Accepted Article

DR. KARTHIK VINAY MAHESH (Orcid ID : 0000-0001-7163-1190)

Article type : Original Article

TITLE PAGE

Title: Carbamazepine Versus levetiracetam in epilepsy due to neurocysticercosis

Authors: Akhil P Santhosh1, Manoj Kumar Goyal2, Manish Modi2, Parampreet S Kharbanda2, Chirag
K Ahuja3, Naresh Tandyala2, Nandita Prabhat2, Rajveer Singh2, Sahil Mehta2 , Karthik Vinay
Mahesh2

1Department of Internal Medicine, Postgraduate Institute of Medical Education and Research,

Chandigarh, India- 160012

2Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh,

India- 160012

3Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and

Research, Chandigarh, India- 160012

Corresponding author

Dr Karthik Vinay Mahesh, MD, DM

Senior Resident, Department of Neurology, PGIMER, Chandigarh, India-160012

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/ANE.13355
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 Email: skarthikvm@gmail.com
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Ph: 91-1722756691

Ph: 91-7087007347

Other authors

1. Dr Akhil P Santhosh, MD
Junior Resident,
Department of Internal Medicine
PGIMER, Chandigarh, India-160012
Email: santhoshakhilps@gmail.com
Ph: 91-1722756691
2. Dr Manoj Kumar Goyal, MD, DM
Additional Professor, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: goyal_mk@yahoo.com
Ph: 91-7087008271; 91-172275691
3. Dr Manish Modi, MD, DM
Professor, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: modim72@yahoo.com
Ph: 91-7087009694; 91-172275691
4. Dr Parampreet Singh Kharbanda, MD, DM
Professor, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: neuroparam@hotmail.com
Ph: 91-7087009696; 91-172275691
5. Dr Chirag Kamal Ahuja, MD, DM
Assistant Professor, Department of Radiodiagnosis and Imaging, PGIMER, Chandigarh,
India-160012
Email: chiragkahuja@rediffmail.com

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 Ph: 91-7087008565; 91-172275691
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6. Dr Naresh Tandyala, MD
Senior Resident, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: nareshtandyala@gmail.com
Ph: 91-1722756691
7. Dr Nandita Prabhat, MD
Senior Resident Department of Neurology, PGIMER, Chandigarh, India-160012
Email: nandita.prabhat1@gmail.com
Ph: 91-1722756691
8. Dr Rajveer Singh, MD, DM
Assistant Professor, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: rajveersaharan@gmail.com
Ph: 91-172275691
9. Dr Sahil Mehta, MD, DM
Assistant Professor, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: mehtasahilpgi@gmail.com
Ph: 91-172275691
10. Dr Karthik Vinay Mahesh, MD, DM
Senior Resident, Department of Neurology, PGIMER, Chandigarh, India-160012
Email: skarthikvm@gmail.com
Ph: 91-1722756691

RUNNING TITLE: Carbamazepine versus Levetiracetam in NCC

Key words: Neurocysticercosis, Epilepsy, Carbamazepine, Levetiracetam

Source of funding : None

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 Acknowledgements: None
Accepted Article
Conflicts of interest: Authors do not have any conflicts of interest

Data value statement: Data available on request from the authors

Abstract

Carbamazepine Versus levetiracetam in epilepsy due to neurocysticercosis

Background:

The choice of antiepileptic drug (AED) in newly diagnosed neurocysticercosis (NCC) patients
with epilepsy continues to be arbitrary. We compared efficacy and side effect profile of Levetiracetam
(LEV) and carbamazepine (CBZ) for the treatment of seizures in newly diagnosed patients with NCC.

Patients and methods This was an open labelled randomized comparative monotherapy study
including newly diagnosed drug naïve patients of NCC (n=99) presenting with seizures who were
randomized in 1:1 ratio using computed generated numbers. All patients were followed up for at least
six months after start of treatment. The primary outcome measure was seizure control over six months
following start of AEDs.

