Hypotonia, neuromuscular disorders

Floppy infant A floppy infant is an infant with decreased muscle tone

Tone is often defined as resistance to passive movement at a joint.
Muscle tone alterations may also be concluded from a child's posture.
Postural tone is the prolonged contraction of antigravity muscles in response to low intensity stretch of gravity
The maintenance of normal tone requires intact central and peripheral nervous systems
Assessment History taking, Look into the following:
of the floppy FHx: Three-generation pedigree, consanguinity, recurrent infantile deaths, parental age, Hx of neuromuscular diseases
infant Maternal Hx: systemic disease, drug Hx, unrecognized myotonic dystrophy
Pregnancy: fetal movement, drug exposure, poly-/oligohydramnios, breech presentation
Delivery: asphyxia, APGAR, resuscitation, cord gases
Postnatal: feeding, alertness, respiratory effort, spontaneous activity
Course of floppiness
Clinical signs
in a floppy
infant

Frog like posture

Slipping through the fingers on vertical suspension
Ragdoll appearance on ventral suspension
The traction response showing head lag and excessively rounded back
Associations: Flat occiput, hair loss from occipital region, arthrogryposis, congenital dislocation of the hips and inguinal hernia
Causes Hypotonia may be due to a disease affecting:
1) the motor unit (consisting of the anterior horn cell in the spinal cord, its axon in the peripheral nerve, the neuromuscular
junction, and the muscle fibers it supplies)
2) the suprasegmental structures or the "upper motor neuron" (the spinal cord, brainstem, cerebellum, and the cerebral
hemispheres)
Clues to Presence of abnormalities of other brain functions (eg. decrease LOC, seizures)
central Dysmorphic features
nervous Fisting of the hands
system Scissoring on vertical suspension
pathology Malformations of other organ
Normal or brisk deep tendon reflexes
Central Hypotonic Cerebral palsy
disorders Chromosomal disorders including Down’s syndrome and Prader Willi
that could Genetic disorders like familial dysautonomia and Lowe’s syndrome
result in a Peroxisomal disorders like Zellweger’s syndrom
floppy infant Metabolic disorders like
Cerebral malformations
Inborn errors of metabolism like GM1 gangliosidosis
Clues to Absent or depressed DTR
motor unit Fasciculations
disorders Muscle atrophy
No abnormalities of other organs
Causes of Neonatal myotonic dystrophy
peripheral Neonatal myasthenia
weakness Neonatal myopathies eg central core myopathy
SMAs
Hereditary sensorimotor neuropathies
Infantile botulism
Congenital myasthenic syndrome
Muscular dystrophies
Investigations Suspect central cause:
Electrolyte, and glucose, thyroid function, neuroimaging, EEG, genetic review and karyotype if dysmorphic features, TORCH,
metabolic work up
Suspect peripheral cause:
CK, neurophysiologic studies, muscle biopsy, molecular genetics as appropriate
Spinal muscular atrophies
Genetic, AR
The genetic defects associated with SMA types I-III are localized on chromosome 5q13.
The incidence of spinal muscular atrophy is about 1 in 10,000 live births with
a carrier frequency of approximately 1 in 50
Progressive degeneration of the anterior horn cells in the spinal cord and motor nuclei in brain stem
Symmetrical proximal muscle atrophy
SMA1 Presentation: 0-6 m
(Werding Die<2 y
Hoffmann) Floppy infant
bell-shaped chest, paradoxical breathing
Tongue fasciculation
Absent reflexes
Contractures, forearm pronation
Never sit unsupported

