history
(such as checkpoint inhibitors which induce autoimmune encephalitis [9]),
cancer history.
□□If patient continues into refractory status epilepticus or has a poor exam and
EEG with interictal continuum findings, consider F-18 fluorodeoxyglucose
positron emission tomography (FDG-PET) before and during burst suppression
to distinguish between primary and secondary ictal pathologies and guide
further escalation of antiepileptic and multimodal therapy [10].
261
CSF WORKUP TO CONSIDER (AS
SERUM WORKUP TO CONSIDER INDICATED)
Autoimmune encephalopathy panel (Mayo, ARUP) Autoimmune encephalopathy panel
Screening inflammatory workup: ESR, CRP, C3, C4 (Mayo)
Screening primary autoimmune workup: ANA, dsDNA CSF Biofire®
Anti-TPO (steroid-responsive encephalopathy associated with CSF infectious studies (see page 159
autoimmune thyroiditis) to guide workup)
HIV antibodies Flow cytometry/cytology
Consider serology for infectious pathogens guided by RT-QuIC (for Creutzfeldt-Jakob
exposure and risk factors (see page 145) disease)

REFERENCES
1. Glauser T, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children
and adults: report of the guideline Committee of the American Epilepsy Society. Epilepsy Curr.
2016;16(1):48–61.
2. Chamberlain JM, et al. Efficacy of levetiracetam, fosphenytoin, and valproate for established
status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised con-
trolled trial. Lancet. 2020;395(10231):1217–24.
3. Husain AM, et al. Randomized trial of lacosamide versus fosphenytoin for nonconvulsive sei-
zures. Ann Neurol. 2018;83(6):1174–85.
4. Gaspard N, et al. Intravenous ketamine for the treatment of refractory status epilepticus: a retro-
spective multicenter study. Epilepsia. 2013;54(8):1498–503.
5. Alkhachroum A, et al. Ketamine to treat super-refractory status epilepticus. Neurology.
2020;95(16):e2286–94.
6. Gaspard N, et al. New-onset refractory status epilepticus: etiology, clinical features, and outcome.
Neurology. 2015;85(18):1604–13.
7. Thakur KT, et al. Ketogenic diet for adults in super-refractory status epilepticus. Neurology.
2014;82(8):665–70.
8. Niedermeyer E, Freund G, Krumholz A. Subacute encephalopathy with seizures in alcoholics: a
clinical-electroencephalographic study. Clin Electroencephalogr. 1981;12(3):113–29.
9. Williams TJ, et al. Association of autoimmune encephalitis with combined immune checkpoint
inhibitor treatment for metastatic cancer. JAMA Neurol. 2016;73(8):928–33.
10. Akbik F, et al. The PET sandwich: using serial FDG-PET scans with interval burst suppression to
assess ictal components of disease. Neurocrit Care. 2020;33(3):657–69.

262
CONTINUOUS EEG MONITORING, ELECTROGRAPHIC
SEIZURES, AND THE ICTAL-INTERICTAL CONTINUUM
Catherine S. W. Albin and Sahar F. Zafar

INDICATIONS FOR CONTINUOUS EEG MONITORING

Persistent altered mental status (AMS) Inadequate neuro exam
Ongoing poor arousal after generalized, Need for paralysis in patient with high risk of
convulsive seizures seizure (hypothermia or on extracorporeal
membrane oxygenation (ECMO))
Supratentorial brain injury with AMS (particularly
mental status fluctuates or is poor out of Need for pharmacologic sedation (elevated
proportion to injury) intracranial pressure and refractory status
epilepticus)
Unexplained AMS without known CNS injury
Paroxysmal events Prognostication
Witnessed seizure without return to baseline Particularly in traumatic brain injury, hypoxic-
ischemic damage, subarachnoid hemorrhage,
Clinical events: Motor events, paroxysm
and cardiac arrest
autonomic spells, paroxysmal increase in
intracranial pressure to rule out seizure etiology Unfavorable patterns: isoelectric, burst
suppression, periodic patterns, and seizures
Routine EEG demonstrates periodic patterns:
Generalized periodic discharges (GPDs), Favorable: continuity, reactivity to stim, sleep
lateralized periodic discharges (LPDs), etc. (see arch, and spontaneous variability
below)
For more details on cardiac arrest
neuroprognostication, see page 253

Continuous EEG is also used in vasospasm monitoring – see page 237 for more details.

TERMS
The American Clinical Neurophysiology Society recently updated their standardiza-
tion for critical care EEG terminology [1]. The wide variety of features that may be
reported in a continuous EEG report is outside the scope of this chapter. However,
below is a summary of what will be included in a continuous EEG report. For more
information and further details, see the ACNS terminology guidelines and refer to the
Salzburg criteria for seizures [2].

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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A. Background will include information about the symmetry, the predominant fre-
quency, the presence of reactivity and continuity, state changes, voltage, and
presence of a breach. AP gradient and posterior dominant alpha rhythm will
also be noted, if present.
° Note that burst suppression (included in continuity) is defined as a pattern of
attenuation/suppression alternating with higher-voltage activity with 50–99%
of the record consisting of attenuation.
B. Sporadic epileptiform discharges: the presence of spikes, polyspikes, and
sharp waves as applicable and the frequency of their presence from rare to
abundant.
C. Rhythmic and Periodic Patterns
° Main term 1: generalized, lateralized, bilateral independent, unilateral inde-
pendent, multifocal
° Main term 2: periodic discharges, rhythmic delta activity, spike-and-wave/
sharp-and-wave
° Will be modified by the duration, frequency, phases, sharpness, if stimulus
induced, if there evolution/fluctuation, and if there are “+” features.
D. Electrographic seizures (defined briefly as epileptiform discharges average
>2.5 Hz for ≧10 seconds, or any pattern with definite evolution lasting ≧10 sec-
onds) or electrographic status epilepticus (ESz for ≧ 10 continuous minutes or
≧20% of the total duration of a 60-mmin period)
° Electroclinical seizures/status has the same electrographic definition but
requires a definite clinical correlate time-locked to the pattern or EEG and
clinical improvement with IV anti-seizure medication.
E. Brief potential ictal rhythmic discharges: focal or generalized rhythmic activ-
ity >4 hz lasting 0.5–10 seconds that are not part of a burst suppression pattern
and without a definitive clinical correlate.
F. Ictal-interictal continuum (IIC): The ACNS defines a pattern on the IIC as one
that does not meet the definitions of electrographic seizures or electrographic
status epilepticus, but has features to suggest that it may be contributing to
altered mental status, other clinical symptoms, and/or to neuronal injury.
° Periodic discharges (PD) or sharp-wave (SW) pattern that is between 1 and
2.5 Hz over 10 seconds
° A PD or SW pattern between 0.5 and 1 hz that persists for >10 seconds and
has a plus modifier or fluctuation
° Any lateralized RDA (rhythmic delta activity) averaging >1 Hz for at least
10 seconds. With a plus modifier of fluctuation

264
EXAMPLES OF COMMONLY ENCOUNTERED CONTINUOUS EEG FINDINGS
LATERALIZED PERIODIC DISCHARGES (LPDS) LATERALIZED RHYTHMIC DELTA ACTIVITY (LRDA)
Lateralized sharp waves or spikes made have Usually reflects the presence of a focal lesion;
associated slow waves. Commonly encountered in associated with the risk of acute seizures,
stroke, intracerebral hemorrhage, subarachnoid especially nonconvulsive status epilepticus
hemorrhage, tumors, abscesses, Creutzfeldt-Jakob
disease, herpes simplex virus, and other
infectious/autoimmune pathology. LPDs are highly
associated with seizures especially in the setting of
acute illness, metabolic disturbances, or focal
lesions

GENERALIZED PERIODIC DISCHARGES GENERALIZED RHYTHMIC DELTA ACTIVITY

(GPDS) (GRDA)
Tend to be seen in diffuse processes: toxic- A nonspecific pattern that may be seen in
metabolic encephalopathy, sepsis. But may also profound encephalopathy, post-ictally or with
be seen in herpes simplex virus encephalitis and inflammatory, degenerative, traumatic, or
autoimmune encephalopathies. Can be associated toxic-metabolic disorders
with NCSE

265
2HELPS2B SCORE [3]
Predicts seizure risk. The authors propose the 2HELPS2B score can be reported
after 1 hour of screening with IV sedation minimized.
Score = 0, cEEG not needed (although 90 mins of screening should be considered in
patients with coma).
Score = 1, at least 12 hours of monitoring. If the score increases to ≥2 during
12 hours, monitor at least 24 hours.
Score ≥ 2, at least 24 hours of cEEG.
RISK FACTOR SCORE
Frequency >2hza 1 Predicted Seizure Riskd
Independent sporadic epileptiform discharges 1 0 = <5%
LPD/BIPD/LRDA 1 1 = 12
Plus features (superimposed rhythmic, fast, 1 2 = 27%
sharp)b 3 = 50%
Prior seizurec 1 4 = 73%
Bilateral independent periodic discharges 2
5 + = 88%
Total score 0–7
a
Frequency of any periodic or rhythmic pattern of more than
2 Hz except generalized rhythmic delta activity
b
Plus features include superimposed rhythmic, fast, or sharp
activity only on LRDA, LPDs, or BIPDs
c
Prior seizure includes a remote history of epilepsy or recent
events suspicious for clinical seizures
d
Predicted seizure risk based on the 2HELPS2B model

MANAGEMENT OF THE ICTAL-INTERICTAL CONTINUUM FINDINGS

It is important to determine if there is an epileptic clinical correlate – said differently,
does “fixing” the EEG improve the clinical picture?
It is also important to determine if there is a major metabolic derangement that needs
to be corrected, particularly for generalized periodic discharges.
As defined above, if the report contains 10 seconds of a rhythmic pattern that differs
from the background including:
° Periodic discharges (PD) or sharp-wave (SW) pattern that is between 1 and
2.5 Hz over 10 seconds
° A PD or SW pattern between 0.5 and 1 hz that persists for >10 seconds and has
a plus modifier or fluctuation
° Any lateralized RDA (rhythmic delta activity) averaging >1 Hz for at least 10 sec-
onds, with a plus modifier of fluctuation
then it is reasonable to consider a treatment trial, either a benzodiazepine or a
parenteral form of a “Stage II” AED (VPA, LEV, fos-PHT, or LAC). It is very impor-
tant to communicate the timing of administration to the epileptologist or have
the bedside provider mark it as a “push button” event.
266
A PROPOSED ALGORITHM FOR THE TREATMENT OF IIC PATTERNS
A simplified algorithm based on that proposed in Clinical Neurophysiology [4]

*If the EEG improves with administration of AED but there is no clinical improvement,
then continue to monitor as clinical improvement may be delayed. Continued trial of
AED is likely warranted.
**If the EEG continues to have features of the IIC, it is important to use clinical
judgment. Can consider a longer AED trial, advanced neuroimaging as with SPECT
or PET, or discontinue AEDs and continue to evaluate for an underlying cause such
as a toxic-metabolic, infection, and structural abnormality that may contribute to or
cause “cortical irritability.”

REFERENCES
1. Hirsch LJ, et al. American Clinical Neurophysiology Society’s Standardized Critical Care EEG
Terminology: 2021 Version. J Clin Neurophysiol. 2021;38(1):1–29.
2. Leitinger M, Trinka E, Gardella E, et al. Diagnostic accuracy of the Salzburg EEG criteria for non-
convulsive status epilepticus: a retrospective study. Lancet Neurol. 2016;15:1054–62.
3. Struck AF, Ustun B, Ruiz AR, et al. Association of an electroencephalography-based risk score
with seizure probability in hospitalized patients. JAMA Neurol. 2017;74(12):1419–24.
4. Rodríguez V, Rodden MF, LaRoche SM. “Ictal–interictal continuum: a proposed treatment algo-
rithm.” Clin Neurophysiol. 2016;127(4):2056–64.
267
NEUROMUSCULAR CRISES: ICU MANAGEMENT
OF GUILLAIN-BARRÉ SYNDROME AND MYASTHENIA
GRAVIS
Catherine S. W. Albin and Sahar F. Zafar

Neuromuscular emergencies often present with rapidly worsening weakness, respi-

ratory failure, oropharyngeal weakness, and aspiration. In cases of severe myopathy,
acute rhabdomyolysis and cardiac dysfunction may also be presenting features [1].
The approach to new-onset weakness is covered on page 167. This chapter reviews
ICU management of two of the most common causes of neuromuscular crisis.

GUILLAIN-BARRÉ SYNDROME
Polyneuropathy is characterized classically as ascending weakness usually following
a respiratory or GI illness with areflexia and high protein in the CSF without elevation
in cell count.
Respiratory failure occurs in 20–30% of patients with Guillain-Barré syndrome [2].
The need for intubation should be highly considered if [3]:
–– The forced vital capacity (FVC) is <20 ml/kg (~1.5 L in a 70 kg person). A very
rough estimate is having the patient count as high as they can in 1 breath.
Counting to 10 = 1 L, counting to 20 = 2 L.
–– Negative inspiratory force (NIF) of > –30 cm H2O (meaning less negative; 20 −
would be a concerning number).
–– Reduction of these numbers by >30% in a brief time.
–– It is also important to assess neck flexion and extension as these can be proxies
for diaphragmatic weakness.
Note that ABGs and pulse oximetry readings are not sensitive for impending
respiratory failure. Intervention should be persued before the patient is hypercarbic
or hypoxic. Noninvasive ventilation is not appropriate in most cases as it cannot be
used for the duration of time the patients need for recovery. Intubation is likely to be
prolonged in Guillain-Barré syndrome, and in many cases early tracheostomy should
be considered.
Dysautonomia complicates up to 70% of patients in the ICU and may be manifested
by arrhythmias, diaphoresis, labile blood pressure, gastroparesis, urinary retention,
and ileus.

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Meta-analyses have demonstrated that intravenous immunoglobulin (IVIG) at 0.4 g/
kg of the ideal body weight for 5 days and plasma-exchange (PLEX), usually every
other day for five sessions, have equivalent treatment outcomes for GBS [4].
Remember that both IVIG and PLEX diminish the yield of diagnostic testing, so in
cases of diagnostic uncertainty, all workup (serum and CSF) should be completed
prior to starting treatment.

IVIG PLEX
Pros More easily administered (no central line Small study in children demonstrating that in
required) mechanically ventilated patients, PLEX resulted
in shorter duration of ventilation and a
tendency toward shorter PICU stay [5]
Cons Side effects include headache, aseptic Requires a pheresis catheter
meningitis, hypercoagulability resulting in
Citrate-induced hypocalcemia: check iCal
thromboembolic complications, infusion site
during procedure, cardiac monitoring;
reaction, and fever. Anaphylaxis is
citrate-induced metabolic alkalosis
extremely rare; urticaria, flushing, pain, and
nausea/vomiting are normally rate related. Removal of highly protein-bound drugs.
TRALI and TACO are both possible but rare
Allergic reaction to administered FFP if being
Important that patients are well hydrated used; TRALI
before the infusion to prevent thrombosis
Non-plasma replacement fluids may cause
and renal complications
hypokalemia, hypofibrinogenemia and
coagulation factor depletion.

Patients on ACE inhibitors may develop

hemodynamic collapse with PLEX due to
elevated levels of bradykinin, these
medications need to be stopped prior to
treatment.
TRALI transfusion-related lung injury, TACO transfusion-associated circulatory overload

It is important to work with neuromuscular specialist to obtain EMG as this can

provide prognostic insight by illuminating if the patient has a demyelinating or axonal-
variant syndrome.

MYASTHENIA GRAVIS
Pathology occurs via an immune attack against nicotinic acetylcholine receptors at
the neuromuscular junction or related proteins (MUSK = muscle-specific kinase;
LRP4 = low-density lipoprotein receptor-related protein). This causes a fatigable
weakness which frequently involves the bulbar neuromuscular junction resulting in
oropharyngeal weakness (high aspiration risk) and diaphragmatic weakness.

270
Workup
□□In patients without a prior diagnosis or without prior screening, CT chest
imaging should be pursued to rule out the presence of a thymoma.
□□ In patients on treatment, differentiate between a myasthenic crisis and cholin-
ergic crisis from overmedication with cholinesterase inhibitors such as pyr-
idostigmine (Mestinon). Clues to overtreatment with pyridostigmine include
diarrhea, nausea, urinary incontinence, blurred vision and abdominal cramps in
addition to muscle weakness.

ICU Management
Intubation may be needed because of diaphragmatic weakness or because of
difficulty managing secretions/aspiration risk. Patients need close monitoring of neck
flexion/extension weakness, FVC/NIFs (although bulbar weakness may impair the
ability to generate a good seal), cough, and swallowing.
–– Noninvasive ventilation can be considered in patients with mild secretions to
help alleviate work of breathing and reduce ventilator days [6]; intubation should
be pursued if patient has copious oral secretions, weak cough, and if there is
hypercarbia/hypoxia.
–– Intubation should be pursued if the patient’s vital capacity (VC) falls below 15 mL/
kg [7] or for any concern for aspiration or stridor.
–– Do not use succinylcholine for intubation.
–– Stop pyridostigmine when the patient is intubated (to decrease bronchial sec-
tions), but it can be restarted when the patient is ready for ventilator weaning,
usually started at half of the home dose and uptitrated.
–– Patients with new-onset MG should be evaluated for thymoma, although the tim-
ing of thymectomy is debated as the benefit is not immediate.

Treatment
PLEX or IVIG should be initiated urgently in patients suspected of myasthenic crisis.
Plasma exchange is generally preferred as it produces a rapid improvement in 75%
of patients [8]. Steroids may worsen weakness acutely and thus are usually avoided
in crisis but may be considered if the patient is intubated and started in conjunction
with or after initiation of PLEX or IVIG [9]. Prednisone 1 mg/kg/day is the usual
starting dose and is often continued to 4 weeks after the exacerbation. Starting
treatment with a long-term immunosuppressant such as azathioprine, mycopheno-
late mofetil, or cyclosporine should be discussed with the provider that will follow the
patient longitudinally. Newer immune therapies like eculizumab or rituximab may be
pursued for maintenance immunosuppression although this is not typically done
during the ICU phase of illness.
For a list of medications that should be avoided in patients with myasthenia,
see page 343.
271
REFERENCES
1. Damian MS, Wijdicks EFM. The clinical management of neuromuscular disorders in intensive
care. Neuromuscul Disord. 2019;29(2):85–96.
2. Damian MS, et al. The effect of secular trends and specialist neurocritical care on mortality for
patients with intracerebral haemorrhage, myasthenia gravis and Guillain–Barré syndrome admit-
ted to critical care. Intensive Care Med. 2013;39(8):1405–12.
3. Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating mechanical ventila-
tion in Guillain–Barré syndrome. Arch Neurol. 2001;58(6):893–8.
4. Ortiz-Salas P, et al. Human immunoglobulin versus plasmapheresis in Guillain–Barre syndrome
and myasthenia gravis: a meta-analysis. J Clin Neuromuscul Dis. 2016;18(1):1–11.
5. El-Bayoumi MA, et al. Comparison of intravenous immunoglobulin and plasma exchange in treat-
ment of mechanically ventilated children with Guillain Barré syndrome: a randomized study. Crit
Care. 2011;15(4):1–6.
6. Seneviratne J, et al. Noninvasive ventilation in myasthenic crisis. Arch Neurol. 2008;65(1):54–8.
7. Fink ME. Treatment of the critically ill patient with myasthenia gravis. In: Ropper AH, editor.
Neurological and neurosurgical intensive care. 3rd ed. New York: Raven Press; 1993. p. 351–62.
8. Mayer S. Intensive care of the myasthenic patient. Neurology. 1997;48(Suppl 5):70S–5S.
9. Green DM. Weakness in the ICU: Guillain–Barré syndrome, myasthenia gravis, and critical ill-
ness polyneuropathy/myopathy. Neurologist. 2005;11(6):338–47.

272
EVALUATION OF C-SPINE TRAUMA
Catherine S. W. Albin and Sahar F. Zafar

OVERVIEW OF THE C-SPINE ANATOMY

–– Consists of seven vertebrae. C1 is called the atlas; C2 is the axis.
–– The atlas has no vertebral body or spinous process. Each of its lateral masses
contains an articular facet which articulates with the skull’s occipital condyles.
The anterior arch articulates with the dens of the axis.
–– The axis has a characteristic appearance due to the odontoid process (dens)
which is a finger-like projection from the anterior aspect of the vertebra. The
dens articulates with the anterior arch of the atlas and is secured by the trans-
verse ligament of the atlas, creating the medial atlantoaxial joint.
–– The eight cervical roots exit above their respective vertebral body except for C8
which exits below the seventh vertebra.