Results: 15 (15.2%) patients [CBZ- 4(8.2%); LEV- 11(22%)] developed recurrence of seizures. A
trend (P=0.09) was found towards better control of seizures in CBZ compared to LEV. 2 (4%)
patients in LEV group and 17 (34.6%) patients in CBZ group developed drug related minor side
effects (p<0.0001). 3 patients in CBZ group needed discontinuation of therapy due to skin rash. 11
patients who relapsed while on LEV did not have any recurrence of seizures after switching over to
CBZ. Out of 3 patients who relapsed while receiving CBZ and were changed to LEV, two developed
seizures during follow up.

Conclusion: CBZ and LEV could be used as alternatives in newly diagnosed patients of NCC at the
behest of minor side effects in the CBZ group

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 Carbamazepine Versus levetiracetam in epilepsy due to neurocysticercosis
Accepted Article
INTRODUCTION

Antiepileptic drugs (AEDs) play an important role in management of neurocysticercosis (NCC), one
of the commonest cause of adult onset seizures in India and other developing countries.1,2 These
should be continued till the epileptogenic focus (live or degenerating cyst or brain inflammation
surrounding the cyst) resolves completely. The cysts may persist indefinitely or resolve completely or
become calcified, which may still act as a focus of epileptic activity and require a longer coverage
with AEDs.3

In most of the patients of NCC, seizures are well controlled with a single AED. The choice of AED
depends on various factors including efficacy, side effect profiles and cost of the drug, the last factor
being especially important in developing countries.3

A major factor in deciding the choice of AEDs in developing countries such as India is the
affordability. Thus, most of the patients receive carbamazepine (CBZ) or phenytoin (PHT) as first line
therapy owing to their lower cost. However levetiracetam (LEV) is being increasing used as first line
AED in NCC even in countries like India. This puts an additional burden on poor people as cost of
LEV is approximately 3-6 times the cost of other first line agents namely PHT or CBZ. Though there
is data to support use of LEV in focal onset seizures4, the literature is scanty with respect to
comparison of LEV with CBZ in NCC. Thus, we planned to compare LEV and CBZ regarding their
efficacy in the treatment of seizures and side effect profiles in newly diagnosed patients with NCC.

METHODS

This was an open labelled randomized comparative monotherapy study was conducted at a tertiary
care institute in North India from July 2017 to December 2018. The study included newly diagnosed
drug naïve patients of NCC presenting with seizures. They were randomized in 1:1 ratio to LEV or
CBZ as first line AED therapy, using random allocation by computed generated random numbers. All
patients were followed up at 12 and 24 weeks and on as and when required basis to see the efficacy
and side effect profile of both drugs. The total duration of follow up was 24 weeks for all patients

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 .The study was approved by institutional ethics committee and written informed consent was obtained
Accepted Article
from all the patients before inclusion in the study. The inclusion and exclusion criteria for the study
are given below:

Inclusion Criteria:

1. Age greater than 14 years

2. Diagnosis of NCC according to Del Brutto diagnostic criteria1

3. Drug naïve patients with NCC

4. NCC as sole cause of seizure (for instance if it is perceived that NCC seen in index patient
may not be the cause of his seizures, he/ she will be excluded from the study)

5. Patients willing to give written informed consent.

6. Patients willing for follow up.

Exclusion Criteria:

1. Well defined epilepsy syndromes such juvenile myoclonic epilepsy etc.

2. Any other space occupying lesion in brain such as brain tumor

3. Pregnant or lactating women.

4. Hepatic or renal dysfunction.

5. Reversible causes of seizure e.g. hypoglycemia, hypocalcemia etc.

6. History of osteoporosis, Cytopenias ,hyponatremia for carbamazepine

7. History of psychiatric illness for levetracetam

8. Patients not willing for follow up

STUDY DESIGN

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 Once enrolled, all the patients underwent detailed history and examination as per a predesigned
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performa. Neuroimaging [gadolinium enhanced Magnetic resonance imaging (Gd MRI) of brain] was
done in all the patients. All patients of NCC were given standard treatment of steroids either oral or
intravenous at an equivalent dose of prednisolone 1mg/kg and Albendazole 15mg/kg / day for 14
days wherever they were indicated according to the consensus guidelines (12).After ascertaining that
cause of seizures in index patient is NCC, the patient was screened for eligibility for administration of
either CBZ or LEV. If there were no contraindications to either of the drugs, patient was randomized
to receive either LEV or CBZ as first line AED. LEV was started at a dose of 10mg/kg/day i.e 500 mg
per day (250 mg twice daily) which was gradually increased to 20mg/Kg while CBZ was started at a
dose of 4-6 mg/kg/day i.e. 200mg once daily and then gradually increased to 10 mg / kg / day i.e. 400-
600mg daily over a period of 2- 4weeks. Tolerability was defined as the degree to which overt
adverse effects of a drug can be tolerated by a patient.

Patients were followed at 12 and 24 weeks interval to study the efficacy and side effect profile of both
drugs. All the patients were followed for a minimum of six months after starting the study drug. In
case of recurrence of seizures on therapeutic doses of allotted AEDs or occurrence of serious adverse
effects or intolerability the drugs were switched over to each other. All the patients received
additional antihelminthic treatment as well as steroids as per the latest guidelines. All the clinical and
radiological data were noted meticulously . The side effects of the drugs were explained and self-
reported by the patient themselves. All drug related side effects were noted .Patients were advised to
come for follow up in case of seizure recurrence or drug related adverse effects. Clinical screening of
Side effects was done by the investigators(Dr. APS, Dr. MKG, Dr. MM ) involved in the study .
Decision regarding continuation/ increase or decrease in dosage/ stoppage of AED was taken by the
treating team. The outcome measures for the study are given below:

Primary outcome measure:

Seizure control over six months following start of study drug

Secondary outcome measures:

1. Drug related side effects- both dose and non-dose related.5-8,13

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 2. Need to change drug for lack of efficacy or intolerability
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Statistical Analysis

Continuous variables were compared using Student’s t test or Mann Whitney U test depending on
whether variable has a parametric or non- parametric distribution respectively. Two tailed paired t-test
or Wilcoxon Signed rank test was used for paired samples .Independent‘t’ test for comparisons of
unpaired samples . Discrete variables were analyzed by Chi square test and Fisher exact test. P value
<0.05 was considered significant in all statistical evaluations.

RESULTS

Demographic profile: Current study enrolled 99 drug naïve patients suffering from epilepsy due to
NCC. The mean age of study group was 25.06 ± 10.1 years (range: 12-55 years). The mean age in
CBZ group was 22.51±8.9 years (range: 12-44 years), while in the LEV group, it was 27.56±10.7
years (range 13-55 years). Study group included 74 men (LEV group-39; CBZ group -35). On
comparison mean age was found to be significantly lower (p=0.01) in CBZ group compared to LEV
group while gender distribution was similar in two groups. In LEV group, 38 (76%) subjects had
generalized onset tonic clonic seizures (GOTCS/FOBTCS)or focal onset with bilateral tonic –clonic
seizures and 12 (24%) had focal onset seizures without bilateral tonic –clonic (24%), while in CBZ
group, 31 (63.3%) subjects had (GOTCS/FOBTCS) and 18 (36.7%) subjects had focal onset seizures.
Headache was the second most common symptom seen in 43 (43.4%) of patients [CBZ-22; LEV-21].
None of the patients had any evidence of encephalitis, raised intracranial pressure or focal deficits.
None of the patient has any abnormality on neurological examination. 31 (31.3%) [CBZ-13; LEV-18]
patients had calcified lesions. 67 (67.7%) [CBZ-32; LEV-35] patients had single lesion, 14 (14.1%)
[CBZ-10; LEV-4] patients had two lesions, while 18 (18.2%) patients [CBZ-7; LEV-11] had more
than two lesions. The different types of NCC noted among patients with single lesion (n=67) were:
Vesicular – 26 (26.3%) [CBZ-15; LEV-11], colloidal -21 (21.2%) [CBZ-11; LEV-10] and granular-

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 14 (14.1%) [CBZ-9; LEV-6]. These as well as other clinical, laboratory and management data are
Accepted Article
summarized in table 1.