SMA2 Present: 7-18 m

Die<20y
Sit but never walk unsupported
Deteriorating lung function

SMA3 Present >18m

(Kugelberg- slowly progressive proximal weakness. Most children with SMA III can stand and walk but have trouble with motor skills, such
Welander) as going up and down stairs.
Walks unsupported at some stages
Bulbar dysfunction occurs late in the disease.
SMA type IV SMA type IV (adult onset): Onset is in adulthood (mean onset, mid 30s).
In many ways, the disease mimics the symptoms of type III.
Overall, the course of the disease is benign, and patients have a normal life expectancy.
SMA type Sever ,antenatal onset
zero Arthrogryposis multiplex congenita
Ventilator dependent at birth
Investigations Genetic testing, Both prenatal and postnatal tests are now commercially available.
The creatine kinase (CK) level is typically normal in SMA type I and normal or slightly elevated in the other types.
EMG
Treatment Symptomatic therapy: minimizing contractures, preventing scoliosis, good nutritional support, prevent infections
nusinersen (Spinraza), the first drug approved to treat children (including newborns) and adults with SMA.
Nusinersen is an antisense oligonucleotide (ASO) designed to treat SMA caused by mutations in chromosome 5q that lead to
SMN protein deficiency.
The recombinant AAV9-based gene therapy, onasemnogene abeparvovec, was approved in May 2019 for SMA type 1 in children aged 2 years or younger.
 Neuropathies
Hereditary and acquired
-Hereditary sensorimotor neuropathies (charcot-marie-tooth disease)
AD
Onset 2-40 Y, mostly school age
Slowly progressive, symmetrical, distal muscle weakness and wasting. Affect feet first. Later weakness of intrinsic
hand muscles
Toe walking, falls, later foot drop. Foot deformities: pes cavus, high arch
Areflexia. Mild distal sensory loss
Slow nerve conduction velocity, DNA test for duplication in PMP22 (70-80%)
Acquired neuropathies
Guillian –Barre (acute)
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Guillian – Incidence: 1-2/100000
Barre Acute inflammatory demyelinating polyneuropathy
syndrome A prodromal illness within the previous 4 weeks, URTI or GE. Implicated organisms include: mycoplasma, EBV, CMV, influenza A
and B, coxsacki virus. Combylobacter jejuni
Progressive motor weakness, ascending, involving more than one limb, relative symmetry, mild sensory involvement.
Progression of the weakness max after 2 wk in 50% of the patient, 3 wk in 80% and 4 wk in the rest
Areflexia, autonomic dysfunction
CSF: elevated protein ,WBC less than 10
Nerve conduction abnormality
Miller-fisher syndrome
-Probably a variant of GBS
-Triad of ataxia, ophthalmoplegia and areflexia
-Brain stem encephalitis
Management:
-Careful monitoring of the respiratory function
-Intravenous immunoglobulin
-Plasmaphoresis
Muscular dystrophies Dystrophinopathies
A number of clinical phenotypes result from mutations in the dystrophin gene at Xp21: Duchenne/Becker muscular dystrophy, X-linked
cardiomyopathy and myalgia and cramps
This leads in Duchenne/Becker to decreased muscle content of the structural protein dystrophin: in DMD the dystrophin content is 0-5% of
normal, and in BMD the dystrophin content is 5-20% of normal
Clinical The initial feature in most boys with DMD is a gait disturbance
presentation Onset always before 5y, often before 3y
Toe walking and frequent falling
Often , Hx of delayed achieving of motor milestones, global developmental delay
is not uncommon
Intellectual impairment
Symmetric proximal weakness. Waddling gait, Gower sign is present, increased
lordiosis
Calf muscle hypertrophy
Loss of independent ambulation by 13y (in BMD by 16y), wheelchair 8-12 y old
Cardiomyopathy, annual screening
Scoliosis
Respiratory: deterioration of vital capacity to less than 20% of normal to nocturnal hypoventilation
Leading cause of death is cardio/respiratory complications.
Diagnosis CK is 10 times the upper limit of normal then declines about 20% per year
Gene mutation
Muscle biopsy: little or no dystrophin staining
Management -Prednisone
-Aim is to maintain function and prevent contraction; orthoses, scoliosis surgery
-Psychological support
BMD Presentation similar to DMD but variable severity/onset
slow progression
Life expectancy is longer
Biopsy: patchy dystrophin staining Other muscular dystrophies:
-Limb girdle muscular dystrophy
-Facioscapulohumeral dystrophy
Congenital A group of conditions presenting at birth or early childhood with hypotonia, weakness and contractions
muscular static or only slight progression
dystrophies CK normal or slightly elevated
Some are associated with disorders of myelin or neuronal migration or congenital eye abnormalities
Congenital Hypotonia and motor delay
myopathies Static or slowly progressive
CK normal
Muscle biopsy: myopathic without dystrophic changes
-Central core disease
-Minicore disease
-Nemalin rod myopathy
-Centronuclear myopathy
Myotonic Multisystem disorder transmitted by autosomal dominant
dystrophy inheritance with variable penetrance
-Amplification or “trinucleotide-repeat”
-severity depends on length of expansion
-Anticipation: repeat length expand in next generation, so more
sever disease with earlier onset
Cataract, ptosis
Frontal baldness
Myopathic face
Polyhydramnios, reduced fetal movement
Hypotonia, nn. respiratory distress
Arthrogryposis
Myotonia (not at birth):delayed relaxation (prolonged contraction) voluntary contraction
Learning difficulties
Endocrinopathies: insulin resistance, gonadal failure
Diagnosis
Clinical features
Family history
Molecular genetic study
Myasthenic syndromes
Disorders in neuromuscular transmission due to autoantibodies or gen defect
Weakness and fatigability on exercise
Myasthenia Onset 1-17 y
gravis Insidious or sudden onset(with febrile illness)
M:f (1:4)
weakness (proximal)and fatigability, with diurnal variation
Ptosis, ophthalmoplegia
Dysphagia, dysphonia, dyspnea
Antibodies:80% acetylcholine receptor (AChR) antibodies positive 14% muscle specific kinase (MuSK) antibodies positive
Thymoma 10%
Dx: AB, neurophysiology, Tensilon test or trial of pyridostegmine
Rx: anticholinesterase, immunotherapy in sever cases (prednisolone, azathioprine, IVIG, plasma exchange)
Transient Transplacental transfer of AChR antibodies
neonatal 10-15% of myasthenic mothers
myasthenia Hypotonia, weakness, bulber and resp. insufficiency within 4 days of birth
Dx: AB, response to cholinesterase inhibitors
Congenital Genetic disorder, AR
myasthenic Onset 0-24m
syndrome Hypotonia, weakness, bulber, resp. weakness, weak cry, feeding difficulties, recurrent chest infections, episodic apnea
Dx: family Hx, negative AB, response to anticholinesterases, electrophysiology, molecular studies
Drugs that Aminoglycosides. Tobramycin. Gentamycin. ...
impair Fluoroquinolones. Ciprofloxacin. Norfloxacin. ...
neuromuscular Tetracyclines. Clindamycin. ...
junction Penicillins - considered safe, though anecdotes of ampicillin causing resp depression.
transmission
Macrolides. Azithromycin. ...
and may
increase Quinolones.
weakness Ritonavir.
Malignant Presents as generalized muscle rigidity, tachycardia, tachypnea, rhabdomyolysis, acidosis, hyperkalemia, myoglobinuria, raised
hyperthermia CK and hyperthermia( occurs late)
Triggers: inhalational anesthetics(isoflurane, desflurane..) , depolarizing muscle relaxant (succinylcholine)
Associated with: dystrophin deficient muscular dystrophies, myotonic dystrophy
Rx: ICU management of fluid balance and rhabdomyolysis and possible renal involvement, Dantrolene
Very important to warn patients with neuromuscular disorders of the increased risk of anesthetic reactions, so to inform
anesthetists before GA and appropriate anesthetic agents can be used