C-SPINE INJURIES
–– Mechanisms of injury include flexion, flexion-rotation, extension, and vertical
compression.
–– Any patient with a neurologic deficit or radiographic evidence of injury should be
presumed to have an unstable fracture until further workup is completed.

IMPORTANT AND NAMED INJURIES

FRACTURE MECHANISM COMPLICATION
Jefferson Vertical fall onto an extended neck May also rupture the transverse ligament of the
fracture of the atlas. Extremely unstable fracture if the
atlas Compresses the lateral masses of transverse ligament is disrupted
the atlas causing fracture of one
or both anterior/posterior arches
Whiplash Compression to any C-spine May result in damage to the anterior
injuries vertebrae caused by rapid longitudinal ligament
deceleration Compression fractures
And dislocation/subluxation of the cervical
vertebrae, commonly at C2/C3 or C6/C7
which causes spinal cord compression and
potentially death

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273
FRACTURE MECHANISM COMPLICATION
Hangman’s As suggested, injury from May result in the impingement of the spinal
fracture hanging, fracturing the pars cord and be lethal, but morbidity from self-
interarticularis of the axis hangings is more common due to asphyxiation
and anoxia
Dens fracture Usually caused by traffic collisions Type 1: The fracture occurs above the
(Odontoid and falls transverse ligaments. Often stable.
Fracture) Type 2: The fracture occurs at the base of the
dens. Very high rate of nonunion. Unstable.
Often treated with halo.
Type 3: The fracture through the dens and the
upper body of C2. Very Unstable.

Fig. 52.1 Sagittal CT scan on bone window demonstrating a Dens Fracture: Type 2

274
CANADIAN RULES FOR C-SPINE CLEARANCE IN THE ADULT PATIENT [1]
Note the patient must have a GCS of 15 and be hemodynamically stable.

Patients that Mandate C-Spine Imaging:

□□ Age > 65 Dangerous Mechanism
□□ Dangerous mechanism (see box) 1. Fall from elevation ≧ 3 feet / 5
□□ Paresthesias in the extremities stairs
2. Axial load to the head (e.g.,
If No to all above, then answer:
□□ Simple rear-end MVC
diving)
□□ Sitting position in the ED
3. High speed MVC, rollover or
□□ Ambulatory at any time
ejection
4. Motorized recreational vehicles
since trauma
□□ Delayed onset of neck pain
5. Bicycle struck or collision
□□ No midline cervical tenderness
If Yes to any of these, the patient’s collar
may be removed and clinically evaluated.
Test if the patient can rotate his/her neck 45 degrees left and right without pain. If
they can, there is no need for radiology.
If the patient has no “low-risk features” or cannot rotate the neck, imaging should be
obtained.

NEXUS RULE FOR C-SPINE IMAGING [2]

No imaging is needed if all conditions are met:
□□ No posterior midline cervical spine tenderness
□□ No evidence of intoxication
□□ Normal level of alertness
□□ No focal neurologic deficit
□□ No painful/distracting injuries
For patients in whom imaging is required, multidetector CT from the occiput to T1
with reconstructions should be obtained.

C-SPINE COLLAR REMOVAL IN AN AWAKE (GCS 15) PATIENT

If C-spine imaging by CT is normal or the patient has no features to suggest the
need for imaging, the collar may be removed and the patient directly assessed for
pain with range-of-motion testing. If the patient has no pain with neck rotation or
flexion-extension, the collar may stay off. If there is any pain, the collar should be
replaced and MRI C-spine obtained to rule out isolated ligamentous injury.

275
C-SPINE CLEARANCE IN THE OBTUNDED TRAUMA PATIENT
Trauma patients with depressed neurologic status should have CT C-spine imaging
performed. Removal of the collar in this scenario is much more complicated as the
patient cannot endorse pain. There is no consensus about best practice in this
scenario. If the neurologic deficit is expected to improve (such as intoxication), wait
until the patient can be more fully assessed.

SHOULD AN MRI C-SPINE BE OBTAINED?

There is no consensus here.
The Eastern Association for the Surgery of Trauma, which reviewed 12 single-center
trials comparing CT scan in obtunded patients to various adjunct studies including
clinical follow-up, MRI, flexion/ extension plain films, came to the conclusion that
cervical collar removal after a negative high-quality CT was a safe practice. However,
they recognized that the recommendation is “based on very low-quality evidence” [3].
If going to be obtained, MRI should be completed within 48 hours of injury, as the T2
hyperintensity produced by edema improves the conspicuity of the ligaments during
this time and would best demonstrate ligamentous injury, if any [4, 5].
Takeaway: MRI finds surgically important injuries in a tiny fraction of blunt trauma
patients. Of the patients who had surgical management after an abnormal MRI, the
majority had neurologic symptoms.

REFERENCES
1. Steill IG, Wells GA, Vademheen KL, et al. The Canadian C-spine rule of radiology in alert and
stable trauma patients. JAMA. 2001;286:1841–8.
2. Hoffman JR, et al. Selective cervical spine radiography in blunt trauma: methodology of
the National Emergency X-Radiography Utilization Study (NEXUS). Ann Emerg Med.
1998;32(4):461–9.
3. Patel MB, Humble SS, Cullinane DC, Day MA, Jawa RS, Devin CJ, Delozier MS, Smith LM,
Smith MA, Capella JM, et al. Cervical spine collar clearance in the obtunded adult blunt trauma
patient: a systematic review and practice management guideline from the Eastern Association for
the Surgery of Trauma. J Trauma Acute Care Surg. 2015;78(2):430–41.
4. Selden NR, Quint DJ, Patel N, d’Arcy HS, Papadopoulos SM. Emergency magnetic reso-
nance imaging of cervical spinal cord injuries: clinical correlation and prognosis. Neurosurgery.
1999;44:785–92.
5. Chandra J, et al. MRI in acute and subacute post-traumatic spinal cord injury: pictorial review.
Spinal Cord. 2012;50(1):2–7.

276
ICU MANAGEMENT OF SPINAL CORD INJURIES
Catherine S. W. Albin and Sahar F. Zafar

TERMS
Spinal shock: The loss of muscle tone and areflexia in the acute period after spinal
injury before the onset of spasticity.
Neurogenic shock: The loss of vasomotor tone and sympathetic innervation to the
heart. Usually the result of lesions that are at or higher than T6, these injuries result
in peripheral vasodilation and an inability to produce reflexive tachycardia.

ADMISSION CHECKLIST
□□Ensure spinal precautions ordered, C-collar in place (for acute evaluation and
management of C-spine injuries, see page 273).
□□Evaluate the need for intubation if not already done for high lesions (>C5).
□□Emergent consult to orthopedics or neurosurgery (institution dependent) for
surgical evaluation
–– The Acute Spinal Cord Injury study demonstrated that those that undergo
decompressive surgery within 24 hours of injury were twice as likely to have
a two-grade ASIA Impairment Scale improvement at 6 months [1].
□□ Preventive monitoring for early complications of spinal injury:
–– Hypotension and bradycardia: Seen most commonly in patients with T6 or
higher lesions given the involvement of the sympathetic outflow tract. Both
may require conservative fluid administration, vasopressors (Phenylephrine
should be used with caution in T6 and higher lesions, as it may worsen bra-
dycardia) and atropine for bradycardia. Prudent to have external pacing pads
available for high T- and C-spine injuries.
○ MAP goal >85–90 for spinal perfusion should be considered and is
guideline-recommended (however note no randomized trials support this
practice). Duration varies although 5–7 days is used [2].
Respiratory insufficiency: Secondary to chest wall and diaphragm weak-
ness. Close monitoring of respiratory parameters like Negative Inspiratory
Force (NIF) and Vital Capacity (VC), as well as RR and pCO2.
○ Seen most frequently with C-spine injuries.
○ Incentive spirometry and chest physiotherapy is recommended for all
patients to prevent atelectasis and pneumonia.
–– Urinary retention: A Foley should be used for decompression in first days–
week after injury. Switch to intermittent catherization as soon as feasible to
reduce CAUTIs.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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□□Start DVT ppx as soon as hemorrhagic injuries have been stabilized and
surgical management has been completed and allowed some healing time.
Timing should be determined in consultation with surgical teams.
□□ Start GI stress ulcer prophylaxis.
□□ Aggressive bowel regimen to prevent constipation; a paralytic ileus common.
□□ Early nutrition is important; monitor for return of bowel movement prior to
starting a diet.
□□ Note that given the side-effect profile of steroids and the lack of defined
improvement with steroids, this is not routinely recommended and is not
part of the neurosurgery guidelines [3]. See below.

Steroids and Spinal Injury

• Eight trials were included in a Cochrane review [4]. Seven of the eight used
methylprednisolone. The trials demonstrated that methylprednisolone sodium
succinate modestly improved neurologic outcome up to 1 year post-injury if
administered within 8 hours of injury and in a dose regimen of bolus 30 mg/kg
over 15 minutes, with maintenance infusion of 5.4 mg/kg per hour infused for
23 hours. However, high-dose methylprednisolone when evaluated in the
NASCIS trials led to higher rates of ARDS, GI hemorrhage, pneumonia, and
sepsis in patients treated with steroids [5].

278
CLASSIC SYNDROMES
INJURY
LOCATION CLINICAL SYNDROME PICTURE
Central cord Greater loss of motor function in
syndrome the upper extremities compared Loss of motor
function Area of cord

to the lower extremities. Varying damage

degree of sensory loss in the

upper extremities and thorax

Found most commonly in elderly

Incomplete

people and may occur without loss of

motor function

spinal fracture/dislocation.
Cervical stenosis is a risk factor

Anterior cord Paraplegia and bilateral loss of

syndrome pain and temperature with
preservation of position sensation Position, vibration
and touch sense

Can also be the result of vascular

compromise of the anterior spinal
artery after aortic surgery
Area of cord
damage
Loss of motor function
with preservation of
position, vibration, and
touch sense

Brown- Hemisection of the cord, resulting

Sequard in ipsilateral loss of motor tone Area of
cord damage

syndrome and positional sensation with

contralateral loss of pain and
temperature 1 or 2 levels below
the injury
Loss of pain,
temperature,
and light touch
on opposite side
Loss of motor function
and vibiration, position,
and deep touch sensation
on same side as the cord
damage

279
PROGNOSTICATION IN SPINAL CORD INJURIES
The American Spinal Injury Association (ASIA) international standards is the pre-
ferred tool to standardize the exam and classify severity. It is available online.
–– Because of spinal cord swelling or spinal shock, the prognostic evaluation should
be deferred until the end of the acute hospitalization.
A systematic review [6] demonstrated that these factors effected neurologic recovery:
–– The severity of injury measured by the ASIA scale
–– Level of injury
–– The presence of a zone of partial preservation
The following factors affected functional outcome:
–– Severity of neurologic injury
–– Level of injury
–– Reflex pattern
–– Age

SUBACUTE TO LATE COMPLICATIONS

Autonomic dysreflexia: Defined as episodic hypertension and concomitant
baroreflex-mediated bradycardia resulting from unmodulated sympathetic reflexes in
the decentralized cord. Common episodes are triggered by visceral or somatic
stimuli below the injury level, commonly from an overdistended bladder or bowel [7].
Acute hypertensive crises may result in drastic hypertension and even cerebral
hemorrhage, hypertensive encephalopathy, cardiac arrest, and seizures. Headache
and sweating are common accompanying features, and the patient may be hyperten-
sive or bradycardic [8]. Treatment includes moving patients into the upright position
and quickly removing the inciting noxious factor. Nitrate pastes are also recom-
mended for pharmacologic treatment of extreme blood pressure, as they can be
removed when the noxious factor has been addressed.
Other common causes of morbidity and mortality that require a multidisciplinary team
in the chronic phase of spinal cord injury include the following:
–– DVT/PE
–– Pneumonia
–– Pressure sores
–– Anxiety/depression

REFERENCES
1. Wilson JR, et al. Early versus late surgery for traumatic spinal cord injury: the results of a pro-
spective Canadian cohort study. Spinal Cord. 2012;50(11):840–3.
2. Ryken TC, Hurlbert RJ, Hadley MN, et al. The acute cardiopulmonary management of patients
with cervical spinal cordinjuries. Neurosurgery. 2013;72(Suppl 2):84–92.
3. Walters BC, et al. Guidelines for the management of acute cervical spine and spinal cord inju-
ries: 2013 update. Neurosurgery 2013; 60(CN_suppl_1):82–91.
4. Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev 2002;2.
280
5. Bracken MB, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate
for 48 hours in the treatment of acute spinal cord injury: results of the Third National Acute Spinal
Cord Injury Randomized Controlled Trial. JAMA. 1997;277(20):1597–604.
6. Wilson JR, Cadotte DW, Fehlings MG. Clinical predictors of neurological outcome, functional
status, and survival after traumatic spinal cord injury: a systematic review. J Neurosurg Spine.
2012;17(Suppl1):11–26.
7. Eldahan KC, Rabchevsky AG. Autonomic dysreflexia after spinal cord injury: systemic pathophys-
iology and methods of management. Auton Neurosci. 2018;209:59–70. https://doi.org/10.1016/j.
autneu.2017.05.002.
8. Karlsson AK. Autonomic dysreflexia. Spinal Cord. 1999;37(6):383–91.

281
MANAGEMENT OF THE POSTOPERATIVE CRANIOTOMY
PATIENT
Alison Paolino and Catherine S. W. Albin

CRANIOTOMY
• The bone is removed and put back on during the same surgical procedure.

CRANIECTOMY
• The bone is removed and kept off to relieve pressure and is put back on during a
later surgery called a cranioplasty.
A craniotomy is performed for various central nervous system (CNS) pathologies,
such as to clip an aneurysm, remove a tumor, or evacuate a hematoma. A craniec-
tomy is usually performed only to treat high intracranial pressures or prevent
herniation.
The postoperative treatment and expected postoperative ICU course will vary
significantly based on the reason for surgery. It is important for the ICU team to
understand the anatomy, surgical approaches, and what happened in the operating
room to anticipate, avoid, and manage postoperative complications.

Vital Information to Collect During Handoff

From the Surgery Team:
□□Procedure (craniotomy vs. craniectomy) and location of abnormality
□□Pre-surgical exam and expected neurologic deficits in the postopera-
tive period
□□Intraoperative complications (intraoperative hemorrhage, CSF leak)
□□If any intraoperative motoring was used (EEG, angiography, motor
mapping, etc.)
□□Concern for postoperative seizures, stroke, ICP elevation, hemorrhage,
CSF leak
□□Location of surgical drains and type of pressure (gravity, bulb suction)
□□Blood pressure goals
□□Postoperative imaging needed

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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From the Anesthesia Team:
□□Airway management during case (Easy mask? Easy intubation? Direct or
video laryngoscopy? Grade view?)
□□Neuromuscular blockers given/reversed
□□Pain meds and anesthetic used intraoperatively
□□Brain “relaxation” given? (i.e., mannitol, dexamethasone, or hypertonic saline)
□□AEDs given intraoperatively
□□Any difficulty with ICP intraoperatively
□□Any problems with hemodynamics, ventilation/oxygenation
□□Antibiotics received
□□I/Os
□□Glycemic control
□□Postoperative nausea/vomiting and if meds given

CHECKLIST FOR ADMISSION
□□Collect vital information from surgical and anesthesia team (see above)
□□Document comprehensive neuro exam and confirm with surgical team any
changes from baseline
□□ Review postoperative imaging, if obtained
□□ Review and restart antiepileptic therapy, if indicated
□□ Define course for steroids or other ICP-control measures, note if patient was
on steroids before procedure (raising risk for adrenal insufficiency/hypotension)

GENERAL CRANIOTOMY ADMISSION ORDERS

□□Baseline/serial neuro exams (Usually Q2H), but institution-dependent
□□Postoperative imaging, if indicated
□□AEDs, if indicated
□□Steroids, if indicated
□□PRN pain medicine
□□PRN antiemetics
□□Appropriate BP orders, as indicated
□□DVT prophylaxis to start ~POD #2, determine w/ surgical team
□□Incentive spirometry
□□Output documentation from any drains
□□Ventricular drain orders, if indicated
□□PT/OT/Nutrition consults, as indicated
□□Resume home medicines that are not contraindicated
□□Postoperative angiogram checks, if intraoperative angio done (see page 291)
□□See text boxes at the end of the chapter for special considerations for angiog-
raphy and transsphenoidal adenomectomy patients.

284
The best way to prevent complications is by anticipating their probable occurrence
and developing strategies to deal with the complications when they occur.

THINGS THAT AFFECT HOW A PATIENT WAKES UP FROM SURGERY

. Preoperative neuro status and overall health
1
2. Location of abnormality
3. Surgical approach and technique
4. Intraoperative complications
5. Anesthetic care including sedation immediately prior to transfer to ICU

UNEXPECTED CHANGE IN THE NEUROLOGICAL EXAM

Prompt recognition of neurologic deterioration, timely diagnosis, and treatment can
prevent permanent damage. Most postoperative compilations that will require
surgical re-intervention will occur in the first 6 hours after the initial surgery. Any
deviation in expected improvement of neurological exam after anesthesia should
prompt an immediate non-contrasted head CT (See figs. 54.1 and 54.2).
□□If head CT is negative for bleed, cerebral edema, hydrocephalus, pneumo-
cephalus, or the degree of these do not explain the degree of clinical abnor-
mality, consider cEEG.
□□ Consider CT angiogram, CT perfusion, and/or MRI for ischemic stroke.

GENERAL CRANIOTOMY POSTOPERATIVE COMPLICATIONS [1]

Cerebral edema In tumors, may be treated and prevented with dexamethasone (usually initiated
at 4Q6H although surgeons and institutions may vary). For non-tumor related
ICP management, see page 187 for treatment/management.
Hydrocephalus See page 197 for EVD indications and management.
Hemorrhage Intraparenchymal hematomas at the surgical site are the most common type of
postoperative hemorrhage. Subdural hemorrhage my occur if cortical surface
is sheared. Epidural hemorrhages are uncommon but may arise if the middle
meningeal artery is injured.
Seizure AED prophylaxis is not routinely indicated postoperatively unless preoperative
seizures (see page 315 for AED ppx), but center practices vary widely.
Generalized seizures should prompt evaluation for hematoma (STAT NCHCT).
If applicable, check AED level.
Stroke May occur due to arterial compression/injury or venous congestion resulting
infarction. Note that many tumor patients may also have predisposition to
hypercoagable state. When concerned for stroke in the postoperative phase,
obtain CT perfusion and CT angiography in addition to a standard non-
contrast head CT in the workup. May require MRI for diagnosis.
Simple Air in the cranium that is not under tension. May result in lethargy, confusion,
pneumocephalus headache, nausea/vomiting, seizures. Usually resorbs in 1–3 days. Use of
100% oxygen via a non-rebreather may be used.

285
GENERAL CRANIOTOMY POSTOPERATIVE COMPLICATIONS [1]
Tension Air in the cranium that is under pressure. May be located in any CNS
pneumocephalus compartment. Symptoms include headache, nausea, vomiting, seizures,
dizziness, obtundation. May see the “Mt Fugi Sign” on non-contrasted HCT
(two frontal lobe “peaks” surround by air). Requires urgent neurosurgical
evacuation via a new burr hole or insertion of drain via established burr hole.
CSF leak Most commonly seen with basilar skull fractures, transsphenoidal surgeries
(TSA), or posterior fossa craniotomy with dural opening. Clear fluid drains
through the skin incision, the eustachian tube (basilar skull fractures), or nose
and/or back of throat (TSA), especially if the patient leans forward. Puts the
patient at increased risk for infectious complications.
Diagnosis:

□□Consider sending Beta-2-transferrin to confirm cerebral spinal fluid;

this may not be necessary in all cases.
Treatment:

□□Maintain HOB 10–30 o

□□Consider a pneumovax vaccine for TSA-related CSF leaks

□□Consider prophylactic antibiotics
□□If persistent CSF leak, a lumbar drain may be placed to provide a
lower resistance path for CSF. This removes pressure.
□□If continuous CSF leak, surgical exploration and repair of the dural
defect is often required.