Therapy and resolution of lesions

57 (57.6%) patients [CBZ-33; LEV-24] received albendazole (15mg/Kg daily over two weeks), while
71(71.6%) [CBZ-36; LEV-35] subjects received steroids for variable duration. Among 68 patients
with noncalcified lesions, 42 (61.8%) [CBZ-41; LEV-32] subjects showed complete resolution of
lesions, 19 (27.9%) [CBZ-6; LEV-13] showed partial resolution, while 7 (12.3%) [CBZ-2, LEV-5]
did not show any change at follow up (Table.2). There was a non-significant trend towards higher
use of albendazole and complete resolution of lesions in CBZ compared to LEV group.

Control of seizures

All patients were followed for a period of at least 6 months after starting AEDs. Overall, 15 (15.2%)
patients [CBZ- 4(8.2%); LEV- 11(22%)] developed recurrence of seizures. On comparison, the CBZ
group had lesser recurrences 4(8.2%) than LEV group 11(22%) however the differences were not
statistically significant (p=0.09).

Side effects of drugs: Frequency and nature

At used doses, only 2 (4%) patients in LEV group reported drug related side effects, while 17 (34.6%)
patients in CBZ group developed drug related side effects. On comparison this difference was
statistically highly significant (p<0.0001). The low reporting of psychiatric side effects in LEV group
could be attributed the stigma associated with psychiatric symptoms among the patients and general
population despite adequate education about possible psychiatric side-effects(14) .However most of
the side effects in CBZ therapy were minor, dose related and required mild decrease in dose reduction
only and did not require change of therapy. Overall three patients needed discontinuation of therapy
due to CBZ related serious adverse effects (3- skin rash). This difference between the two groups was
statistically insignificant (table 3).

Need for change of drugs

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 Overall 11 patients who relapsed while treatment on LEV, were crossed over to CBZ arm. None of
Accepted Article
the CBZ cross over group (n=11) had any recurrence of seizures on follow up. Out of 3 patients who
had recurrences while receiving CBZ and were change to LEV, 2 developed seizures during follow
up.

Factors affecting follow up control of seizures

In current study, we also determined various factors influencing recurrence of seizures at follow up.
We compared various clinical features, socio demographic characteristics, NCC related parameters
(number of lesions, type of lesions, presence or absence of perilesional edema, resolution of lesions at
follow up, detection of cysticercal antibodies) and type of seizures etc on control of seizures at follow
up. On analysis, only use of CBZ showed anon significant trend (p=0.09) towards better control of
seizures among NCC patients when compared to LEV, however if we had included the patients from
cross over group as well , the recurrence would have been significantly lower in CBZ compared with
LEV without a compromise over minor side effect in CBZ group.

DISCUSSION

Neurocysticercosis is a preventable parasitic infection of the central nervous system which continues
to be one of the leading cause of epilepsy in developing countries including India. Lot of research has
already been done on the epidemiology, etiopathogenesis and diagnostic modalities of the disease.
The predominant presenting complaint in a case of Neurocysticercosis is seizures and worldwide,
very little work has been done on seizure control in NCC.

In our study, we have compared two drugs, namely Levetiracetam and Carbamazepine in terms of
their efficacy for seizure control in all newly diagnosed NCC patients presenting with seizures as their
major complaint. As part of secondary outcomes of our study, we also evaluated incidence and
severity of their adverse effects.