Infections Superficial infection often present earlier (1–2 weeks) and often can be treated
with debridement + systemic antibiotics. Deep infections often develop later
(>2 weeks) and may involve the bone flap (osteomyelitis). These infections
require surgical wound revision and removal of infected flap, as well as broad
spectrum coverage (gram positive, gram negative, and anaerobic).
Pseudomeningocele An abnormal collection of cerebrospinal fluid that occurs due to leakage from
CSF-filled spaces. Minor pseudomeningoceles can usually be followed. Large
collections may require a lumbar drain for CSF diversion.
OR positioning Depends on the surgical positioning, which should always be clarified with
complications anesthesia. Complications include compartment syndrome or peripheral nerve
entrapment syndrome. Laceration and pain may also be related to rigid
fixation of the skull during the operation.

286
Fig. 54.1 Significant tension pneumocephalus in a post-craniectomy patient. Suspected to have
resulted from air entrapment by malfunctioning shunt

Fig. 54.2 Diffuse pneumocephalus seen on CT scan in a patient that developed a CSF leak 1 week
after TSA

287
Special Case
Cerebral Angiogram & Craniotomy
During some craniotomies for vascular abnormalities, a cerebral angiogram is
performed intra-operatively in order to ensure the treatment aim has been achieved.
See page 291 for postoperative management specific to endovascular procedures.

Special Case
Sub-occipital/Retrosigmoid/Translabyrinthine Craniotomies
Used to access the cerebellopontine angle and cerebellum
□□May require EVD for obstructive hydrocephalus caused by post-operative
swelling infratentorially or to reduce pressure on healing dural incision
(thus lowering the risk of a CSF leak)
□□ Lower cranial nerve injuries may result in a high risk of aspiration and
dysphagia
□□ Fifth/seventh nerve injury may result in weakening of the corneal reflex,
leading to corneal ulceration (need eyedrops or eyelid taped shut during
recovery)
□□ Higher risk for CSF leaks, monitor incision site closely
□□ Usually complicated by nausea/vomiting neck muscle spasms, treat
aggressively

288
Special Case
Management Considerations for TSA/Pituitary Surgery Patients
Endocrine Considerations:
□□Post-operatively, high risk for Diabetes Insipidus (for management, see page
307) seen in 8–31% of patients, usually begins 24–48 hours after surgery
[2]; many patients will recover endogenous vasopressin secretion within
several days. Some will require lifelong exogenous ADH replacement. A
very small number of patients will have a “triple phase response” resulting
in a pattern of (1) transient DI, (2) SIADH, and then (3) permanent DI.
□□ Post-operatively, AM cortisol should be drawn for at least 2–3 mornings
after stress dose steroids have been stopped.
□□ AM Cortisol >450 nM = no concern for ACTH depletion. <100 nM =
requires baseline physiologic steroids; 100–450 = may have ACTH
depletion and likely require baseline steroids or at least stress dose
steroids during times of illness, endocrine should be consulted.
Special Monitoring:
□□Visual field testing
□□Asking specifically every morning about nasal drainage, a salty taste, fluid
cooling in the back of the throat – signs of a CSF leak
□□See above for management strategies for CSF leak.
Special Orders Needed for TSA Patients:
□□No positive pressure non-invasive ventilation
□□Sinus precautions
□□Consider pneumovax vaccine; if a CSF leak develops the patient is at high
risk for pneumococcal meningitis
□□Vasospasm and delayed cerebral ischemia has been described [3].
Postoperative transcranial doppler monitoring or CTAs can be considered.

REFERENCES
1. Kumar M, et al., editors. Neurocritical care management of the neurosurgical patient E-Book.
Elsevier Health Sciences; 2017.
2. Ricarte IF, et al. Symptomatic cerebral vasospasm and delayed cerebral ischemia following trans-
sphenoidal resection of a craniopharyngioma. J Stroke Cerebrovasc Dis. 2015;24(9):e271–3.
3. Hensen J, Henig A, Fablbush R, Meyer M, Boehnert M, Buchfelder M. Prevalence, predictors
and patterns of postoperative polyuria and hyponatremia in the immediate course after transs-
phenoidal surgery for pituitary adenomas. Clin Endocrinol. 1999;50(4):431–9.

289
POSTOPERATIVE MANAGEMENT
OF CEREBROVASCULAR PATIENTS
Alison Paolino and Catherine S. W. Albin

The same information should be collected as for other post-operative patients (Chap.
54), with the following additions:
□□ Any injury to catheterized arteries
□□ Excess bleeding from access site Postoperative Angiogram Checks
□□ Particularly important to clarify □□
Vital signs and neuro assess-
blood pressure goals ment at least Q2H
□□
Neurovascular and pulse checks
Postoperative Complications to
Monitor for:
□□
Groin (or access site) checks
–– Q15 minutes × 4
□□ Stroke –– Q30 minutes × 4
□□ Injury to catheterized arteries –– Q1 hour × 3
□□ Allergic reaction to the contrast
dye and other medicines used
in the procedure
□□ Hematoma and/or pseudoaneurysm development at access site, placing
patient at risk for arterial thromboembolic complications (monitoring for cold/
pulseless feet (groin access) or hand (radial access site)). Retroperitoneal
hematomas, arteriovenous fistula, arterial occlusion, femoral neuropathy, and
infection are all far less common access site complications.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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291
COMMONLY TREATED NEUROVASCULAR PATHOLOGIES
CEREBRAL
ARTERIOVENOUS
CEREBRAL MALFORMATION CAVERNOUS MOYA-MOYA
ANEURYSM (AVM) MALFORMATION DISEASE
Definition Bulging of the See Fig. 55. 1 See Fig. 55. 2 A A progressive
cerebrovascular A high-flow developmental vasculopathy
wall caused by connection between abnormality made causing stenosis
loss of the arteries and veins up of dilated, and occlusion of
internal elastic that bypass thin-waled unilateral and
lamina and capillaries. Graded capillaries ranging bilateral ICAs.
disruption of (Spetzler-Martin) in size from a few The MCAs and
the media. based at the millimeters to several PCAs develop
Most commonly beginning: on size, centimeters with no abnormal
found at the location, and venous intervening brain collaterals to
bifurcations of drainage which tissue maintain cerebral
the circle of predicts surgical perfusion
Willis outcomes. Higher
grades have more
complicated courses
and higher morbidity
postoperatively.

292
COMMONLY TREATED NEUROVASCULAR PATHOLOGIES (Continued)
CEREBRAL
ARTERIOVENOUS
CEREBRAL MALFORMATION CAVERNOUS MOYA-MOYA
ANEURYSM (AVM) MALFORMATION DISEASE
Procedure Craniotomy for Craniotomy for Craniotomy for Craniotomy for
clip ligation vs. resection of resection. superior temporal
endovascular AVM. Many can These are artery (STA) to
coiling, web, or also be treated with angiographically MCA (direct
flow diverter to endovascular silent lesions. bypass)
prevent rupture embolization in
or re-rupture conjunction with Craniotomy for
radiosurgery or Encephaloduroar-
See page 241 resection teriomyosynangio-
for details sis (EDAMS)
regarding (indirect bypass)
treatment
strategies and
229–244 for
SAH
management
Intraoperative Intraoperative Intraoperative Depending on the Intraoperative
monitoring cerebral cerebral angiogram, location cerebral
angiogram SSEPs, and/or neuromonitoring angiogram
intraoperative EEG may be used.
may be used
Major Rupture or Hemorrhage or Ischemia/ Rupture or
intraoperative re-rupture of re-hemorrhage of Hemorrhage re-rupture of
complications aneurysm; AVM; ischemia fragile arteries
ischemia from Seizures leading to
clip migration Note that DMSO, if cerebral
or coil prolapse used, can induce Damage to hemorrhage
(endovascular) vasospasm, surrounding
[1] angionecrosis, structures Ischemia
arterial thrombosis,
Peri-procedural and vascular rupture Peri-procedural
vasospasm [2] vasospasm

293
COMMONLY TREATED NEUROVASCULAR PATHOLOGIES (Continued)
CEREBRAL
ARTERIOVENOUS
CEREBRAL MALFORMATION CAVERNOUS MOYA-MOYA
ANEURYSM (AVM) MALFORMATION DISEASE
Notable Ischemia Normal Venous infarct if a MMD patients
postoperative perfusion developmental have chronically
complications Seizures pressure venous anomaly deranged CBF
breakthrough (DVA) is disrupted and CVR which
Complications (NPPB): Restoration during surgery puts them at risk
of rerupture, if of normal perfusion for:
occures after AVM resection Brainstem cavernous
results in increase in malformations often Ischemia/
Peri-procedure arterial flow to lay adjacent to hypoperfusion
vasospasm adjacent areas and critical structures, (can result from
tissue that has and resection may the failure of CVR,
theoretically been result in cranial hypoperfusion
deprived of normal nerve palsies, due to competition
vascular ataxia, spasticity, between graft and
autoregulation. May and swallowing native collaterals,
led to hyperemia, difficulties graft occlusion).
edema, and COSS trial 15%
potentially of patients had
ICH. Treated by perioperative
conservatively stroke [3]
lowering patients’
SBP for 24 hours Cerebral
post-procedure hyperperfusion
syndrome
ICH may also result (CHS): similar to
from can use NPPB, occurs due
micro-perforation of to rapid increase
the vessels or in blood flow to
thrombosis of the chronically poorly
adjacent venous autoregulated/
system resulting in ischemic regions
occlusive hyperemia of the brain

294
COMMONLY TREATED NEUROVASCULAR PATHOLOGIES (Continued)
CEREBRAL
ARTERIOVENOUS
CEREBRAL MALFORMATION CAVERNOUS MOYA-MOYA
ANEURYSM (AVM) MALFORMATION DISEASE
Vascular SBP goal − SBP ~10–20% Goal normotension Antiplatelets are
craniotomy- determined lower than baseline to prevent commonly used to
specific based on if the to prevent NPPB hemorrhage maintain graft
postoperative aneurysm is − Normovolemia patency
orders considered fully
secured Some centers may
seeak a
Note that MAP>90–100 (or
flow-diverted slightly above
aneurysms are baseline) for at
not considered least 24 hours for
secured until cerebral
endothelization perfusion.
which is not
completed in Avoid
the acute phase compressing
of management donor side of
graft (such as with
a CPAP or
tight-fitting nasal
canula)
Misc. See page 235 ~7% AVMs have Most supratentorial; The late
for details on associated flow- 9–35% infratentorial development of a
management of related aneurysms SDH or an EDH
aneurysm- [4] are two late
associated SAH complications to
be aware of [5]

295
Fig. 55.1 Spetzler-Martin grade 4 right parietal paramedian arteriovenous malformation primarily
supplied by the distal anterior cerebral artery and branches of PCA with superficial venous drainage
into the superior sagittal sinus and superficial venous drainage in the cortical veins and vein of
Labbe. Deep venous drainage is noted into the distal vein of Galen

296
Fig. 55.2 T2 FLAIR MRI sequence showing a cavernous malformation in the pons with internal hem-
orrhage products of different ages

REFERENCES
1. Brisman JL, Song JK, Newell DW. Cerebral aneurysms. N Engl J Med. 2006;355(9):928–39.
2. Chaloupka JC, et al. A reexamination of the angiotoxicity of superselective injection of DMSO in
the swine rete embolization model. Am J Neuroradiol. 1999;20(3):401–10.
3. Powers WJ, et al. Extracranial-intracranial bypass surgery for stroke prevention in hemo-
dynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.
JAMA. 2011;306(18):1983–92.
4. Stapf C, et al. Concurrent arterial aneurysms in brain arteriovenous malformations with haemor-
rhagic presentation. J Neurol Neurosurg Psychiatry. 2002;73(3):294–8.
5. Andoh T, et al. Chronic subdural hematoma following bypass surgery—report of three cases—.
Neurol Med Chir. 1992;32(9):684–9.

297
PREPARATION FOR BRAIN DEATH TESTING
Catherine S. W. Albin and Sahar F. Zafar

Hospital policies differ on the exact testing procedures, timing, the requirement of
who can declare, and need for multiple examiners [1]. Always print out and exactly
follow the hospital’s policy. To help, the AAN has an easily accessible checklist/
worksheet based on their guidelines [2] that is free and available online by searching
“AAN brain death guidelines.”
One important element that frequently delays testing or erroneously prevents
testing is the perception that the patient is breathing over the ventilator.
Patients that appear to meet criteria for brain death but are “triggering” the
vent should be assessed for auto-triggering the ventilator.
VENTILATOR AUTOTRIGGERING & BRAIN DEATH
A brain-dead patient can appear to have respiratory effort due to the cardiopulmo-
nary consequences of brain death and the hyperdynamic state that often accompa-
nies this syndrome leading to [3–5]:

Mvmt of air w/
Displacement in "Breath" in the
A hyperdynamic each cardic cycle
intrathoracic contents absence of
precordium triggers the vent
w/ each cardiac cycle respiratory drive

Further understanding of this requires understanding how the ventilator is triggered

to deliver a breath:

Change in GAS FLOW allows the inspiratory

valve to open

The lower the number (such as 1L/min)

FLOW
means the patient does less "work"
TRIGGERING
TYPES OF TRIGGERS

(more sensitive)

Normal is between 1L and ~6L.

Inspiratory effort must generate a

SUFFICIENT REDUCTION IN AIRWAY
PRESSURE below the set trigger

PRESSURE Threshold range -0.5 cm H2O to -2.0 cm

TRIGGERING H2O

A lower number (such as -0.5 cm H2O)

means the patient must make less effort
(more sensitive)

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299
If the trigger is set to be very sensitive (such as at 1 L/min or −1.0 cm H2O), the
cardiogenic oscillations can cause enough shift in the intrathoracic volume to trigger
a breath and make it appear that the patient has respiratory effort.
To confirm that this is not the case, the ventilator trigger should be set at a higher
limit and the patient observed again. The patient with no respiratory drive will be
confirmed in apnea testing. This test is just a bedside assessment to deter-
mine whether it is appropriate to proceed with formal brain death testing,
including the apnea test.

PREPARATION FOR BRAIN DEATH TESTING

Other important steps to ensure are completed prior to brain death and apnea
testing:
□□ Confirm that the patient has an explained and neuroradiographic evident cause
of irreversible coma (not just in a locked-in state or deep coma as may be the
case with a devastating brainstem injury).
□□ The AAN Guidelines do not specify if there must be evidence of diabetes
insipidus (pituitary death), but legal policy requires more than just “brainstem”
death and states “whole brain death.” If there is any uncertainty if the patient
qualifies, seek expert guidance.
□□ Patients with facial injuries and/or baseline cranial nerve deficits will need
confirmatory testing and cannot be declared with clinical examination alone.
□□ Review the medication list: all sedatives and paralytics need to be off for at
least five half-lives and may need longer in patients who have been treated with
therapeutic hypothermia. Train of four should be used to confirm the patient is
not paralyzed. Work with unit pharmacist to determine the appropriate time for
testing. In patients with suspected drug overdoses or intoxications, serial urine
toxicology or serum toxicology screens may be appropriate or ancillary testing
should be used in conjuction with clinical testing. Seek expert guidance.
□□ Screen labs for major metabolic derangements such as uremia and hyperam-
monemia; mild hypernatremia is permissible.
□□ Screen for endocrine abnormalities such as hypothyroidism that might con-
found the exam.
□□ Optimize the patient hemodynamically. SBP should be ≧ 100 mmHg.
–– Diabetes insipidus is common in herniation and may result in profound hemo-
dynamic collapse. Ensure this is treated. See page 307.
–– Pressors are okay.
□□ Patient must be ≧ 36°C.

300
For Apnea Testing:
□□ Patient must be normocapnic (paCO2 35–45 mmHg unless baseline CO2 is
suspected to be higher; hospitals have different policies on how this should be
handled).
□□ Patient should be pre-oxygenated for a goal PaO2 > 200 mmHg.
□□ Arterial line for hemodynamic monitoring and blood gas sampling.
□□ Pressors should be available – ideally in the room and already in line – as
progressive acidemia will lead to vasodilation and often hypotension.
Once these requirements are met, the patient is ready for bedside testing.
Supplies you will need:
□□A bright pen light
□□Tongue depressor to check gag
□□Q-tip to check corneal reflex
□□50 cc of ice-cold water in a syringe with a tubing attachment that can go into
the ear canal (x2)
□□Tracheal suctioning supplies if there is no in-line suctioning
□□An insufflation catheter for apnea testing (respiratory therapists should be
available to help with the apnea test)
When doing brain death testing, it is incredibly important to document
precisely.

ANCILLARY TESTING
Ancillary testing must be completed if clinical examination cannot be fully performed
or if the apnea testing is aborted. This can be done with a cerebral angiogram,
nuclear medicine 99mTc-HMPAO SPECT, or TCD test. EEG is no longer preferred.
MRA, CTA, and SSEPs are not accepted. If an ancillary test is needed, speak to the
technologists and interpreting physicians ASAP, as these tests may require special
credentialing for interpretation and often require some coordination.

NOTES ON ORGAN DONATION

The chance for organ donation is an incredibly important component of brain death
declaration, and the coordinators for organ donation should be notified for all patients
in whom brain death testing is being considered. However, it is critically important that
the treating physician is not involved in this process, as there should be no conflict
of interest or even appear to the family that there could be a conflict of interest.
It is best practice to disclose the results of the clinical test (and ancillary tests, as
appropriate) with the family and to inform them that another team will meet with them
to discuss the next steps.

301
REFERENCES
1. Greer DM, et al. Variability of brain death determination guidelines in leading US neurologic
institutions. Neurology. 2008;70(4):284–9.
2. Wijdicks EFM, et al. Evidence-based guideline update: determining brain death in adults: report
of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology.
2010;74(23):1911–8.
3. Arbour R. Cardiogenic oscillation and ventilator autotriggering in brain-dead patients: a case
series. Am J Crit Care. 2009;18(5):496–88.
4. Wijdicks EFM, Manno EM, Holets SR. Ventilator self-cycling may falsely suggest patient effort
during brain death determination. Neurology. 2005;65(5):774.
5. Cole RP. Cardiogenic oscillations and apparent ventilation in suspected brain death.
Resuscitation. 2003;56(3):335.

302
NUTRITION IN THE NEUROICU
Carmen Lo

GOALS
• Feed early: In patients who are not in shock, start patients on tube feeds (TF)
within 24–48 h (even only 10 ml/h if unable to advance rate). This helps establish
feeding tolerance and benefits GI integrity and immune response.
• Meet 80–100% nutritional needs by ICU days 3–7 for optimal clinical outcome:
° Achieving 80% energy need and close to 100% protein need (1.2 g/kg protein) in
48–72 h correlates with improved mortality in ICU patients [1] especially for BMI
>30, BMI <18.5, and NUTRIC score* >5 populations.
° TBI patients: early enteral nutrition promotes neurologic recovery [2]. One study
reported that every 10 kcal/kg increase of energy intake during the first 5 days
(up to 25 kcal/kg) reduced the 2-week post-injury mortality by 30–40% [3].
*NUTRIC score: score to quantify the risk of critically ill patients developing
adverse event that may be modifiable by aggressive nutrition therapy; variables
include age, Apache II, SOFA, number of comorbidities, days from hospital to
ICU admission, and IL-6.
• Avoid underfeeding/overfeeding:
° Underfeeding can worsen the patient’s nutritional status and compromise clinical
outcome. Limit interruption and holding of feeding as able.
–– Compensatory feeding helps make up the difference when TF interruption is
needed. If a protocol like this exists in the institution, then the RN can adjust
TF rate up to a maximum of ~150 ml/h to catch up the daily TF goal volume.
–– When pursuing compensatory feeding, check the gastric residual order
(>200 ml: start promotility agent; >500 ml: stop TF) which helps deliver TF
safely and reduces unnecessary holding.
° Overfeeding can lead to increased oxygen requirement/ventilator dependency,
blood sugar/insulin requirement, electrolyte derangement, and GI burden, which
can contribute to the worsening of clinical outcome. The ICU RD (registered
dietitian) can help you assess patient and customize TF goal to best match
patient needs in different phases of ICU care.
° For patients on IV medication in lipid emulsions such as propofol (1.1 kcal/ ml)
and clevidipine (2 kcal/ml), seek RD guidance to avoid under-/overfeeding.
• Factors that might influence tube feeding strategy: BMI, pre-admission nutritional
status, renal function, blood glucose, and volume status.

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303
STARTING TUBE FEEDS
(Institutions may vary in their approach and preferred formula; below is an
example to guide but tailor to your specific institution.)
• First 24 hours:
° For sick and potentially unstable patients: Osmolite 1 calorie at 10 ml/h and
reevaluate in the next 24 hours.
° If clinically stable: Osmolite 1 calorie at 20 ml/h, advance by 10 ml/h Q4H to goal
50 ml/h. Daily TF goal volume 1200 ml. Amino acid hydrolysate/Prosource × 1
pkt Q12H.
• After 24–48 hours:
° Continue to advance TF as tolerated.
° By TF/ICU days 3–7: The patient should receive 80–100% TF goal or ~25 kcal/kg.
° If due to clinical instability or due to GI intolerance <60% of needs are being met
by day 7, discuss with RD because this patient may be appropriate for parental
nutrition.

TIPS
Food-drug interactions: Certain medications (such as levothyroxine and phenyt-
oin) require holding of TF 1 hour before and after medication administration. Work
with the RD to adjust TF order with a compensated rate for the shortened daily TF
infusion time.
Electrolyte derangements (especially hypophosphatemia): Common in malnour-
ished patients who are at high risk of refeeding syndrome (though this can also occur
in patients with normal nutritional status). Nutritional support can exacerbate electro-
lyte derangements and therefore requires close electrolyte monitoring and aggres-
sive repletion. Phos repletion goal ≥2.6.
• If Phos <1.5: Consider holding TF. Replete and recheck ~2 hours after
replacement.
• If Phos 1.5–2.5: Can start/continue TF.
• Recommend BID Phos check until TF is at goal and Phos is stable.
• Replete with IV Phos (15–45 mmol × 1) if Phos <1.8 or repeatedly low.
• Replete with PO/Enteral Phos NAK (1 pkt QID ~32 mmol) if Phos ≥1.8.
Blood sugar management when on tube feeds: Insulin requirements for patients
with hyperglycemia may change as TF are adjusted. Upon new TF recommendation
for changes, RD will notify the responding clinician on the difference of carbohydrate
provision.

304
APPROX ML/H GOAL FOR
FIRST 24–48 H (BASED
CALORIE ON AVERAGE-SIZED
FORMULA COUNT ADVANTAGES PERSON, ABOUT ~70 KG)
Osmolite 1.06 cal/mL Isotonic. Easy to tolerate, easily absorbed. 50 mL/h (total calorie
1 cal No fiber. A good default choice unless there 1272)
are factors that make an alternative choice
better
Osmolite 1.5 cal/mL Concentrated. Advantageous in situations 35 mL/h (total calorie
1.5 where lower water balance is preferred: 1260)
Need for negative TBB and SIADH. Can
also be used if there is a high energy need.
Not suggested for patient with high
refeeding risk due to high caloric density
Promote 1.0 cal/mL Higher protein formulation. Best for obese 50 mL/h (total calorie
patients (BMI > 30) or those on high-dose 1200)
propofol for an extended period
Nepro 1.8 cal/mL Best for end-stage renal patients where 30 mL/h (total calorie
volume overload or electrolytes have been 1296)
difficult to manage (i.e., Phos and K are
high, and there is low UOP). Many patients
with mild CKD/AKI can be managed with
Osmolite
Glucerna 1.0 cal/mL Low in carbs but high in fat (which may slow 50 mL/h (total calorie
down gastric emptying). Not the preferred 1200)
choice of ICU patient, not optimal for
long-term feeding but can be used
adjunctively with insulin for patients with
refractory hyperglycemia
Jevity 1.0 cal/mL Fiber-containing formula. Can be used for 50 ml/h (for Jevity
and bowel management in well-established 1.0 cal/mL)
1.5 cal/ mL tube-feeding patient. Helps liquid stool at or
times. Avoid when patient is 35 ml/h (for Jevity
hemodynamically unstable or with distended 1.5 cal/mL)
abdomen

305
REFERENCES
1. Heyland DK, et al. Identifying critically ill patients who benefit the most from nutrition therapy: the
development and initial validation of a novel risk assessment tool. Crit Care. 2011;15(16):R268.
2. Taylor SJ, et al. Prospective, randomized, controlled trial to determine the effect of early
enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head
injury. Crit Care Med. 1999;27(11):2525–31.
3. Hartl R, et al. Effect of early nutrition on deaths due to severe traumatic brain injury. J Neurosurg.
2008;109(1):50–6.

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HYPERNATREMIA IN THE NEUROICU
Melissa Bentley and Catherine S. W. Albin

HYPERNATREMIA
IATROGENIC FREE WATER DEFICIT DIABETES INSIPIDUS (DI)
Etiology Most commonly, From lack of fluid Commonly seen:
from hypertonic administration during − In herniation
saline hospitalization, − After transsphenoidal surgery (if
administration impaired thirst disruption of the pituitary stalk)
mechanism, − With pituitary tumors or
insensible losses, GI inflammation of the pituitary
losses, and diuretics gland (such as those seen with
sarcoidosis)
− Pituitary stalk compression
− Pituitary/hypothalamus damage
Pathophysiology Salt administration Free water loss via Decreased anti-diuretic hormone
the kidney and gut or (ADH) production from damage to
insensibly with the pituitary gland results in
impaired mechanism excessively large dilute urine output
to replenish free
The rapid loss of dilute urine leads
water
to a very abrupt and significant
increase in serum sodium levels.
Monitor Monitor serum Monitor serum *() denotes the findings that are
sodium sodium; stricts I/O concerning for uncontrolled DI*
recording − Urine output (usually >200 cc ×
2 hours in the absence of a large
fluid intake)
− Serum Na (often >145 mg/dL)
− Serum Osm (>290 mmol/L)
− Urine Osm (<200 mOsm/kg)
Signs/ Thirst Thirst Polydipsia, polyuria, tachycardia,
symptoms hypotension
Complications Acute kidney Acute kidney injury Hypotension, hemodynamic
injury (may be (secondary to low collapse, and death (if uncorrected)
related to the volume status and
metabolic acidosis prerenal AKI)
caused by the
concurrent
administration of
chloride)

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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307
TREATMENT OF HYPERNATREMIA NOT DUE TO DIABETES INSIPIDUS

–– The free water deficit (which is based on serum sodium and weight) can be cal-
culated using online calculators like Nephromatic.com.
–– Note that in the NeuroICU many patients have cerebral edema, and rapid shifts
in sodium could result in worsening cerebral edema and herniation. As such,
D5W is not routinely used to correct hypernatremia in the NeuroICU.
–– Whenever possible, free water should be administered enterally.
–– If the patient has hypovolemia hypernatremia, correcting volume status will often
slowly correct the sodium.
–– If the patient is hypervolemic, consider diuresis with an agent that promotes
natriuresis such as metolazone, hydrochlorothiazide, or chlorothiazide (which
inhibit sodium reabsorption at the distal tubule).

MANAGEMENT AND TREATMENT OF DIABETES INSIPIDUS

Note: Anti-diuretic hormone = vasopressin = arginine vasopressin = Vasostrict (TM)
= Pitrussin (TM). These are all names for ADH; the difference is in preparation/
brand name.

Note II: These are very closely related to desmopressin = DDAVP; these compounds
are slightly modified to have less vasoactive properties (ie. they are not pressors).
Management:
□□Admit to ICU for dose finding.
□□Hourly fluid I&Os.
□□At least Q4H Uosm.
□□Frequent serum sodiums (Q4H–Q6H is appropriate initially).
□□Given frequent blood draws, consider placing an arterial line.

Treatment:
**Serum sodium is a reflection of what “has” happened; Urine Osm is a reflection of
how management is “currently” going.**
–– In a situation where the patient is at risk for DI, consider administration of anti-
diuretic hormone when urine output is >200 cc/hour × 2 hours and Urine
Osm 100–200 mmol/L – no need to wait for sodium to rise.
–– When this threshold is met, vasopressin 2.5–5 units IV × 1 (although institutional
thresholds and doses may vary) should be administered, while an infusion is
being prepared. This bolus dose of vasopressin has an effect for 4–6 hours.
–– Begin vasopressin infusion at 0.5–1 units/hour and titrate to a urine osmolarity of
300–500 mmol/L.
–– The goal is that intake should match output. If the patient is awake, they should
be encouraged to drink to thirst. If they are not, replace lost fluid with an isotonic

308
solution like Plasm-A-lyte (hypotonic solutions like LR are generally avoided in
brain injuried patients).
–– If sodium is rising despite the infusion and administration of crystalloid, consider
either an additional bolus of vasopressin or increasing the drip rate or increasing
the amount of free water given in the gut. D5W is typically avoided in patients
with severe brain injuries, but there are some situations were this may be
appropriate.
Converting to oral DDAVP:
–– There is variability in the absorption of oral DDAVP; thus conversion from vaso-
pressin to DDAVP is not an exact science.
–– Generally, try either 0.1 or 0.2 mcg of oral DAVP and watch Uosm and urine
output. If urine output remains high, a higher dose is required. When urine osmo-
larity begins to fall 100 mmol/L × 2 checks, the patient probably requires
another dose.
–– Generally the effect lasts between 8 and 24 hours. Some patients may require
very high initial doses and then slowly be weaned to just a nighttime doses.
–– If exceedingly high doses are required, consider switching to subcutaneous or
intranasal spray formulations which have much more consistent absorption and
are thus order of magnitudes more effective. Intranasal sprays should not be
used in post-TSA patients.
–– Note that concurrent glucocorticoid administration may require an increased
DDAVP dose.

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HYPONATREMIA IN THE NEUROICU
Catherine S. W. Albin and Sahar F. Zafar

Hyponatremia

Hypervolemic Euvolemic Hypovolemic

Heart failure, Cirrhosis SIADH Cerebral Salt Wasting

Lab Findings:
Lab Findings: UOsm>100 mosmol/kg
Lab Findings: UNa<10 mEq/L UOsm>100 mosmol/kg UNa (often)>25 mmol/L
FeNa< 1% UNa>25 mmol/L

(Note that renal losses, extra-renal losses, and primary polydipsia are also etiologies of hypotonic
hyponatremia, but as these are less common in the neuroICU population, they are not covered here.)

SYNDROME OF INAPPROPRIATE ANTI-DIURETIC HORMONE (SIADH)

–– Mechanism: CNS pathology commonly causes a sustained rise in ADH (arginine
vasopressin) which is secreted by the posterior pituitary. This results in highly
concentrated urine (Uosm >100 mOsm/kg) despite any expansion in TBW con-
tent. Thus, fluid intake results in a higher percentage of solute loss and free
water retention, even when normal saline is administered.
–– Commonly seen with brain tumors, CNS pathology, and subarachnoid hemorrhage.
–– Review medications such as carbamazepine, oxcarbamazepine, and SSRIs
may all promote increased ADH.

Treatment
–– In patients not at risk for vasospasm or who can tolerate a net negative fluid
balance: fluid restriction and increase solute intake; in extreme cases
a vaptan drug can be considered.
–– In patients at risk for vasospasm or who otherwise cannot be volume restricted:
° Hypertonic saline (3% infusion often used)
° Salt tabs (sample dose ~1–2 g TID may cause nausea).
° Oral urea 15 g QD to Q8H [1].
° Fludrocortisone should not be used as it promotes sodium retention and water
retention. But, because ADH is already over-secreted, this can result in water
being retained more than sodium and worsen hyponatremia.

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CEREBRAL SALT WASTING
–– Most commonly seen in patients with subarachnoid hemorrhage.
–– Exact mechanism is not well understood.
–– Should be differentiated from SIADH by assessing volume status (check I/O,
hematocrit, BUN/Cr, tachycardia, UOP) or by administering a small normal saline
challenge. If administering normal saline improves the sodium, it is likely cere-
bral salt wasting. If a NS challenge results in worsening hyponatremia, then the
patient most likely has SIADH.

Treatment
–– Salt replacement. Maintain even to slightly positive fluid balance.
–– Volume replacement with normal saline.
–– Can consider salt tabs to reduce number of fluid boluses.
–– Can trial fludrocortisone which promotes sodium retention. When used, closely
monitor for hypokalemia [2].

REFERENCES
1. Soupart A, et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of
patients with SIADH. Clin J Am Soc Nephrol. 2012;7(5):742–7.
2. Misra UK, Kalita J, Kumar M. Safety and efficacy of fludrocortisone in the treatment of cerebral
salt wasting in patients with tuberculous meningitis: a randomized clinical trial. JAMA Neurol.
2018;75(11):1383–91.

312
PRESSORS AND INOTROPES COMMONLY USED
IN THE NEUROICU
Catherine S. W. Albin and Megan E. Barra

BRIEF OVERVIEW OF THE PHYSIOLOGY [1, 2]

β1 adrenergic receptors stimulated ➔ Ca2 +-mediated actin-myosin complex
binding with troponin C and results in increased contractility. Ca2+ channel activation
results in increased chronicity.
β2 adrenergic receptor stimulated ➔ increased Ca2+ uptake in the sarcoplasmic
reticulum by vascular smooth muscle ➔ vasodilation.
α1 adrenergic receptor stimulated ➔ through G protein–mediated mechanism
increases smooth muscle contraction and increases systemic vascular resistance.
Phosphodiesterase inhibitors increase the level of cAMP ➔ increase myocardial
contractility and reduces afterload by vasodilation.

DOSE
DRUG MECHANISM BEST FOR (MCG/KG/MIN)A MONITOR FOR
Norepinephrine α > > β1 > β2: Vasodilatory 0.01–3 mcg/kg/min Tachycardia,
(Levophed) Results in shock, (~0.5–150 mcg/min) bradycardia,
− Vasoconstriction cardiogenic arrhythmias,
− Increases cardiac shock, ischemia, severe
contractility neurogenic hypertension (pts
shock on B-blockers)
Phenylephrine Alpha only: Vagally 0.1–9 mcg/kg/min Bradycardia,
(Neosynephrine) − Potent mediated or (~20–500 mcg/min) severe peripheral
vasoconstriction medication- and visceral
− Minimal effect on induced vasoconstriction
HR, may cause hypotension
Avoid in
reflex bradycardia
cardiogenic
shock, increases
afterload or
neurogenic shock
T5 and above

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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DOSE
DRUG MECHANISM BEST FOR (MCG/KG/MIN)A MONITOR FOR
Vasopressin V1 (vascular smooth Vasodilatory, 0.03–0.04 units/ min Arrhythmias, HTN,
muscle) cardiogenic for shock decreases CO (at
V2 (renal collecting shock doses>0.4 U/min)
duct system) Effective in
Severe peripheral
acidotic
vasoconstriction
tissues. Use in
resulting in tissue
RHF as effect
ischemia
on SVR > PVR.
Epinephrine Potent α > β1 > β2 Cardiogenic 0.01–0.5 Cardiac
and mcg/kg/min arrhythmias,
Beta effects are more
vasodilatory (~0.5–40 mcg/min) extreme
pronounced at lower
shock, hypertension,
doses, alpha effects
symptomatic cardiac ischemia
at higher doses
bradycardia
Milrinone Phosphodiesterase Vasospasm 0.125–1.25 Hypotension,
inhibitor management mcg/kg/min ventricular and
(see page Some centers may supraventricular
235), heart use a higher dose; arrhythmias,
failure this is usually only in hypotension,
a research context. cardiac ischemia
Dobutamine β1 > β2 > α1. Heart failure, 2.5–20 mcg/kg/mg Tachycardia,
Lowers CVP and SVR without shock ventricular
but has little effect on physiology; arrhythmias,
pulmonary vascular sepsis-induced hypotension
resistance (PVR) cardiac
dysfunction,
symptomatic
bradycardia
Max doses are in many ways arbitrary and hospital dependent. Titrate to the lowest dose that achieves
a

the goal. For shock, this is usually MAP ≧ 65.

REFERENCES
1. Overgaard CB, Dzavík V. Inotropes and vasopressors: review of physiology and clinical use in
cardiovascular disease. Circulation. 2008;118(10):1047–56.
2. Lannes M, et al. Milrinone and homeostasis to treat cerebral vasospasm associated with
subarachnoid hemorrhage: the Montreal Neurological Hospital protocol. Neurocrit Care.
2012;16(3):354–62.

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SEIZURE PROPHYLAXIS IN THE NEUROICU
Amanda Rivera, Stephanie Seto, and Megan E. Barra

ROUTINE
PROPHYLAXIS
INDICATION INCIDENCE INDICATED RECOMMENDATIONS
Traumatic brain 4–42% − Administer empiric prophylaxis for
injury (TBI) [1] 7 days post-injury
− More beneficial in early vs. late PTS
− Agents: Preferred – levetiracetam, phenytoin
Aneurysmal 1–18% − Administer empiric prophylaxis until
subarachnoid aneurysm is secured
hemorrhage (aSAH) − Short-course (3–7 days) prophylaxis
[2] preferable if indicated
− Phenytoin is not recommended routinely for
seizure prophylaxis
Brain neoplasm [3] 10–45% −R
outine prophylaxis not recommended as
shown to be ineffective in preventing first
seizure and have potential side effects
− No benefit shown in patients undergoing
supratentorial meningioma resection or in
metastatic brain tumors
− A short course may be indicated
postoperatively in patients presenting with
seizures
Intracerebral 5.5–24% − Insufficient evidence to support the use of
hemorrhage [4, 5] prophylactic AEDs
Ischemic stroke [3] 4–23% −R
isk factors: hemorrhagic conversion,
cortical involvement, involvement of >1 lobe
− Insufficient evidence to support the use of
prophylactic AEDs
Postoperative 15–20% − L imited evidence to support the prophylactic
craniotomy [3] use of AEDs in post neurosurgery patients
− Levetiracetam preferred over phenytoin
(due to lower ADEs)
Vascular lesions [3] Variable − Insufficient evidence to support the use of
prophylactic AEDs
Cerebral venous Up to 40% − Insufficient evidence to support the use of
thrombosis (CVT) [3] prophylactic AEDs

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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ROUTINE
PROPHYLAXIS
INDICATION INCIDENCE INDICATED RECOMMENDATIONS
Posterior reversible Up to − Insufficient evidence to support the use of
leukoencephalopathy 68.8% prophylactic AEDs
syndrome (PRES) [3]
Meningitis [3] Up to 27% − Insufficient evidence to support the use of
prophylactic AEDs
= routine prophylaxis indicated, = may consider routine prophylaxis, = routine prophy-
laxis not indicated*
*Use best judgment in cases where routine prophylaxis is not advised, as it may be indicated on
a case-by-case scenario.

REFERENCES
1. Yerram S, Katyal N, Premkumar K, Nattanmai P, Newey CR. Seizure prophylaxis in the neurosci-
ence intensive care unit. J Intensive Care. 2018;6(1):17.
2. Carney N, Totten AM, O’Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R,
Harris OA, Kissoon N, Rubiano AM. Guidelines for the management of severe traumatic brain
injury. Neurosurgery. 2017;80(1):6–15.
3. Gilmore EJ, Maciel CB, Hirsch LJ, Sheth KN. Review of the utility of prophylactic anticonvulsant
use in critically ill patients with intracerebral hemorrhage. Stroke. 2016;47(10):2666–72.
4. Hemphill JC III, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, Fung
GL, Goldstein JN, Macdonald RL, Mitchell PH, Scott PA. Guidelines for the management of
spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke. 2015;46(7):2032–60.
5. Diringer MN, Bleck TP, Hemphill JC, Menon D, Shutter L, Vespa P, Bruder N, Connolly ES,
Citerio G, Gress D, Hänggi D. Critical care management of patients following aneurysmal sub-
arachnoid hemorrhage: recommendations from the Neurocritical Care Society’s Multidisciplinary
Consensus Conference. Neurocrit Care. 2011;15(2):211.