Mean age of study group was 25.1±10.1 years which is consistent with other studies9 from
subcontinent. Thus, NCC affects people in prime of their life. The gender ratio was also consistent
with other studies from Indian subcontinent 9. The likely reason for male predominance is related to
more exposure of men to NCC acquiring risk factors while working outdoors.

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 In the study of Carrabin et al 10, seizures were the most common presenting symptom (78.8%)
Accepted Article
followed by headache (37.9%), focal deficits (16%) and signs of raised ICP (11.7%). These results
were in contrast to our study. This is likely the result of inherent bias in selection of patients in our
study. In current study, patients who were already on AEDs at time of presentation were excluded.
The patients with more serious manifestations of NCC are likely to be on treatment from outside and
were likely to be on AEDs at time of 1st presentation to our institute and thus got excluded. In current
study, calcified cysts contributed to 31.3%, which was similar to previously published data.11 Type,
number and location of NCC was similar to that reported previously from our center.11

All subjects in present study fulfilled the Del-Brutto diagnostic criteria for NCC. LEV and CBZ were
administered in fixed dose combinations via randomization (computer generated numbers) and
patients were followed up for a period of 6 months for analysing control of seizures and side effects.

In the CBZ group, only 4 subjects (8.2%) developed recurrence, while in the LEV group, 11 (22%)
subjects developed seizure recurrence. On comparison, a non-significant trend was found towards
better control of seizures in CBZ compared to LEV group. There was not enough data in literature to
compare this finding with those of other authors. Overall 11 patients who relapsed while treatment on
LEV, were switched over to CBZ arm. They did not have any recurrence of seizures at follow up. Out
of 3 patients who relapsed while receiving CBZ and were change to LEV, two developed seizures
during follow up. All these observations suggest that CBZ may provide better control of seizures at
lower cost in newly diagnosed patients of NCC when compared to LEV.

This is an important observation in the sense as LEV is currently one of the most commonly
prescribed 1st line agent for control of seizures. The cost of LEV is approximately 3-5 times that of
CBZ and it puts a heavy burden on people in developing countries to use such costly drugs for
prolonged periods. Results of our study indicate that we can continue to use CBZ to be used as first
line agent for control of seizures in NCC especially in economically weaker strata. The other aspect
including the possible effects of drug interactions between Albendazole and CBZ needs to be
highlighted but since the combination will used only in the initial cysticidal therapy and CBZ needs a
longer anti-epileptic therapy, this interaction will be short lasting.

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 With respect to the side effect profile, only 2 (4%) of patients in LEV group reported drug related side
Accepted Article
effects, while 17 (34.6%) developed drug related side effects in CBZ group. On comparison this
difference was statistically highly significant (p<0.0001). However most of the side effects in CBZ
therapy were minor, dose related and required mild decrease in dose reduction only and did not
require change of therapy. The use of a sustained release formulation of CBZ may tide over a majority
of these side effects. Overall only three patients needed discontinuation of therapy due to CBZ related
skin rash.

The main limitation of current study was that cohort of NCC patients was not consecutive as patients
who were on antiepileptic drugs from elsewhere got excluded. Also, patients who presented with
flurry of seizures or status epilepticus got excluded as they need to be given parenteral drugs and CBZ
is not available in parenteral form. Main strength was a stringent and strict protocol and no loss to
follow up. To conclude results of our study could suggest that both CBZ and LEV could be used as
alternatives in newly diagnosed patients of NCC at the behest of minor side effects in the CBZ group.
Future studies employing larger sample size and employing more drugs will further help in clarifying
status of different AEDs in NCC.

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1. Del Brutto OH, Rajshekhar V, White AC, et al. Proposed diagnostic criteria for
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2. Del Brutto OH. Neurocysticercosis. Handb Clin Neurol 2014;121:1446–159.

3. Sharma M, Singh T, Mathew A. Antiepileptic drugs for seizure control in people with
neurocysticercosis. Cochrane Database Syst Rev 2015;3:1550-1555.