316
VENOUS THROMBOEMBOLISM PROPHYLAXIS
IN THE NEUROICU
Stephanie Seto and Megan E. Barra

PHARMACOLOGIC AGENTS
USUAL
DRUG DOSING DOSE ADJUSTMENTS CONSIDERATIONS
Unfractionated 5000 units SQ Obesity (e.g. BMI > 40 kg/m2, The q8h strategy is preferred
heparin q12h or q8h weight > 150 kg): Consider in trauma patients
7500 units SQ q8h
Renal dysfunction: No dose
adjustment required
Enoxaparin 40 mg SQ Obesity (e.g. BMI > 40 kg/m2, More frequent dosing such as
q24h weight > 120 kg): Consider 30 mg SQ q12h may be
40 mg SQ q12h if normal better for trauma and spinal
renal function cord injury patients
Low body weight (<50 kg):
Consider 30 mg SQ q24h
Renal dysfunction:
− CrCl 15–29 mL/min consider
30 mg SQ q24h (or use UFH)
− CrCl <15 mL/min use UFH
− Avoid use if fluctuating renal
function or high bleed risk

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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INDICATIONS FOR VTE PROPHYLAXIS [1, 4, 5]
INCIDENCE TIMING OF VTE PREFERRED
INDICATION OF VTE INITIATION RECOMMENDATIONS AGENT
Ischemic stroke 1.2–2.5% As soon as feasible, − LMWH preferred over LMWH
hold VTE UFH (PREVAIL, Lancet
prophylaxis 24 2007),[2] in addition to
hours post tPA intermittent IPC
− Initiate pharmacologic or
mechanical prophylaxis
immediately after
hemicraniotomy or
endovascular procedure,
except if received rTPA
(delay for 24 h)
Intracranial 1–5% As soon as feasible, − Initiate IPC and/or GCS at Unknown/
hemorrhage 24–48 h after the beginning of hospital insufficient
admission if admission (CLOTS-3, evidence
hemorrhage stable Lancet 2013) [3]
on interval scan − Add UFH or LMWH in
patients who have stable
hematomas and no
ongoing coagulopathy
beginning within 48 h of
hospital admission
−C
ontinue mechanical VTE
prophylaxis with IPCs in
patients started on
pharmacologic prophylaxis
Aneurysmal 1.5–24% As soon as feasible, − Initiate IPCs as soon as If LMWH is used,
subarachnoid except in those with patient is admitted to anti-Xa levels may
hemorrhage unsecured ruptured hospital be checked to
aneurysms ensure proper
expected to range. Check ~ 4
undergo surgery hours after the 3rd
(start 24–48 h after dose (e.g. goal
secured) 0.2–0.4 IU/mL)
Traumatic 13–17% Within 24–48 h of − Initiate IPC on LMWH may be
brain injury presentation or presentation; then preferred in
craniotomy consider LMWH or UFH patients with
after surgery or if stable; polytrauma,
discuss timing with NSGY particularly long
team bone or pelvic
fractures

318
INCIDENCE TIMING OF VTE PREFERRED
INDICATION OF VTE INITIATION RECOMMENDATIONS AGENT
Brain tumor Up to 31% As soon as feasible − Initiate pharmacologic LMWH
prophylaxis upon
hospitalization if low risk
of major bleeding and
lack signs of hemorrhagic
conversion
− May consider
combination
pharmacologic/
mechanical prophylaxis if
high risk
Spinal cord Up to 80% As soon as feasible, − Pharmacologic LMWH preferred.
injury within 72 h of prophylaxis as soon as When UFH used
injury bleeding is controlled q8h preferred
− If pharmacologic over q12h
prophylaxis is not
possible, initiate IPC
− Mechanical prophylaxis
alone not recommended
if can tolerate
pharmacologic agent
Neuromuscular 3–7% As soon as feasible − Pharmacologic Unknown/
disease during acute prophylaxis preferred insufficient
hospitalization over IPCs/GCS but can evidence
use mechanical methods
when risk of bleeding
deemed high

IPC intermittent venous compression stockings, GCS graduated compression stockings

REFERENCES
1. Nyquist P, Bautista C, Jichici D, Burns J, Chhangani S, DeFilippis M, Goldenberg FD, Kim K, Liu-
DeRyke X, Mack W, Meyer K. Prophylaxis of venous thrombosis in neurocritical care patients: an
evidence-based guideline: a statement for healthcare professionals from the Neurocritical Care
Society. Neurocrit Care. 2016;24(1):47–60.
2. Sherman DG, Albers GW, Bladin C, Fieschi C, Gabbai AA, Kase CS, O’Riordan W, Pineo GF,
PREVAIL Investigators. The efficacy and safety of enoxaparin versus unfractionated heparin for
the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an
open-label randomised comparison. Lancet. 2007;369(9570):1347–55.

319
3. CLOTS (Clots in Legs Or sTockings after Stroke) Trials Collaboration. Effectiveness of
intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients
who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. The Lancet.
2013;382(9891):516–24.
4. Sauro KM, Soo A, Kramer A, Couillard P, Kromm J, Zygun D, Niven DJ, Bagshaw SM, Stelfox
HT. Venous thromboembolism prophylaxis in neurocritical care patients: are current practices,
best practices? Neurocrit Care. 2019;30(2):355–63.
5. Viarasilpa T, Panyavachiraporn N, Jordan J, Marashi SM, Van Harn M, Akioyamen NO, Kowalski
RG, Mayer SA. Venous thromboembolism in Neurocritical care patients. J Intensive Care Med.
2019;7:0885066619841547.

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PART V

IMPORTANT REFERENCES
BRAINSTEM ANATOMY
Catherine S. W. Albin and Sahar F. Zafar

Midbrain

CN III Basilar Artery

Cerebral Peduncle;
with CST

Red Nucleus

Substantia Nigra
Medial Longitudinal
Fasciculus
Oculomotor
nucleus
ML+
Spinothalamic tract
Mesencephalic nucleus of the
PAG trigeminal nerve

Cerebral Aquaduct

CST = spinothalamic tract

PAG = periaquaductal gray
ML = medial lemniscus

Pons

Basilar
Artery
CST CN VI

ML
CN VII

Spinothalamic tract

CN VIII
Trigeminal Nucleus

Cochlaear
MLF Nucleus
Facial Vestibular
colliculus VII nucleus Nuclei
4th Ventricle PPRF & VI
Inferior Cerebellar
Nucleus
Peduncle
MLF = medial longitudinal fasciculus
CST = spinothalamic tract
ML = medial lemniscus

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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Medulla

CST
Vertebral Artery
CN XII
Inferior Olivary Nuclei
ML

CN X

Spinothalamic Tract
Nucleus Ambiguus

Descending Tract of Trigeminal Nuclei

Inferior Cerebellar Peduncle

Vestibular Nuclei
MLF
Hypoglossal CN X Sub-Nuclei
Nucleus
MLF = medial longitudinal fasciculus
CST = spinothalamic tract
ML = medial lemniscus

324
NEUROICU INTRAVENOUS FLUID COMPOSITIONS
Megan E. Barra

PREFERRED NEUROICU SOLUTIONS

OSMOLALITY NA+ CL−
SOLUTION (MOSM/L) (MEQ/L) (MEQ/L) OTHER
23.4% 8008 120 mEq/30mL 120 mEq/30mL –
NaCl
3 % NaCl 1027 513 513 –
0.9% 308 154 154 –
NaCl
Plasma-Lyte Aa 294 140 98 K+ = 5 mEq/L;
Acetate = 27 mEq/L;
Mg 2+ = 1.5 mEq/L
D5 0.9% 560 154 154 Dextrose 50 g/L
NaCl
“Buffered” 1024 512 256 Acetate 256 mEq/L
hypertonic salineb
Mannitol 20% 1098 - - Mannitol 200 g/L
a
Also contains gluconate
b
Buffered hypertonic saline = sodium chloride 256 mEq/L + sodium acetate 256 mEq/L mixture. This medica-
tion has almost equivalent sodium content and osmolality as 3% NaCl. Useful if your patient is hyperchloremic
with or without associated non-anion gap metabolic acidosis while on hypertonic saline therapy

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OTHER AVAILABLE INTRAVENOUS FLUIDS
OSMOLALITY NA+ CL− DEXTROSE
SOLUTION (MOSM/L) (MEQ/L) (MEQ/L) (G/L) OTHER
LR 273 130 109 – K+ = 4 mEq/L;
Lactate 28 mEq/L;
Ca2+ = 3 mEq/L
0.45% NaCl 154 77 77 –
D5W 252 – – 50
D5 0.45% 406 77 77 50
NaCl
D10W 505 – – 100
D10 0.9% 813 154 154 100
NaCl
D5 LR 524 130 109 50 K+ = 4 mEq/L;
lactate 28 mEq/L;
Ca2+ = 3 mEq/L
Albumin 5% 310 145 +/– 15 145 +/– 15 –
Albumin 25% 310 145 +/– 15 145 +/– 15 –

326
ANTI-SEIZURE MEDICATION CHART FOR USE IN ADULTS
Megan E. Barra and David Fischer

The following pages contain important pharmacologic information

on anti-seizure medication (ASM)

ANESTHETIC INFUSIONS FOR REFRACTORY STATUS:

NAME DOSING SIDE EFFECTS
Propofol 1–2 mg/kg bolus, followed by Hypotension, propofol-related infusion syndrome
2–10 mg/kg/hr (0–83 mcg/ metabolic acidosis, rhabdo, cardiac failure,
kg/min) hypertriglyceridemia if given >72 hours.
Recommended to use Promote as the tube feed.
Midazolam 10 mg (or 0.2 mg/kg) bolus, Hypotension (less than propofol or pentobarbital).
followed by 0–10 mg/hr Can also build up, especially in patients with lower
(0.05–0.5 mg/kg/hr) infusion, renal function. May result in a prolonged wake up.
max 2 mg/kg/hr
Pentobarbital 5–15 mg/kg bolus, followed Hypotension, cardiac depression, ileus, potassium
by 0.5–5 mg/kg/h abnormalities
Ketamine 1–2 mg/kg bolus, followed by Hypertension, tachycardia, hallucinations
1.2–7.5 mg/kg/hr (20–125
mcg/kg/min)

Notes for the ASM chart:

–– T ½ = half-life. Tpeak = time to peak serum concentration.
–– Most ASMs can cause symptoms such as dizziness, blurred vision, diplopia, ataxia,
and mental fog.
–– First-generation ASMs are associated with osteoporosis and hormonal contracep-
tive failure.
–– For pregnancy risk: STerat = structural teratogenicity risk (i.e., major congenital malfor-
mations), CTerat = cognitive teratogenicity risk (i.e., any impact on neurodevelopment
and potential association with autism), BF = breastfeeding risk. Structural teratogenic-
ity considered unknown if there are fewer than 50 cases reported for that ASM.
–– In general, drug level monitoring is recommended during pregnancy. Though thera-
peutic ranges are not always known, large increases in level may be concerning for
toxicity, and large decreases in level may be concerning for treatment failure.
–– “OCPs” meant to signify oral contraceptive pills as well as other hormonal contra-
ceptive agents. In ASM that strongly decrease hormonal contraceptives, IUD or
Depo-Provera recommended. In ASMs that weakly decrease hormonal contracep-
tives, IUD, Depo-Provera, progestin implant, and high-dose OCP recommended.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_65
327
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Brivaracetam, Broad Synaptic vesicle Initial: 50 mg Load: Mood changes (may Metabolism: 60% T ½: 9 hr Incr’d by
BRV (Briviact) spectrum protein 2A BID. 100– be less than LEV), hydrolysis, 30% CYP Tpeak: 1 hr (PO) CBD. Dec’d by
binding Dec to 25 BID or 400 mg as N/V, constipation, Enzyme: CYP2C19 – CBZ, LEV, PHT
inc up to 100 IVPush taste distortion with genetic polymorphisms STerat/CTerat
BID. 1:1 PO to IV IV. Bone marrow may affect conc unknown, BF
Dose adjust: conversion suppression Protein binding: <20% unknown
hepatic
Carbamazepine, Focal Na+ channels Initial: 200 mg Can be N/V, weight gain Metabolism: hepatic Goal trough T½ initial: 25–65 hr Monitor WBC,
CBZ (tegretol, seizures (L-type Ca+, BID given as Bone marrow Enzyme: CYP3A4 4–12 mcg/ T½ at steady state: Na, LFTs. Used for
carbatrol) (some depresses nucleus Inc to short-term suppression, hypoNa (major) mL. Measure at 8–22 hr trigeminal
efficacy for ventralis of the 200–400 mg replacement (inc ADH response), Active metabolite 3, 6, and 9 Tpeak: neuralgia. Inc’d
generalized, thalamus) TID or 2–3 mg/ for stable SJS (test Asians for Inducer: Multiple weeks. May 4–5 hr (IR tab) by BRV,
but can also kg divided oral HLA-B*1502, which Protein binding: 75% need to 1.5 hr (susp) VPA. Dec’d by
worsen BID-QID Max regimen, at increases risk) increase after PHT, PHB,
generalized) 1600 mg/day 70% oral 2–3 months RUF. Toxicity inc’d
Oral suspension dose divided 2/2 CYP by LTG, LEV. Dec’s
should be QID q6h autoinduction OCPs (strong),
ER better IV (though usually warfarin, NOACs,
tolerated formulation completed by corticosteroids
Dose adjust: may not be 3–5 weeks) STerat moderate
renal Avoid in available (inc with dose),
liver failure CTerat low, BF
safe
Cannabidiol, Lennox- Precise 2.5 mg/kg Inc LFTs, anemia, Metabolism: hepatic T ½: 56–61 hr Monitor LFTs at
CBD (Epidiolex) Gastaut mechanism for BID. Inc after 1 AMS, and rash Enzyme: CYP2C19, Tpeak: 2.5–5 hr baseline, 1, 3,
syndrome, AED effects are week to 5 mg/ Hepatotoxicity CYP3A4, UGT1A7, and 6 months
Dravet unknown kg BID as UGT1A9, UGT2B7 to after initiation and
syndrome tolerated. Max active metabolite then periodically
dose 10 mg/kg 7-OH-CBD then to Incr’d by VPA,
BID inactive metabolite to strong CYP3A4
More rapid 7-COOH-CBD inhibitors. Dec’d
uptitration every Active metabolite by PHT, strong
other day in Inhibitor: CYP2C19 CYP2C19 and
increments of (moderate), CYP1A2 CYP3A4 inducers
2.5 mg/kg BID (weak), BSEP/ABCB11 STerat/CTerat
may be Protein binding: >94% unknown, BF
considered unknown.

328
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Clobazam, CLB Broad Benzodiazepine, Initial: 5 mg BID. Aggression, Metabolism: hepatic Clobazam: T ½: 36–42 hr Dec’s OCPs
(OnfI) spectrum, inc freq of GABA Adjust: Inc irritability, fever, Enzyme: CYP3A4, 30–300 ng/mL T ½ of active (weak). Inc’d by
Lennox- qweekly up to excessive salivation, 2C19 Norclobazam: metabolite: 71–82h CBD
Gastaut 20 mg BID URI Active metabolite. 300–3000 ng/ Tpeak: STerat/CTerat
syndrome (10mg for Inhibitor: CYP2D6 mL 0.5–4 hr(tab) unknown, BF
weight < 30 kg) (weak) Not routinely 0.5–2 hr(susp) unknown (in milk).
Dose adjust: Inducer: CYP3A4 measured Max onset: 5–9 days Risk of neonatal
hepatic (weak) withdrawal
Protein binding: ~80%
Clonazepam, Adjuvant for Benzodiazepine, Initial: 0.5–1 mg Paradoxical Metabolism: hepatic 15–70 ng/mL, T ½: 17–60 hr Dec’d by
CZP (Klonopin) myoclonic inc freq of GABA TID. aggression and Enzyme: CYP3A4 though not well Tpeak: 1–4 hr PHT. Inc’d by VGB
and atonic receptor Can dec to QD, anxiety established Onset: 2–40 min STerat
seizure Cl- channel or inc qweekly low-moderate,
opening up to 20 mg/ CTerat unknown,
day. Can inc BF unknown (in
quickly as milk). Risk of
inpatient neonatal
withdrawal
Diazepam, DZ Abortive for Benzodiazepine, 2–10 mg For sz <5 Hypotension, Metabolism: hepatic T ½: 33–45 hr, STerat/CTerat
(Valium) prolonged or inc freq of GABA BID-QID min: 0.15 respiratory Enzyme: CYP3A4, prolonged with multiple unknown, BF
cluster receptor mg/kg IV (5 depression 2C19 doses unknown (in milk).
seizures Cl- channel mg/min) or Paradoxical Active metabolites: T½ CNS:15–20 min Risk of neonatal
opening PR up to aggression and N-desmethyldiazepam T ½ of active withdrawal
10 mg per anxiety and temazepam which metabolite: 100 hr
dose (5 mg/ then metabolize to Tpeak: 1 min (IV)
min), repeat oxazepam 15 min–2hr (PO)
q5 min Onset: 1–3 min(IV),
2–10 min (PR)
Eslicarbazepine Focal Na+ channels Initial: 400 mg Nausea Metabolism: hepatic, T ½: 13–20 hr Na, LFTs before
ESL (Aptiom) seizures (can QD. Rash, SJS, PR UGT Prodrug for active Tpeak: 1–4 hr starting and on
worsen Inc by prolongation, monohydroxy maintenance.
generalized) 400–600 mg hepatotoxicity, metabolite (MHD) Dec’d by CBZ,
q1–2 weeks up hypoNa Inducer: CYP3A4, UGT PHB, PHT,
to 800 mg QD 1A1 (weak) PRM. Toxicity
(recommended), Inhibitor: CYP2C19 inc’d by CBZ,
or max dose (mod) OXC. Dec’s OCPs
1600 mg QD Protein binding: <40% (weak), warfarin.
Dose adjust: STerat/CTerat
renal. Avoid in unknown, BF

329
liver failure unknown (in milk)
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Ethosuximide, Absence T-type Ca+ Initial: 500 mg/ N/V, hyperactivity Metabolism: hepatic 40–100 mcg/ T ½: 50–60 hr Neuropathic pain
ESX (Zarontin) seizures channels day SJS, DRESS, Enzyme: CYP3A4 and mL Tpeak: 1–7 hr med. Dec’d by
Depresses motor Inc by 250 mg agranulocytosis, non-CYP Check levels PHT. Inc’d by
cortex q4–7 days. bone marrow Protein binding: 5% after 1–2 weeks VPA. STerat
Usual dose: suppression moderate, CTerat
20–40 mg/kg unknown, BF
(divided QD-TID) unknown (in milk)
Ezogabine Focal KCNQ Initial: 100 mg Retinal pigmentary Metabolism: hepatic, T ½: 7–11 hr, Not available in
[within the USA], seizures voltage-gated K+ TID. Inc by abnormalities non-CYP increased by 30% in the
retigabine channels (GABA) ≤150 mg resulting in vision Active metabolite elderly USA. Ophthalmic
[outside the qweekly up to loss (~30% of N-acetyl active Tpeak: 0.5–2 hr, exam (acuity,
USA], (Potiga, 400 mg TID (no patients), with black metabolite (NAMR) delayed by 0.75 hr fundoscopy, OCT)
Trobalt) added benefit box warning. Protein binding: 80% when given with at baseline and at
>900 mg/day) Urinary retention high-fat food 6-month intervals
Elderly: 50 mg Dec’d by CBZ,
TID, up to PHT
250 mg TID STerat/CTerat
Dose adjust: unknown, BF
renal and unknown
hepatic
Felbamate, FBM Focal Inhibits NMDA, Initial: 1200 Anorexia, N/V, Metabolism: 50% T ½: 20–23 hr, CBC and LFT at
(Felbatol) seizures, augments GABA mg/day divided constipation, URI hepatic, 50% renal increased by 9–15 hr baseline and
Lennox- (TID-QID). Aplastic anemia excretion without in renal impairment q1–2 months,
Gastaut Inc by 600 mg (black box warning), metabolism Tpeak: 2–6 hr even after FBM
syndrome q2 weeks up to liver failure (black Enzyme: CYP3A4 dc’ed. Dec’d by
3600 mg/day box warning) (major), CYP2E1 CBZ, PHB, PHT,
Dose adjust: Protein binding 25% PRM. Dec’s OCPs
renal (weak) STerat/
CTerat unknown,
BF unknown (in
milk)
Gabapentin, GBP Focal Voltage-gated Initial: 300 mg Peripheral edema. Excreted entirely in 2–20 mcg/mL, T ½: 5–7 hr, prolonged Neuropathic pain
(Neurontin) seizures (can Ca+ channel, TID. urine, with no though not well in renal impairment med. Dec’d by
worsen inhibits NT Max dose: metabolism established Tpeak: 2–4 hr (IR) 8 hr antacids (give
generalized) release (Na+, 2400 mg/day Protein binding: <5% (ER) GBP 2 hr after
Ca+) (divided TID) antacids). STerat
Dose adjust: low-moderate,
renal CTerat unknown,
BF unknown (in

330
milk)
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Lacosamide, LCM Focal Na+ channels Initial: 100 BID Second line N/V Metabolism: 30% T ½: 13 hr Obtain EKG
(Vimpat) seizures as monotherapy, for sz > 5 PR prolongation, CYP450, 20% Tpeak: 1–4 hr before starting,
(may or 50 BID as min: bradycardia, non-CYP. Enzyme: and at
exacerbate adjunct. Load: hypotension CYP2C19 (genetic maintenance dose
seizures in Inc qweekly 200– polymorphisms may Dec’d by CBZ,
Lennox- 50–100 mg/ 400 mg affect conc), 2C9, 3A4 PHT, PHB. Toxicity
Gastaut day up to 400 (over 30–60 Protein binding: <15% inc’d by CBZ.
syndrome) mg/day. Dose min) STerat/Cterat
adjust: renal, 1:1 PO:IV unknown, BF
hepatic conversion unknown (in milk)
Lamotrigine, LTG Broad Na+ channels, Initial: 25 QD Nausea. Rash, SJS, Metabolism: hepatic 2.5–15 mcg/ T ½: 25–33 hr Mood stabilizer.
(Lamictal) spectrum inhibits release of (QOD if hepatotoxicity Auto-induction of mL, though not (15–70 hr if drug Dec’d by CBZ,
(can worsen glutamate (Ca+) concurrent VPA) metabolism via well established interactions) PHT, PRM, OCPs.
myoclonic Inc by 50 mg UGT-glucuronidation Tpeak: 1–5 hr (IR) Inc’d by
seizure) QD q2 weeks, Protein binding: 55% 4–11 hr (ER) VPA. Toxicity inc’d
up to 375 mg by VPA. Dec’s
QD (500 mg OCPs (weak)
QD if on STerat low/safest
inducer). ER QD, (inc with dose).
IR BID. Dose CTerat low/safest.
adjust: for BF safe (in milk).
concurrent VPA/ Level dec in
CBZ/PHT/PHB pregnancy
Levetiracetam, Broad Synaptic vesicle Initial: First line for Irritability, mood Metabolism: 24% 10–45, though T ½: 6–8 hr Dec’d by CBZ.
LEV (Keppra) spectrum protein 2A 500–2000 mg sz > 5 min: changes (can occur hydrolysis in the blood, the effect is not Tpeak: 1 hr (IR) STerat low/safest
binding (Ca+, BID. Inc by 60 mg/kg, outside initial titration >65% renally excreted level dependent 4 hr (ER) CTerat low/ safest
K+, GABA) 500–1000 mg or 1–3 g period), weight loss. without metabolism Tpeak extended if taken BF safe (in milk)
q14 days (faster (max 4.5 g) Bone marrow Protein binding: <10% with food Level dec in
as inpatient) up over 15 min. suppression, pregnancy,
to 4000 mg/ 1:1 PO:IV eosinophilia, SJS starting in the first
day. Dose conversion trimester
adjust: renal

331
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Lorazepam, LZ Abortive for Benzodiazepine, For sz <5 Hypotension, Metabolism: hepatic, T ½: 12 hr (PO) Olanzapine IM +
(Ativan) prolonged or inc freq of min: 2 mg respiratory conjugated to 14 hr (IV) LZ IV inc’s risk of
cluster GABA receptor For sz >5 depression lorazepam glucuronide T ½ CNS: 2–3 hr CV/respiratory
seizures Cl- channel min: 0.1 (inactive) Tpeak: 2 hr (PO) depression. Inc’d
opening mg/kg up to Protein binding: 90% Onset: <10 min (IV) by VPA
4 mg per STerat/CTerat/BF
dose unknown (in milk).
Risk of neonatal
withdrawal
Midazolam, MZ Abortive for Benzodiazepine, For sz <5 Hypotension, Metabolism: hepatic T ½: 3 hr STerat/CTerat
prolonged or inc freq of min: can be respiratory Enzyme: CYP3A4 Tpeak: 0.5–1 h (IM) unknown, BF
cluster GABA receptor given IM at depression, sedation Inhibitor: CYP2C8, Onset: 15 min (IM) unknown (in milk)
seizures Cl- channel 0.2 mg/kg CYP2C9 (weak) T ½ prolonged in renal
opening up to 10 mg dysfunction
per dose
Oxcarbazepine, Focal seizure Na+ channels Initial: N/V, hypoNa (inc Metabolism: hepatic, Optimal MHD T ½: Dec’d by CBZ,
OXC (Trileptal) (can worsen (Ca+, K+), 300–600 mg responsiveness to non-CYP level 2–55 2 hr (OXC IR) PHT, PHB, VPA,
generalized) similar to CBZ QD. ADH) Prodrug for active mcg/ml (maybe 7–11hr (OXC ER) PRM. Inc’d by
Inc up to Rash, DRESS, SJS monohydroxy 8–35), though 9 hr (MHD IR) PER.
2400 mg daily (test Asians for metabolite (MHD) no clear 9–11 hr (MHD ER) Dec’s OCPs
(divided BID or HLA-B*1502, which 30% renally excreted evidence for Tpeak: 3–13 hr, (strong).
TID). Can load increases risk), as active MHD therapeutic median 4.5 hr (IR); 7 hr STerat moderate,
with 30 mg/kg. hypothyroidism Inducer: CYP3A4 importance of (ER) CTerat unknown,
May require Protein binding: 40% level Prolonged in renal BF unknown (OXC
higher doses as as MHD impairment and MHD in milk)
ER Level dec in
Dose adjust: pregnancy
severe renal
impairment

332
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Perampanel, PER Broad AMPA antagonist Initial: 2 mg Nausea, weight Metabolism: hepatic Monitor free T ½: 105 hr Dec’d by CBZ,
(Fycompa) spectrum Loading doses of qnightly gain, hostility/ Enzyme: CYP3A4/5 (unbound) conc Tpeak: 0.5–2.5 hr PHT, OXC, PRM
12-24 mg have Inc by 2 mg aggression with (major), 1A2/2BG in renal or (delayed 1–3 hr with Dec’s OCPs
been used for qweekly, up to suicidal/homicidal (minor), hepatic food) (strong)
Status. Discuss 12 mg QD ideation, rash. Acute glucuronidation impairment Takes 2 weeks to reach STerat/CTerat
with pharmacist Dose adjust: psychosis, DRESS, Protein binding: 95% On 6 mg QD, steady state unknown. BF
before using a renal, hepatic, hypertriglyceridemia average peak unknown
loading dose concurrent PHT/ conc is 460
CBZ/OXC ng/mL
On 12 mg QD,
average peak
conc is 800
ng/mL
Phenobarbital, Focal seizure Barbiturate, inc Initial: Second line Hypotension, Metabolism: hepatic, 10–40 mcg/ T ½: ~79 hr (53–118 Inc’d by OXC,
PHB/PB (some GABA duration 50–100 mg for sz > 5 bradycardia, 25% excreted renally mL, 25–50 in hr) PHT, RUF,
efficacy for (AMPA, Na+, BID-TID min: sedation, respiratory Enzyme: CYP2C19 status Tpeak: 0.5–4 hr PO VPA. Dec’s
generalized) Ca+, depresses Loading dose = 15–20 mg/ depression (major; genetic epilepticus. Onset: >1 hr (PO) warfarin, NOACs,
sensory cortex) desired kg (100 SJS, polymorphisms may Check 1–2 hr 5 min (IV) corticosteroids
level – measured mg/min), thrombocytopenia, affect conc), 2E1/2C9 after load Peak CNS depression Dec’s OCPs
level x (0.5 x can give agranulocytosis, (minor) As output, after IV dose is (strong)
ideal body additional megaloblastic Inducer: CYP2A6, check level in >15 min STerat high,
weight) 5–10 mg/kg anemia CYP3A4, UGTA1 3–4 weeks CTerat high,
Dose adjust: 1:1 PO:IV (strong) BF unknown (in
renal, hepatic conversion Protein binding: 55% milk)
Level dec in
pregnancy

333
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Phenytoin, PHT Focal seizure Na+ channels IR: 100 mg TID First line for Bradycardia, Metabolism: hepatic 10–20 mcg/ml, Michaelis-Menten Folic acid (0.5
(Dilantin) (some (Ca+) To inc, given sz > 5 min: hypotension (IV), Enzyme: CYP2C19 15–20 in status kinetics: first-order mg/day) may dec
efficacy for kinetics, Phenytoin gingival hypertrophy, (genetic polymorphisms epilepticus. kinetics at low conc, risk of gingival
generalized consider only 20 mg/kg body hair increase, may affect conc), 2C9, Check 2 hr but 0-order at hyperplasia. Ca
but can also additional load, (<50 mg/ folic acid depletion, 3A4 after dose therapeutic conc and vitamin D in
worsen with dose = min), can decreased bone Inducer: CYP3A4, PGP, See (enzymes saturated, chronic therapy.
generalized) (desired give density UGT1A1 (strong), “Pharmacology metabolism rate Monitor EKG and
level – measured additional Arrhythmia (IV), bone CYP1A2, 2B6 (weak) Tips for constant). Thus, small BP with IV
level) × (0.7 × 5–10 mg/ marrow suppression, Protein binding: 90% Commonly dose changes can yield formulation
weight in kg). kg, or hepatotoxicity, rash, Used AEDs” for big conc changes Inc’d by BRV,
Use adjusted fosphenytoin DRESS, SJS (test correction in T ½: 7–42 hr, dose CBZ, ESL, ESX,
body weight if 20 PE/kg Asians for patients with dependent FBM, OXC, RUF,
obese (150 mg/ HLA-B*1502, which low albumin Tpeak: 1.5–3 hr (IR) CBD. VPA dec’s
Otherwise, min) can increases risk). Purple As outpatient, 4–12 hr (ER) PHT protein
adjust qweekly give glove syndrome (IV) check level 2–3 Onset: 0.5–1 hr (IV) binding, may inc
up to 600 mg/ additional 5 weeks after the free level Dec’d by
day mg/kg first dose CBZ, PHB,
ER: Load with 1 Monitor EKG VGB. Altered by
g in 3 doses 2 and BP CZP
hr apart (400, 1:1 PO:IV Dec’s OCPs
300, 300). Then conversion (strong), warfarin,
100 mg TID (or NOACs,
300 mg QD), corticosteroids
adjust qweekly STerat moderate,
up to 200 mg CTerat low, BF
TID safe (in milk)
Pregabalin, PGB Focal seizure Voltage-gated Initial: 150 mg/ Peripheral edema, >95% renally excreted T ½: 6.3 hr Used for
(Lyrica) Ca+ channel, day (divided weight gain, visual without metabolism Tpeak: 0.7 hr fasting, 3 neuropathic pain
inhibits NT BID-TID) loss Protein binding: 0% hr with food (IR) STerat/CTerat
release Inc up to 600 8 hr (ER) unknown. BF
mg/day unknown (in milk)
Dose adjust:
renal

334
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Primidone, PRM Broad Barbiturate, inc Initial: 100 mg N/V Metabolism: 75% Follow level T ½ (age dependent): Used for tremor
(Mysoline) spectrum GABA duration qnightly. After 3 Bone marrow hepatic, 25% renally (and PHB level) PRM 5–16 hr, PEMA Inc’d by FBM,
(AMPA, Na+, days, BID. After suppression, rash excreted in renal or 16–50 hr, PHB ~79 hr VPA. Dec’d by
Ca+, depresses 3 days, Metabolized to hepatic Tpeak: 0.5–9 hr PHT. Toxicity inc’d
sensory cortex) TID. Usual dose phenobarbital and impairment. by TPM. Dec’s
750–1500 mg PEMA (which enhances Goal 5–12 OCPs (strong),
(divided activity of mcg/ml (SI warfarin, NOACs,
TID-QID), max of phenobarbital) 23–55 corticosteroids
2 g/day Inducer: CYP3A4 micromole/L). Pregnancy risk
Dose adjust: (strong), CYP1A2, Toxicity rare for presumed similar
renal, hepatic 2B6, 2C9 (weak) level <10 (SI to PHB: STerat
Protein binding: 10% 46). Toxicity high, CTerat high,
>15 (SI >69). BF unknown (in
Two weeks for milk)
steady state
Rufinamide, RUF Broad Prolongs inactive Initial: 400–800 N/V, QT interval Metabolism, hepatic, T ½: 6–10 hr Dec’d by CBZ,
(Banzel) spectrum, state of Na+ mg/day shortening non-CYP. Renally Tpeak: 4–6 hr, PHB, PHT, PRM.
Lennox- channels (divided BID), Bone marrow excreted prolonged by food Inc’d by VPA
Gastaut <400 mg/day if suppression Inducer: CYP 3A4 Dec’s OCPs
syndrome concurrent VPA (weak) (weak)
Inc by Inhibitor: CYP2E1 STerat/CTerat
400–800 mg (weak) unknown. BF
per day q2 days Protein binding: 35% unknown
up to 3200 mg/
day
Avoid in liver
failure
Tiagabine, TGB Focal seizure Inhibits GABA Initial: 4–8 mg Nausea, infection, Metabolism: hepatic Trough of T ½: 7–9 hr STerat/CTerat
(Gabitril) (can worsen reuptake QD. accidental injury Enzyme: CYP3A4 50–250 nmol/L Tpeak (fasting): 45 min unknown. BF
generalized) Inc by 4 mg Edema, rash Protein binding: 95% has been unknown
qweekly, up to suggested, not
32–56 mg/day well established
(BID-QID)

335
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Topiramate, Broad Multi-(Na+, Ca+, Initial: 25 mg Paresthesia, Metabolism: <30% Level of 5–20 T ½: IR 12–24 hr, Monitor HCO3.
TPM/TOP spectrum GABA, BID metabolism acidosis hepatic non-CYP, >65% correlates with Qudexy XR 56 hr, Migraine ppx, IIH
(Topamax, antagonist of Inc by 50 mg (inhibits carbonic renally excreted response for Trokendi XR 31 hr treatment. Dec’d
Qudexy, NMDA) qweekly up to anhydrase, causing without metabolism most patients Tpeak: IR 2 hr by CBZ, PHT.
Trokendi) 200 mg BID renal bicarb loss), Inducer: CYP3A4 Qudexy XR 20 hr, >200 mg/day,
(400 mg QD ER) anorexia, weight Inhibitor: CYP2C19 Trokendi XR 24 hr dec’s OCPs
Dose adjust: loss, diarrhea. Protein binding: 10% (weak). STerat
renal, hepatic Nephrolithiasis, moderate-high
glaucoma (e.g., oral cleft),
CTerat unknown,
BF unknown (in
milk). Small for
gestational age
risk. Level dec in
pregnancy
Valproic acid, Broad Multi–(GABA, Initial: 15 mg/ First line for Hyperammonemia Metabolism: hepatic Total level: T ½: 9-19 hr Migraine ppx and
valproate, VPA spectrum, Na+, Ca+) kg/day sz > 5 min: (30% of pts, treat Enzyme: multiple Goal 50–100 Tpeak: mood stabilizer.
(depakote, idiopathic (regular/ 20–40 mg/ with levocarnitine), CYP450 mcg/ml, 4 hr (IR) Monitor LFTS 1–2
depakene, genetic depakene and kg (200 hair loss, N/V, Inducer: CYP2A6 70–140 in 4-17 hr (ER) times per year.
divalproex) epilepsy delayed/ mg/min), weight gain. (weak/mod) status Divalproex is
syndromes depakote can give Thrombocytopenia, Inhibitor: CYP2C9 epilepticus. valproate +
BID-QID; ER additional hypothyroidism, (weak) Check >1 hr valproic acid,
QD). Inc 20 mg/kg PCOS, pancreatitis, Protein binding: 95% after loading dissociates to
qweekly by 1:1 PO:IV parkinsonism dose. Toxicity valproate in GI
5–10 mg/kg/ conversion 100–150. As tract. Dec’d by
day, up to 60 output, check CBZ, PHT, OCPs.
mg/kg/day trough level Inc’d by FBM,
When 1–2 weeks, PRM. Toxicity
converting goal 50–125 inc’d by
depakote to ER: mcg/ml. Free TPM. Inc’s
inc dose by level goal: warfarin (dec’s
8–20% 5–15 mcg/ml protein binding).
Dose adjust/ STerat high,
caution: hepatic CTerat high, BF ok
if fetus already
exposed in utero
(in milk)

336
OTHER (E.G.,
MONITORING,
SIDE EFFECTS DRUG
SEIZURE (COMMON, RARE METABOLISM/ INTERACTIONS,
NAME TYPE MECHANISM PO DOSING IV DOSING BUT BAD) BINDING LEVEL INFO PHARMACOKINETICS PREGNANCY)
Vigabatrin, Focal seizure Irreversibly Initial: 500 mg N/V/D, visual loss >90% renally excreted T ½: 10.5 hr STerat/CTerat
VGB/VBT (Sabril) (can worsen inhibits GABA-T BID (black box warning), without metabolism Tpeak: 1 hr (2 hr with unknown. BF
generalized) enzyme, Inc by 500 mg blurred vision Protein binding: 0% food) unknown (in milk)
increasing GABA qweekly up to White matter
1500 mg BID changes, rash, URI
Dose adjust:
renal
Zonisamide, ZNS Broad Na+, Ca+ Initial: 100–200 Anorexia Metabolism: hepatic T ½: 63 hr Dec’d by PHT,
(Zonegran) spectrum, mg/day (QD or Metabolic acidosis, Enzyme: CYP3A4 Tpeak: 2–6 hr PHB
myoclonic BID) nephrolithiasis Protein binding: 40% STerat low, CTerat
epilepsy Inc up to 600 (carbonic anhydrase unknown, BF
mg/day. No inc inhibitor), decreased unknown (in milk).
response >400 sweating Small for
mg/day, with gestational age
inc adverse risk
effects >300
mg/day
Dose adjust:
renal, hepatic
(slow titration)

337
DRUG-DRUG INTERACTIONS COMMON
IN NEUROLOGY PATIENTS
Stephanie Seto, Amanda Rivera, and Megan E. Barra

DEFINITIONS [1]
• Substrate: A substrate is a drug that binds to a specific enzyme and metabolized by
that enzyme. Substrate metabolism may be affected by enzyme inhibitors or
enzyme inducers.
• Inducer: Compounds that either increase the production of the enzyme or increase
the activity of the enzyme, which results in increased metabolism and therefore
lower concentrations of substrate. The time course of induction is dependent on
drug half-life and time required to upregulate metabolizing enzymes and may take
several weeks to see effect. Enzyme induction may persist for several weeks after
inducer discontinuation and may result in decreased substrate efficacy.
• Inhibitor: Compounds that inhibit the activity of the enzyme, which results in
decreased metabolism and therefore higher concentrations of substrate. The time
course of inhibition dependent on drug half-life, but usually see the effects of
enzyme inhibitors on affected agents within 24–48 hours. Enzyme inhibition will
resolve several days after inhibitor discontinuation and increased the risk for
substrate toxicity.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
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339
CYP EXAMPLE OF SUBSTRATES [3] INDUCERS INHIBITORS
3A4 Neurologic Aripiprazole, Carbamazepinea, Amiodarone, azole
carbamazepine, modafinil, antifungals,
ethosuximide, oxcarbazepine, diltiazem, ritonavir,
haloperidol, phenytoin, verapamil
mirtazapine, phenobarbital,
quetiapine, sertraline, primidone, rifampin
trazodone, zolpidem
Analgesics Fentanyl, hydrocodone,
methadone, oxycodone
Anti-thrombotic Apixaban, rivaroxaban,
warfarin, prasugrel,
ticagrelor
Cardiovascular Amiodarone, diltiazem,
verapamil, nicardipine,
nimodipine, statins
Immunosuppressants Cyclosporine,
tacrolimus
Anti-infectives Atazanavir, efavirenz,
ritonavir, clarithromycin,
erythromycin
1A2 Neurologic Amitriptyline, Carbamazepine, Amiodarone,
clozapine, desipramine, phenobarbital, ciprofloxacin,
duloxetine, phenytoin, primidone, isoniazid
fluvoxamine, rifampin, smoking
haloperidol,
rasagilinae, ropinirole
Analgesics Methadone,
cyclobenzaprine
Anti-thrombotic Warfarin
2C8 Cardiovascular Amiodarone Phenytoin, Gemfibrozil,
phenobarbital, trimethoprim
rifampin
2C9 Neurologic Diazepam, phenytoin, Carbamazepine, Amiodarone,
ramelteon, zolpidem phenobarbital, fenofibrate,
Anti-thrombotic Warfarin phenytoin, primidone, fluconazole,
rifampin fluoxetine, isoniazid,
valproic acid

340
CYP EXAMPLE OF SUBSTRATES [3] INDUCERS INHIBITORS
2C19 Neurologic Citalopram, phenytoin, Carbamazepine, Esomeprazole,
primidone phenobarbital, felbamate,
Analgesics Methadone phenytoin, rifampin fluconazole,
Anti-thrombotic Clopidogrel fluoxetine, isoniazid,
Anti-infective Voriconazole modafinil,
omeprazole,
voriconazole
2D6 Neurologic Aripiprazole, Amiodarone,
clozapine, donepezil, bupropion,
duloxetine, haloperidol, duloxetine,
risperidone, tricyclic fluoxetine,
antidepressants methadone,
Analgesics Codeine, hydrocodone, paroxetine,
meperidine, sertraline
oxycodone, tramadol
Cardiovascular Carvedilol, metoprolol,
propranolol
PgP Anti-thrombotic Apixaban, dabigatran, Carbamazepine, Amiodarone,
efflux rivaroxaban phenytoin, rifampin erythromycin,
Cardiovascular Digoxin verapamil, ritonavir

Note: This is not an all-inclusive list of drug-drug interactions, but an overview of strong, moder-
ate, or notable interactions with commonly used medications. Please use clinical judgment
before the concomitant use of other medications not listed in the table above.
a
Carbamazepine is an autoinducer; therefore, over time, carbamazepine will induce its own
metabolism resulting in lower serum concentrations of the drug

MAJOR DRUG-DRUG INTERACTIONS COMMON IN NEUROLOGY PATIENTS

• AED-AED interactions
° See Comprehensive AED Guide for interactions and effects between AEDs
(page 327).
• Valproate-Carbapenems [1, 5, 6]
° Valproate levels are significantly decreased (up to 90%) within 24–72 hours of
carbapenem administration (meropenem, ertapenem, imipenem/cilastatin).
° It may take 1–4 weeks for valproate levels to recover after discontinuation of
therapy (even if only one dose is given!)
° Bottom line: Use an alternative AED when concurrent carbapenems are utilized.