4. Abou-Khalil B, Hemdal P, Privitera MD. An open-label study of levetiracetam at

individualised doses between 1000 and 3000 mg day (-1) in adult patients with refractory
epilepsy. Seizure 2008;12(2):141–9.

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 5. Al Khalili Y, Jain S. Carbamazepine Toxicity. StatPearls [Internet]. Treasure Island (FL):
Accepted Article StatPearls Publishing; 2019 Jan-2019 Apr 14.

6. Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of
their efficacy and tolerability. Epilepsia 1997;38(4):859—80.

7 Arif H, Buchsbaum R, Weintraub D, et al. Comparison and predictors of rash associated with
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8. Valencak J, Ortiz-Urda S, Heere-Ress E, et al. Carbamazepine-induced DRESS syndrome with

recurrent fever and exanthema. Int J Dermatol 2004;43(1):51-54.

9. Saxena S, Chaudhary A, Bansal N, et al. Neurocysticercosis. IOSR-J Dental Mental Sci

2016;15(1):2279-2285.

10. Carabin H, Ndimubanzi PC, Budke CM, et al. Clinical manifestations associated with
Neurocysticercosis: A Systematic Review. PLoS Neg Trop Dis 2010;34(2):246-52

11. Goyal M, Chand P, Modi M, et al. Neurocysticercosis: An uncommon cause of drug-refractory

epilepsy in North Indian population. Epilepsia 2015;56(11):1747-52.

12. García HH, Evans CAW, Nash TE, et al. Current consensus guidelines for treatment of
neurocysticercosis. Clin Microbiol Rev. 2002. doi:10.1128/CMR.15.4.747-756.2002

13. Kanner AM, Ashman E, Gloss D, et al. Practice guideline update summary: Efficacy and
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Accepted Article
Table 1: Comparison of demographic, clinical and laboratory profile between two study
groups

Parameter Carbamazepine group Levetiracetam group p

Number of patients Number of patients
(percentage) (percentage)
(n=49) (n=50)
Mean (± SD)age in years 22.51±8.9 27.56±10.7 0.01
Male sex 35 (71.4%) 14 (28.6%) NS
Type of seizures NS
Focal to bilateral tonic –clonic or 31 (63.3%) 38 (76%)
generalised onset
Focal onset without bilateral 18 (36.7%) 12 (24%)
tonic-clonic
Headache 22 21 NS
Type of NCC NS
Calcified 13 18
Vesicular 15 11
Colloidal 11 10
Granular 9 6
Multiple types 1 5
Presence of Perilesional edema 38 37 NS
Scolex seen 21 20 NS
Number of lesions
One 32 35 NS
Two 10 4
>2 7 11
NCC serology positive 6 12 NS
Abb. NS- nonsignificant; NCC- neurocysticercosis, SD- standard deviation

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Accepted Article
Table 2: Comparisons of neurocysticercal specific therapies and resolution of
neurocysticercosis at follow up among two groups

Parameter CBZ group (n=49) LEV group (n=50) p

Use of albendazole 33 24 0.07
Use of steroids 36 35 0.92
Resolution of lesions 0.08
Complete 41 32
Partial 6 13
Nil 2 5
Abb. CBZ- carbamazepine; LEV- Levetiracetam

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Accepted Article
Table 3: Comparison of seizure control between CBZ and LEV groups

Lab parameter CBZ LEV P value

(n=49) (n=50)

Seizure recurrence 4(8.2%) 11 (22%) 0.09

Drug related 17(34.6%) 2 (4%) (Dizziness- <0.0001

adverse effects* (dizziness-6, 1; Drowsiness-1)
drowsiness-6, skin
rash-3,gait ataxia-
1, weight gain-1)
Need for 3 nil NS
discontinuation
due to side effects
Abb. CBZ- carbamazepine; LEV- Levetiracetam

*Reported by patients and assessed by the investigators

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