341
• Valproate-Phenytoin [2]
°V alproate displaces phenytoin from plasma protein binding sites, significantly
increasing free (active) phenytoin. Total phenytoin concentration may remain the
same or decrease. Exercise extreme caution when interpreting total phenytoin
levels on patients receiving both valproate and phenytoin.
° Bottom line: Avoid combination when possible. If combination therapy is
used, recommend monitoring free phenytoin levels.
• Phenytoin, Phenobarbital, Carbamazepine, and Anticoagulation
° DOACS: Phenytoin, phenobarbital, and carbamazepine significantly induces the
metabolism of DOACs (apixaban, dabigatran, rivaroxaban, edoxaban) and may
result in therapeutic failure. Avoid the combination of phenytoin, phenobarbital,
or carbamazepine with DOAC anticoagulants [4].
° Warfarin: Many AEDs impact warfarin; closely monitor INR during initiation and
dose changes of AED and/or warfarin.

REFERENCES
1. Spoelhof B, Farrokh S, Rivera-Lara L. Drug interactions in neurocritical care. Neurocrit Care.
2017;27(2):287–96.
2. Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for con-
cern? Epilepsia. 2013;54(1):11–37.
3. CYP450 drug interactions. Pharmacists Lett 2006.
4. Galgani A, Palleria C, Iannone LF, et al. Pharmacokinetic interactions of clinical interest between
direct oral anticoagulants and antiepileptic drugs. Front Neurol. 2018;9:1067.
5. Mori H, Takahashi K, Mizutani T, et al. Interaction between valproic acid and carbapenem antibi-
otics. Drug Metab Rev. 2007;39(4):647–57.
6. Al-Quteimat LA. Valproate interaction with carbapenems: review and recommendations. Hosp
Pharm. 2020;55(3):182–8.

342
MYASTHENIA GRAVIS: MEDICATIONS TO AVOID
Megan E. Barra and John Y. Rhee

• The following medications have been reported to cause worsening of myasthenia

gravis symptoms and/or precipitate myasthenic crisis in patients with a diagnosis of
myasthenia gravis [1–11].
• Clinicians should use alternative agents when possible to avoid complications of
myasthenia gravis. If these agents are required and benefit deemed to outweigh
risk associated with use, patient education and close monitoring of exacerbation of
symptoms should occur.

MEDICATION
CLASS EXAMPLES COMMENTS
Antimicrobials [3]
Aminoglycosides Amikacin, gentamicin, Avoid use, unless no alternative therapy
tobramycin available. Impairs neuromuscular transmission.
Colistin/ Colistin, colistimethate Use cautiously and only if no alternative
polymyxin B sodium, polymyxin B treatment available. Impairs neuromuscular
transmission.
Fluroquinolones Ciprofloxacin, Avoid use, if no alternative available use very
levofloxacin, moxifloxacin cautiously. Black box warning for use in
MG. Disrupts neuromuscular transmission.
Lincosamides Lincomycin Avoid use. Pre- and post-synaptic effects on
neuromuscular junction.
Macrolides Azithromycin, Avoid use, if no alternative available use very
clarithromycin, cautiously. Telithromycin has black box warning
erythromycin, telithromycin for use in MG. Inhibits neuromuscular
transmission.
Penicillamine Penicillamine, Avoid use. Induces autoimmune myasthenia
penicillamine (D-) gravis and reported to occur in 1–7% of all
patients on penicillamine.
Antimalarial Chloroquine, Avoid use if possible, case reports of impaired
hydroxychloroquine [4] neuromuscular transmission with
hydroxychloroquine and chloroquine
utilization.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_67
343
MEDICATION
CLASS EXAMPLES COMMENTS
Cardiac agents [5]
Procainamide Use with caution, may worsen MG. Pre- and
post-synaptic impairment of neuromuscular
transmission.
Beta Blockers Atenolol, labetalol, Use with caution, may worsen MG. Dose-
metoprolol, propranolol, dependent reduction in neuromuscular
sotalol transmission in experimental studies with both
pre- and post-synaptic effects. Nonselective
beta-blockers (e.g., propranolol) may have
more marked effects than selective beta-
blockers (e.g., metoprolol)
Miscellaneous
Immune Atezolizumab, avelumab, Immune checkpoint inhibitors have been shown
checkpoint ipilimumab, nivolumab to both exacerbate and precipitate myasthenia
inhibitors [7] pembrolizumab gravis. Coordination between oncologists and
neurologists should occur prior to therapy
initiation to develop therapy plans that mitigate
the risk of worsening of MG symptoms.
Iodinated Loxitalamate meglumine, Weigh risk versus benefit associated with
contrast lobitridol imaging. Reports of worsening of MG
symptoms with both high- and low-osmolality
contrast media, though modern contrast agents
appear safer. In one study, 6.3% of MG
patients had worsening of MG symptoms
within 1 day of iodinated contrast
administration compared to 0.6% of those who
received unenhanced CT.
Live vaccines Yellow fever vaccine Use is not recommended in patients with
myasthenia gravis. Risk of yellow fever
vaccine-associated viscerotropic disease.
Magnesium Magnesium sulfate, Use parenteral magnesium cautiously and only
(Intravenous) magnesium chloride if no alternative treatment available
Magnesium inhibits release of ACh from
neuromuscular junction and can worsen
symptoms of MG. Avoid hypermagnesemia.

344
MEDICATION
CLASS EXAMPLES COMMENTS
Neuromuscular Depolarizing Relative resistance and prolonged duration of
Blocking agents neuromuscular blocking action due to decreased Ach receptors. Often
agents (e.g., higher doses are required (up to 2× normal
succinylcholine) dose). Inhibition of hydrolysis of succinylcholine
in patients on anti-cholinesterase inhibitors (e.g.
pyridostigmine) at baseline further prolongs
duration of action.
Nondepolarizing Increased sensitivity and prolonged duration of
Neuromuscular blocking action. Often significantly lower doses are
agents (e.g., required (50% of normal dose). May be
Cisatracurium, preferred neuromuscular blocker over
rocuronium, vecuronium) succinylcholine.
Steroids Hydrocortisone, May cause transient worsening of myasthenia
(Intravenous) dexamethasone, gravis within first 2 weeks of use. Initiation of
methylprednisolone, steroids for treatment of myasthenia gravis or
triamcinolone other indications should be closely monitored.
Many different agents have, in rare instances, been associated with worsening of
myasthenia gravis or development of new-onset myasthenia gravis in case
reports or in experimental studies exhibiting impaired neuromuscular
transmission. Clinical significance of these interactions is less clear compared to
those listed above and may include:
Cardiac agents Calcium channel blockers To mitigate risk with these agents: Use lowest
(e.g. verapamil), statins dose necessary and observe for worsening of
[6] (e.g. atorvastatin, symptoms
rosuvastatin, simvastatin) • Worsening respiratory symptoms with NIF
Antimicrobials Bactrim and VC either trending down. High concern
(sulfamethoxazole/ if NIF < 20 cm H2O and/or VC <1 L. Can
trimethoprim), also check with weakening neck flexion,
clindamycin, doxycycline, inability to count to >20 with one breath,
nitrofurantoin, ampicillin rapid worsening of weakness of baseline
Antiepileptic Carbamazepine, myasthenia weakness.
drugs [9] ethosuximide, gabapentin,
phenobarbital, phenytoin
CNS agents Amitriptyline,
dexamphetamine,
imipramine, haloperidol,
lithium
Misc [10, 11] Riluzole, glatiramer

Avoid use
Consider other agents
Case reports, unclear significance

345
REFERENCES
1. Mehrizi M, Fontem RF, Gearhart TR, Pascuzzi RM. Medications and myasthenia gravis (a ref-
erence for health care professionals). Myasthenia Gravis Foundation of America; 2015. http://
www.myasthenia.org/portals/0/draft_medications_and_myasthenia_gravis_for_MGFA_web-
site_8%2010%2012.pdf.
2. Myasthenia Gravis Foundation of America. Cautionary drugs. New York: Myasthenia Gravis
Foundation of America, Inc; 2019.
3. Jones S, Sorbello A, Boucher R. Fluoroquinolone-associated myasthenia gravis exacerbation:
evaluation of postmarketing reports from the US FDA adverse event reporting system and a
literature review. Drug Saf. 2011;34(10):839–47.
4. Jallouli M, Saadoun D, Eymard B, et al. The association of systemic lupus erythematosus and
myasthenia gravis: a series of 17 cases, with a special focus on hydroxychloroquine use and a
review of the literature. J Neurol. 2012;259(7):1290–7.
5. Jonkers I, Swerup C, Pirskanen R, et al. Acute effects of intravenous injection of beta-
adrenoreceptor- and calcium channel at antagonists and agonists in myasthenia gravis. Muscle
Nerve. 1996;19(8):959–65.
6. de Sousa E, Howard J. More evidence for the association between statins and myasthenia gra-
vis. Muscle Nerve. 2008;38(3):1085–6.
7. Safa H, Johnson DH, Trinh VA, et al. Immune checkpoint inhibitor related myasthenia gravis: sin-
gle center experience and systematic review of the literature. J Immunother Cancer. 2019;7:319.
8. Lee SC, Ho ST. Acute effects of verapamil on neuromuscular transmission in patients with myas-
thenia gravis. Proc Natl Sci Counc Repub China B. 1987;11(3):307–12.
9. So EL, Penry JK. Adverse effects of phenytoin on peripheral nerves and neuromuscular junction:
a review. Epilepsia. 1981;22(4):467–73.
10. Restivo DA, Bianconi C, Ravenni R, et al. ALS and myasthenia: an unusual association in a
patient treated with riluzole. Muscle Nerve. 2000;23(2):294–5.
11. Frese A, Bethke F, Lüdemann P, et al. Development of myasthenia gravis in a patient with mul-
tiple sclerosis during treatment with glatiramer acetate. J Neurol. 2000;247(9):713.

346
PARKINSON’S DISEASE: MEDICATIONS TO AVOID
Amanda Rivera and Megan E. Barra

• The following medications have been reported to cause worsening of Parkinson’s

disease symptoms in patients with a diagnosis of Parkinson’s disease [1–4]
• Clinicians should use alternative agents when possible to avoid complications of
Parkinson’s disease. If these agents are required and benefit deemed to outweigh
risk associated with use, patient education and close monitoring of exacerbation of
symptoms should occur

ALL PARKINSON’S DISEASE PATIENTS

Medications to AVOID Mechanism of What can I use!?
interaction
Typical antipsychotics Haloperidol, Blockade of dopamine Quetiapine
chlorpromazine, D2 receptors in the
fluphenazine, loxapine, CNS If IV agent required,
thioridazine, consider benzodiazpine
thiothixene, for acute sedation to
trifluoperazine, facilitate administration
pimozide, of oral antipsychotic
perphenazine
If acute life-threatening
agitation, benefit may
outweigh risk for IV
typical antipsychotics
(i.e. haloperidol)
Atypical antipsychotics Olanzapine, Blockade of dopamine Quetiapine
risperidone, receptors in the Clozapine may be
ziprasidone, CNS. More rapid considered in severe
lurasidone, dissociation from D2 chronic cases
paliperidone, receptor compared to
iloperidone, typical antipsychotics. Both clozapine and
brexpiprazole, Cause less parkinsonism quetiapine have been
cariprazine, asenapine symptoms than typical observed in randomized
antipsychotics. clinical trials to be
effective without
Per AAN, olanzapine significant worsening of
has an unacceptable motor symptoms
risk of motor
deterioration and
should be avoided.

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8_68
347
ALL PARKINSON’S DISEASE PATIENTS
Antiemetics Chlorpromazine, Blockade of dopamine Ondansetron
metoclopramide, D2 receptors in the
prochlorperazine, CNS
promethazine,
droperidol
GI motility Metoclopramide Blockade of dopamine Erythromycin
D2 receptors in the
CNS
Antihypertensives Resperpine, Decrease dopamine Typical anti-hypertensive
methyldopa stores or inhibition of agents (i.e. ACEi, ARBs,
enzymatic conversion of CCB, BB) appropriate
L-dopa to dopamine
Antidepressants Phenelzine, Block monoamine SSRIs, SNRIs, burpropion,
tranylcypromine, oxidase nonselectively. etc. Agent selection
isocarboxazid If taken in combination individualized to patient
with certain classes of symptoms. Use
PD meds, these serotonergic agents with
medications could result caution/close monitoring
in dangerous increases in patients on rasagiline
in blood pressure and or selegiline (increased
agitation risk of serotonin
Amoxapine Although classified as a syndrome)
tricyclic anti-depressant,
it can also block
dopamine receptors
In patients on rasagiline or selegiline ONLY
*MAO-B inhibitors have potential additive serotonergic effect when used in
combination with other serotonergic medications via inhibition of serotonin
metabolism and activation of the 5HT receptors*
Medications to AVOID
Antidepressants Most antidepressants interact with MAO-B inhibitors including SSRIs, SNRIs,
trazodone, isocarboxazid, nefazodone, phenelzine, tranylcypromine, St.
John’s Wort
Neurologic Cyclobenzaprine
Analgesics Meperidine, methadone, tramadol
Pulmonary Dextromethorphan, pseudoephedrine, ephedrine
Anti-infectives Linezolid

348
REFERENCES
1. DeMaagd G, Philips A. Parkinson’s disease and its management: part 3 Nondopaminergic and
nonpharmacologic treatment options. PT. 2015;40(10):668–79.
2. Grissinger M. Delayed administration and contraindicated drugs place hospitalized Parkinson’s
patients at risk. PT. 2017;43(1):10–2.
3. Parkinson’s Disease Update Quality Measurement Development Work Group. Am. Acad. Neurol.
Minneapolis, MN; 2015:1–56.
4. Rebecca Gilbert. Medications to be avoided or used with caution in Parkinson’s disease.
American Parkinson Disease Association. New york; 2018: p. 1–10.

349
NIH Stroke Scale [1, 2]

C. S. W. Albin, S. F. Zafar (eds.), The Acute Neurology Survival Guide,
https://doi.org/10.1007/978-3-030-75732-8
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NIH Stroke Scale [1, 2]

352
353
NIH Stroke Scale [1, 2]

354
355
NIH Stroke Scale [1, 2]

356
357
REFERENCES
1. Brott T, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864–70.
2. Lyden P, Brott T, Tilley B, Welch KM, Mascha EJ, Levine S, et al. Improved reliability of the NIH Stroke Scale
using video training. NINDS TPA Stroke Study Group. Stroke. 1994;25:2220–6.

358
Index

A Angio-negative subarachnoid hemorrhage, 230

Abducens (CN VI) nerve palsy, 15 Ani-NMDA-R encephalitis, 155
Acute demyelinating encephalomyelitis (ADEM), Anisocoria, 13
155, 175, 177 Anterior cord syndrome, 279
Acute ischemic stroke Anticoagulation
anticoagulation, 103 atrial fibrillation
computed tomography, 34–36 annualized stroke risk, 99–100
emergency department management, 61–64 mechanical valves, 100
endovascular treatment and screening, 64–65 symptomatic carotid stenosis, 100
large vessel occlusion hemorrhagic transformation, 101–103
anterior circulation occlusion, 65–66 intracranial hemorrhage
posterior circulation occlusion, 66 early management, 225
scoring metrics, 67 risk factors, 226
Acute necrotizing encephalopathy, 155 subacute and late management, 225–226
ADEM, see Acute demyelinating timing of resumption, 226
encephalomyelitis (ADEM) weighing risk/benefit of, 103
AEDs, see Anti-epileptic drugs (AEDs) Anti-epileptic drugs (AEDs)
α1 adrenergic receptors, 313 AAN practice guidelines, 138
Altered mental status (AMS), 129 lacosamide, 143
high yield exam, 130 levetiracetam, 141
management, 131 phenytoin, 143–144
review chart/history, 130 valproate, 142
testing, 131 ANTI-MOG syndrome, 177
workup of, 130 Anti-platelet agents, 215
Andexanet alfa, 221–222 Anti-seizure medication (ASM) chart
Anesthetic infusions for refractory status, 327 in adults, 327–337
Aneurysmal subarachnoid hemorrhage (SAH) Autoimmune encephalitis testing, 163–164
admission and early management, 231–232 Autoimmune encephalopathy, 163
daily management principles Autonomic dysreflexia, 280
cerebral edema, 238
delayed cerebral ischemia, 236–238
hydrocephalus, 235–236 B
systemic complication, 238–239 β1 adrenergic receptors, 313
seizure prophylaxis, 315 β2 adrenergic receptors, 313
venous thromboembolism prophylaxis, 318 Bradycardia, 277

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Brain death testing, 50 major intraoperative complications, 293
ancillary testing, 301 postoperative complications, 294
organ donation, 301 procedure, 293
preparation for, 300–301 vascular craniotomy-specific postoperative
ventilator autotriggering, 299–300 orders, 295
Brain lesions, 133–135 Cerebral edema, 238
Brainstem, anatomy, 323–324 Cerebral perfusion pressure (CPP), 50
Brain Trauma Foundation Guidelines, 188 Cerebral venous thrombosis (CVT), 315
Brain tumor Cerebrovascular patients, 291–297
seizure prophylaxis, 315 Chronic subdural hematomas, 248
venous thromboembolism prophylaxis, 319 Coma exam
Brown-Sequard syndrome, 279 decerebrate posturing, 10
decorticate posturing, 10
GCS, 9
C herniation syndrome, 11
Carotid artery stenting (CAS) mental status, 10
vs. CEA, 95–96 Computed tomography (CT)
plaque instability, 96 acute hemorrhage, 32
treatment herniation syndrome, 33
after surgery/stenting, 97 hydrocephalus assessment, 33
prior to surgery, 96 indications, 29
surgery timing, 97 neuroanatomy, 30–31
Carotid endarterectomy (CEA) in stroke, 34–36
vs. CAS, 95–96 Constructive Inference in Steady State (CISS), 134
interventional vs. medical treatment, 95 Continuous EEG monitoring
plaque instability, 96 examples of, 265
treatment 2HELPS2B score, 266
after surgery/stenting, 97 indications, 263
prior to surgery, 96 terminology, 263–264
surgery timing, 97 Convulsive status epilepticus, 259
Cavernous malformation Cranial nerve testing
definition, 292, 297 anisocoria, 13
intraoperative monitoring, 293 caloric testing, 17
major intraoperative complications, 293 cough reflex, 19
postoperative complications, 294 extraocular eye movement abnormalities, 14–16
procedure, 293 facial weakness patterns, 18
vascular craniotomy-specific postoperative gag reflex (pharyngeal reflex), 19
orders, 295 Craniectomy, 283–284
Cavernous sinus (CS) pathology, 16 Craniotomy, 283, 288
CEA, see Carotid endarterectomy (CEA) case study, 288–289
Cell-binding assay, 163 checklist for admission, 284
Central cord syndrome, 279 complications, 285–286
Cerebellitis, 159 diffuse pneumocephalus, 285, 287
Cerebellum, 159 general admission orders, 284
Cerebral amyloid angiopathy, 209, 226 neurological exam, 285, 287
Cerebral aneurysm tension pneumocephalus, 285, 287
definition, 292 wakes up from surgery, 285
intraoperative monitoring, 293 Cerebral perfusion pressure (CPP), 187
major intraoperative complications, 293 Cerebrovascular resistance regulation
postoperative complications, 294 (CVR), 187–188
procedure, 293 C-spine trauma
vascular craniotomy-specific postoperative anatomy, 273
orders, 295 Canadian rules, 275
Cerebral angiogram, 288 clearance in the obtunded trauma
Cerebral arteriovenous malformation (AVM) patient, 276
definition, 292, 296 collar removal, in awake patient, 275
intraoperative monitoring, 293 Dens fracture, 274
360
injuries, 273–274 External ventricular drains (EVDs), 191,
MRI, 276 197–198, 207
NEXUS rule, 275 Extracranial disease, 113
CT angiogram (CTA), 34–36
CVR, see Cerebrovascular resistance
regulation (CVR) F
Factor-Xa inhibitor reversal therapy, 221–223
Fast Imaging Employing Steady-state Acquisition
D (FIESTA), 134
Decerebrate posturing, 10 18
FDG-PET brain, 134
Decorticate posturing, 10 Fibrinolytics, 219
Delayed cerebral ischemia (DCI) Flow cytometry, 163
monitoring for, 236–237
treatment and prevention of, 237–238
Demyelinating lesion, 175–177 G
Diabetes insipidus, management and treatment Generalized periodic discharges (GPDS), 265
of, 308–309 Generalized rhythmic delta activity
Diffuse pneumocephalus, 287 (GRDA), 265
Diffuse traumatic brain injury, 248 Glasgow Coma Scale (GCS), 9
Digital subtraction angiography (DSA), 134 Guillain-Barre syndrome, 173, 269–270
Direct oral anticoagulants (DOACs), 119
Dix-Hallpike maneuver, 180
Dizziness H
definition, 179 2HELPS2B score, 266
diagnosis, 181 Hemorrhage
localization, 181 computed tomography, 32
management, 182–183 magnetic resonance imaging, 41
TiTraTE method, 179–180 Hemorrhagic transformation (HT), 101–103
treatment, 181 Herniation syndrome, 11, 33
Dizzy patient, 179–183 High frequency filter (HFF), 55
Drug-drug interactions, in neurology Hydrocephalus, 235–236
patients, 339–342 Hypernatremia
complications, 307
etiology, 307
E monitor, 307
EEG, see Electroencephalogram (EEG) in NeuroICU, 307–309
Electroencephalogram (EEG) pathophysiology, 307
data optimization, 55 signs/symptoms, 307
electrodes, 55 treatment of, 308
LPDs, 54 Hyperosmolar therapy, 194–195
seizures, 53, 56–57 Hypertensive hemorrhage, 225
spectrogram, 56–57 Hyponatremia, in NeuroICU, 311–312
Electrographic seizures, 264 Hypotension, 277
Encephalitis
CNS penetration, 149–150
signs, 145 I
treatment, 148–149 ICH, see Intracranial hemorrhage (ICH)
workup, 146–147 Ictal-interictal continuum (IIC), 264
Endovascular thrombectomy management of, 266
large vessel occlusion proposed algorithm, 267
anterior circulation occlusion, 65–66 IIC, see Ictal-interictal continuum (IIC)
posterior circulation occlusion, 66 Immunofluorescence assay (IFE), 163
treatment and screening, 64–65 Induction immunosuppression, 157
Enzyme immunoassay, 163 Infectious workup, 159–161
Epley Maneuver, 182 Inflammatory/autoimmune encephalitis, 155–157
External ventricular catheters, 197–198 Intracerebral hemorrhage, 315

361
Intracranial hemorrhage (ICH) in infectious/inflammatory/neoplastic
anticoagulation management, 225–227 conditions, 42–43
landmark trials, 211–213 sequences, 37–38
venous thromboembolism prophylaxis, 318 in stroke, 39–40
Intracranial pressure (ICP), 50 Malignant middle cerebral artery infarction, 199–203
invasive ICP monitoring, 190–191 Maximum intensity projection (MIP), 36
management of, 193–196 Mean arterial blood pressure (MAP), 187–189
theory and formulas central to neurocritical MAP, see Man arterial blood pressure (MAP)
care, 187–189 Mechanical thrombectomy (MT), 66, 109–112
waveform interpretation, 191–192 Medial longitudinal fasciculus (MLF) injury, 15
Intracranial stenosis, 114 Meningitis
Intraparenchymal fiberoptic sensor, 191 infectious
Intraparenchymal hemorrhage CNS penetration, 149–150
admission checklist, 207 CSF findings, 148
early management, 207, 210 signs, 145
labs, 207 treatment, 148–149
non-traumatic, 205–206 workup, 146–147
ongoing management, 207 non-infectious, 151–153
scoring systems, 208–209 seizure prophylaxis, 316
Intravenous fluid compositions, 325–326 Mental status examination, 10
Invasive neuro-monitors, 190 Microbleeds, 226
Ischemic stroke, 50 Middle meningeal artery (MMA) embolization, 248
admission checklist, 75–77, 90 Miosis, 13
anticoagulation, 99–103 Moya-moya disease
aspirin vs. anticoagulation, 92 definition, 292
CAS, 95–97 major intraoperative complications, 293
CEA, 95–97 postoperative complications, 294
extracranial vs. intracranial, 91 procedure, 293
history, 89 vascular craniotomy-specific postoperative
pathophysiology, 90 orders, 295
seizure prophylaxis, 315 MRI, see Magnetic resonance imaging (MRI)
signs and symptoms, 89 Multiple sclerosis (MS), 175, 177
symptomatic definition, 95 McDonald criteria, 175, 176
venous thromboembolism prophylaxis, 318 Myasthenia gravis, 173, 270–271
medications class, 343–345
Mydriasis, 13
L
Lacunar syndrome, 27
Large vessel occlusion (LVO) N
anterior circulation occlusion, 65–66 Neurogenic shock, 277
outcomes, 64 NeuroICU
posterior circulation occlusion, 66 hypernatremia, 307–309
Lateralized periodic discharges (LPDs), 54, 265 hyponatremia, 311–312
Lateralized rhythmic delta activity (LRDA), 265 intravenous fluid compositions, 325–326
L’Hermitte sign, 175 nutrition, 303–305
Lindegaard Ratio (LR), 49 pressors and inotropes, 313–314
Linnoila and Pittock and the Mayo Clinic seizure prophylaxis, 315–316
Laboratories antibody matrix, 163–164 venous thromboembolism prophylaxis, 317–319
Lumbar drains (LDs), 197 Neurologic complications, 254
LVO, see Large vessel occlusion (LVO) Neuromuscular disease, 319
Neuromyelitis optica (NMO), 177
spectrum disorders, 155
M Neuroprognosis
Magnetic resonance imaging (MRI) history, 255
contrast enhancement, 45 monitoring for, 254
diffusion restriction patterns, 44 perspective in, 255
in hemorrhage, 41 Neuroprotection, 254
362
Neurovascular pathologies, 292–297 neurological exam, 285, 287
New onset weakness wakes up from surgery, 285
differential diagnosis, 167 Potential injury, anatomical locations of, 167
evaluation, 168 Pre-rounding patient
Guillain-Barré, selected variants of, 173 on ICU patients, 5
selected screening evaluation, 169–172 neuro floor patients presentation, 3–4
upper and lower motor neuron findings, 168 NeuroICU patients presentation, 6–7
Non-contrasted head CTs (NCHCT) on neurology patients, 3
acute hemorrhage, 32 PRES, see Posterior reversible leukoencephalopathy
herniation syndrome, 33 syndrome (PRES)
hydrocephalus assessment, 33 Pressors and inotropes, in NeuroICU, 313–314
indications, 29 Pulsatility index (PI), 49
neuroanatomy, 30–31
in stroke, 34–36
Nonconvulsive status epilepticus (NCSE), 259 R
Non-traumatic intraparenchymal Radioimmunoassay (RIA), 163
hemorrhage, 205–206 RCVS, see Reversible cerebral vasoconstriction
Normothermia, 253, 255 syndrome (RCVS)
Nutrition, in NeuroICU, 303–305 Refractory status epilepticus (RSE), 259
Respiratory failure, with Guillain-Barré
syndrome, 269
O Respiratory insufficiency, 277
Oculomotor (CN III) nerve palsy, 14 Reversal of selected antithrombotics, 215–219
One-and-a-half syndrome, 16 Reversible cerebral vasoconstriction
Optic neuritis, 155 syndrome (RCVS)
Oral anticoagulants, 215–218 clinical features, 123
imaging characteristics, 124
management principles, 125
P medications, 123
Paraneoplastic antibody panel, 163 Reversing direct factor Xa-inhibitor-related
Parenteral anticoagulants, 218 hemorrhages, 221–223
Parkinson’s disease, medications class, 347–348 Rhombencephalitis, 159
Perfusion imaging Rhythmic and periodic patterns, 264
ischemic core vs. penumbra, 72–73
techniques, 71
Perimesencephalic non-aneurysm SAH, 229 S
Peripheral weakness, etiology of, 169 Seattle Severe traumatic Brain Injury Consensus
Pressure reactivity index (PRx), 189 Conference (SIBICC) algorithm, 193
PFO closure, 114–115 Seizure, 137–138
Polyneuropathy, 269 Seizure prophylaxis, in NeuroICU, 315–316
Posterior reversible leukoencephalopathy Severe traumatic brain injury (sTBI), 193
syndrome (PRES) Spinal cord injury
clinical features, 123 ICU management of
imaging characteristics, 124 admission checklist, 277–278
management principles, 125 classic syndromes, 279
medications, 123 prognostication, 280
seizure prophylaxis, 316 steroids and spinal injury, 278
Postoperative craniotomy subacute to late complications, 280
complications, 285–286 venous thromboembolism prophylaxis, 319
diffuse pneumocephalus, 285, 287 Spinal shock, 277
seizure prophylaxis, 315 Sporadic epileptiform discharges, 264
tension pneumocephalus, 285, 287 Status epilepticus, 259–262
Postoperative management adjunctive workup, 261–262
cerebrovascular patients, 291–297 definitions, 259
craniotomy patient medications, 260–261
checklist for admission, 284 treatment preparation, at onset of
general admission orders, 284 seizure, 259–260
363
Stroke middle cerebral artery, 48
anterior circulation, 21–24 monitoring, 49
anticoagulation, 105–107 posterior cerebral artery, 48
anti-platelets, 105 principles, 47
arterial hypercoagulable state, 79–80 SAH, 49
computed tomography, 34–36 Transient ischemic attack (TIA), 112–113
etiology, 87 Transverse myelitis, 168
lacunar syndrome, 27 Traumatic brain injury (TBI)
magnetic resonance imaging, 39–40 dexamethasone, 248
posterior circulation, 25–27 emergent management, 245–246
thromboembolic disease, 82–83 focal lesions, 248
vasculopathy, 84–86 framework for, 245
venous hypercoagulable state, 81 Glasgow Coma Scale, 245
Subarachnoid hemorrhage (SAH) ICU management, principles of, 247
aneurysmal SAH middle meningeal artery embolization, 248
admission and early management, 231–232 monitor ICP, 246
daily management principles, 235–239 seizure prophylaxis, 315
application in, 49 surgical management, 248
differential, 229–230 trials, 251–252
notable trials, 241–243 venous thromboembolism prophylaxis, 318
scoring systems, 233 Trochlear (CNIV) nerve palsy, 14
Subjective Data, Objective Data, Assessment, Plan
(SOAP) style, 3–4
Sub-occipital/retrosigmoid/translabyrinthine U
craniotomies, 288 Uhthoff phenomenon, 175
Superrefractory status epilepticus (SRSE), 259 Urinary retention, 277
Syndrome of inappropriate anti-diuretic hormone
(SIADH), 311–312
V
Vascular lesions, seizure prophylaxis, 315
T Vasculopathy, 84–86
TBI, see Traumatic brain injury (TBI) Venous sinus thrombosis (VST)
TCDS, see Transcranial dopplers TCDS acute treatment, 119
Temporal lobe encephalitis anatomy, 117
with HSV limbic encephalitis, 159 chronic treatment, 119–120
with post-HSV anti-NMDA-R encephalitis, 157 neuroimaging findings, 118
Tenecteplaste (TNK), 62–64 risk factors, 117–118
Tension pneumocephalus, 287 symptoms, 118
Thromboembolic disease, 82–83 workup, 119
TIA, see Transient ischemic attack (TIA) Venous thromboembolism prophylaxis, in NeuroICU
Tissue factor pathway inhibitor (TFPI), 221 indications, 318–319
Tissue plasminogen activator (tPA) pharmacologic agents, 317
criteria for, 62 VITAMIN Mnemonic, 169
mechanical thrombectomy, 66, 109–112 VST, see Venous sinus thrombosis (VST)
TNK screening, 62–64
tPA, see Tissue plasminogen activator (tPA)
Transcranial dopplers (TCDS) W
application of, 47, 50 Western blot (WB), 163

364

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The Acute Neurologi

Uploaded by

The Acute Neurologi

Uploaded by

The

The Acute Neurology

© Springer Nature Switzerland AG 2022

For the trainee in neurology, neurosurgery, or intensive care medicine—and

Aaron Berkowitz, MD, PhD

Atlanta, GA, USA Catherine S. W. Albin

Part I A Comprehensive “How-To” Guide

Part II Vascular Neurology

11 Perfusion Imaging����������������������������������������������������������������������������������������� 71

Part III Nonvascular Inpatient Neurology

25 Approach to Infectious Encephalitis and Meningitis������������������������������� 145

40 Intracranial Hemorrhage – Management of Anticoagulation ��������������� 225

56 Preparation for Brain Death Testing��������������������������������������������������������� 299

Part V Important References

Catherine S. W. Albin, MD Department of Neurology, Emory University School of

John Y. Rhee, MD, MPH Department of Neurology, Massachusetts General

A COMPREHENSIVE “HOW-TO” GUIDE

PRE-ROUNDING ON NEUROLOGY PATIENTS

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

PRE-ROUNDING ON ICU PATIENTS

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

PRESENTING NEUROICU PATIENTS

GLASGOW COMA SCALE

Minor brain injury = 13–15 points; moderate brain injury = 9–12 points; severe brain injury = 3–8 points

their arms to their “Core”

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

Fig. 3.1 Decorticate and Decerebrate Posturing

TIPS FOR THE MOTOR EXAM

Step 3: Look for associated pathology.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

Pupil-sparing/subtle right CN III:

Full right CN III (looking straight):

Right CN IV palsy: Patients may complain of diplopia when

Patient told “Look right”

Right one-and-a-half (due to R-INO + R-CN

Patient told “look right”

Pathology in the CS usually starts with a III

Test both the patients ability to raise eyebrows and

Smile weak but eyebrow Both smile and eyebrow

Upper Motor Neuron Lower Motor Neuron

Localizes to an injury Localizes to the 7th

TESTING COUGH REFLEX

ANTERIOR CIRCULATION ANATOMY

Anterior ICA Terminus

Recurrent artery Lenticulostriate

Adapted from Adams and Victor’s Principles of Neurology [1].

ANTERIOR CIRCULATION – MAJOR BRANCHES

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

Anterior ICA Medial Contralateral hemiplegia and

Recurrent ACA Caudate Variable. Weakness of

Medial Proximal Anterior Variable. Dysarthria, stuttering

MCA – MCA Wernicke’s Superior quadrantanopia or

Chief Indications for Non-Contrast Head CT (NCHCT)

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

AT THE LEVEL OF THE AT THE LEVEL OF THE

1 – Pons 1 – Pons 1 – Midbrain/Cerebral Peduncle

1 – Midbrain 1 – Thalamus 1 – Frontal Lobe

EXAMPLES OF ACUTE HEMORRHAGE

Often qualified as “deep” “Casting of the Ventricles” refers

EXAMPLES OF HERNIATION SYNDROMES ON CT SCAN

blood matter predominate

T2 Dark: edema in a patient with

• Minerals: iron, copper, calcium Posterior Reversible

• Highly cellular lesions Syndrome (PRES)

• Acute, early subacute and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022

GRE: Large R parieto-­

SWI: Small, cortical bleed

DWI demonstrating restriction in the left frontal lobe

ADC dark area confirming ischemia in the same

GRE demonstrating hypointense blood products with

GRE sequence demonstrating focal blood

MR Venography demonstrates patchy filling

T2 FLAIR: Medial Temporal Lobe T2

DWI: Diffusion restriction due to an

Reconstructed Perfusion Image

Atlanta, GA, USA Catherine S. W. Albin

Part I A Comprehensive “How-To” Guide

Part II Vascular Neurology

11 Perfusion Imaging�� 71

Part III Nonvascular Inpatient Neurology

25 Approach to Infectious Encephalitis and Meningitis�� 145

40 Intracranial Hemorrhage – Management of Anticoagulation �� 225

56 Preparation for Brain Death Testing�� 299

Part V Important References

PRE-ROUNDING ON NEUROLOGY PATIENTS

PRE-ROUNDING ON ICU PATIENTS

PRESENTING NEUROICU PATIENTS

GLASGOW COMA SCALE

TESTING COUGH REFLEX

ANTERIOR CIRCULATION ANATOMY

ANTERIOR CIRCULATION – MAJOR BRANCHES

1 – Pons 1 – Pons 1 – Midbrain/Cerebral Peduncle

EXAMPLES OF ACUTE HEMORRHAGE

EXAMPLES OF HERNIATION SYNDROMES ON CT SCAN

• Minerals: iron, copper, calcium Posterior Reversible

• Highly cellular lesions Syndrome (PRES)

• Acute, early subacute and

GRE: Large R parieto-

BASIC PRINCIPLES [1]

COMMON APPLICATION OF TCDS

OPTIMIZING EEG DATA

EMERGENCY DEPARTMENT MANAGEMENT

TPA (TNK) SCREENING

ENDOVASCULAR TREATMENT AND SCREENING

SUMMARY OF WHO IS LIKELY TO BENEFIT FROM THROMBECTOMY IN ANTERIOR

POSTERIOR CIRCULATION OCCLUSIONS

CONFIRM PATIENT ORDERED FOR

ISCHEMIA DUE TO ARTERIAL HYPERCOAGULABLE STATE

ISTORICAL POINTS, SIGNS, AND SYMPTOMS THAT SHOULD RAISE CONCERN

INTERVENTIONAL VS. MEDICAL TREATMENT

CAROTID ENDARTERECTOMY (CEA) VS. CAROTID STENTING (CAS)

TREATMENT PRIOR TO SURGERY

FACTORS THAT DEMONSTRATE PLAQUE INSTABILITY

TREATMENT AFTER SURGERY OR STENTING

PART 1: RISK AND BENEFIT OF ANTICOAGULATION BY POPULATION SUBGROUP:

ATA ABOUT THE EFFECTIVENESS OF ANTICOAGULATION IN ATRIAL FIBRILLATION

Symptomatic Carotid Stenosis

PART 3: WEIGHING RISK/BENEFIT OF EARLY ANTICOGAULATION

DUAL ANTIPLATELET FOR MINOR STROKE/TRANSIENT ISCHEMIC ATTACK

PFO CLOSURE TRIALS