Chapter 4: Neuromuscular

junction disorders
Learning objectives
• Approach to common neuromuscular junction disorders
• Myasthenia gravis: Diagnostic approach & treatment
• Congenital myasthenic syndromes
Presenting complaints
• 11-24% : Disease onset in childhood or adolescents
• Slight female pre-ponderence- 3:2
• Peak: 3rd & 6th decades
Clinical features
• Weakness + fatiguability: ocular, bulbar & diplopia
• Ocular manifestations: Ptosis, diplopia
• Bulbar manifestations: dysarthria, dysphagia, dysphonia, dyspnea
• Masticatory weakness: jaw fatigue, jaw-closure weakness
• Proximal limb + axial muscles are generally weaker than distal muscles
• Diurnal variation: weakness worsens as the day progresses
• Worsening with: stress, illness, exertion
Mysathenia Gravis foundation of America (MGFA)
classification System
Neonatal Transient Myasthenia gravis
• In infants of myasthenic mothers
• Placental transfer of antibodies results in NM transmission impairment
Clinical features
Weak suck/cry Generalized decreased body
Feeding intolerance movements
Ptosis Floppy baby (hypotonia)
Dysphagia Respiratory distress

• Hypotonia & weakness usually resolves in 1st 4 weeks of life

• Occasionally may result in persistent weakness & bulbar dysfunction
Juvenile Myasthenia Gravis
• Onset usually >10 years
• Before puberty in almost 50% cases
• Prepubertal : Ocular MG more common
• Post pubertal : Generalized MG more common
• Female predominance: >10 years age
• <1 year: highly uncommon
Congenital myasthenic syndromes
• Inherited disorders of abnormal NMJ
• Present with fatigue able weakness
• Presentation:
• Neonatal period
• Floppy new-born
• Poor suck, weak cry
• Symmetrical eyelid ptosis
• Stridor, respiratory distress, choking spells, apnoeic episodes
• May have worsening of symptoms with crying or by the evening
Congenital myasthenic syndromes
• Delayed motor milestones development
• May lag behind peers in physical activities
• Abnormal fatigue on exertion
• Impaired eye movements
• Decreased muscle bulk & spinal deformities later in life
• Milder forms: may present with fatigue able oculo-bulbar & limb
girdle weakness later in life
• Examples: Dok7, Rapsyn mutations, Choline acetyltransferase
deficiency, AchR deficiency Acetylcholine-esterase deficiency
Clinical features
• Ptosis most common initial feature
• 1/3 cases: unilateral ptosis at onset
• Facial & oropharyngeal weakness
• Bulbar weakness: dysphagia, nasal dysarthria
• Proximal muscle weakness (Generalized weakness)
• Myasthenic crisis: respiratory failure from- diaphragmatic weakness,
intercostal weakness or airway failure secondary to bulbar weakness
Examination
• Ptosis
• Fatiguability on upgaze
• Restriction of extraocular movements/presence of diplopia
• Ice pack test: Put ice pack over eye for 2 minutes- observe for
improvement
• Testing for weakness of orbicularis oculi muscle
• Signs of bulbar weakness
• Single breath count
• Proximal muscle fatiguability: outstretched arm test at 90o – normal
>240 seconds
1. Ptosis with Medial rectus adduction
2. Ptosis Left eye
Clinical and Lab tests
• Neostigmine challenge test : Demonstrable improvement in ptosis
• RNST (repetitive nerve stimulation test): a decremental response is
suggestive of myasthenia (post-synaptic receptor defect)
• Single fiber electromyography: most sensitive test for MG in adults,
however poorly tolerated in children
• Antibody testing:
• Anti-AChR: adults: 85% +ve, 50% ocular myasthenia +ve, children - ~50%
prepubertal, 90% post-pubertal, however, variable positivity rates have been
observed
• Anti-Musk: positive in 40-70% of AChR negative patients
 Diagnostic approach
Suspected *CECT thorax for
myasthenia/fatigue able thymoma screening
weakness

Repetitive nerve
stimulation test Consider alternate
etiology, congenital
myasthenic
-ve syndromes
Decremental response Non-conclusive

-ve -ve
+ve Neostigmine challenge test Antibody testing
Consider oral
+ve pyridostigmine trial
AchR antibodies +ve
+ve Antibody positive MG*
-ve +ve

Anti Musk antibodies +ve Antibody negative MG

-ve
 Treatment Remission

Continue pyridostigmine
Initiate treatment with pyrostigmine, adjust dose
to response
Not in remission
Severe generalized disease
• Dysphagia, requiring NG feeding, pooling of secretions
Consider:
• Respiratory weakness, at risk for intubation
• Thymectomy
• Poor ambulation, unable to get up from squat or
• Start prednisolone
sitting position
• Start steroid sparing agents (eg-
azathioprine, cyclosporine, mycophenolate)
Not sufficiently Improved
Improved Consider:
• Alternate steroid sparing agent
Initiate slow steroid taper and/or • Periodic IvIg or plasmapheresis
continue steroid sparing agent • Thymectomy if not already done

Consider:
Long term IvIg / Plasmapheresis,Rituximab, Cyclophosphamine Not Improved
Congenital myasthenic syndromes: Treatment
Drugs Disease
Pyridostigmine Endplate acetylcholine-receptor deficiency and those
with fast- channel syndromes

Amifampridine (3,4- Di amino pyridine) Alone or in combination with pyridostigmine in same

conditions

Fluoxetine and quinidine Slow-channel syndrome

Salbutamol and ephedrine COL Q, DOK-7, laminin β2, low-expressor mutations of

the acetylcholine receptor
Lambert Eaton Myasthenic syndrome (LEMS)
• Rare in pediatric population
• Pre-synaptic defect
• Fatiguability & weakness : limb girdle distribution
• Maximum on waking up in morning
• Transient improvement with exercise
• 50%: mild ptosis, dysarthria, diplopia, dysphagia
Lambert Eaton Myasthenic syndrome (LEMS)
• Autonomic symptoms: decreased salivation & tearing, blurred vision
• Examination: Limb girdle weakness
• Diagnosis : RNST
• Low amplitude CMAPs- increase after exercise
• Decremental response at 2-5 Hz
• Incremental response at >20Hz
• A/w small cell Ca lung, hematological malignancies , Renal cell
carcinoma
Botulism
• Presynaptic toxin binding: decreased Ach release
• Development of bulbar symptoms, diplopia, dysarthria & dysphagia 12-36 hours
after ingestion of toxin
• Descending weakness
• Extraocular movement restriction
• Sluggish pupillary reactions
• Types:
• Infantile botulism
• Foodborne botulism
• Wound botulism
Q1: What differential diagnosis will you consider in a child who is
presenting with ptosis and opthalmoparesis?

Q2: Which all drugs should be avoided in patients with myasthenia

gravis?
Answer 1
• Neuromuscular junction disease (Myasthenia Gravis, Lambert-Eaton,
Botulism)
• Mitochondrial myopathy
• Congenital myopathies
• Centronuclear myopathy
• Multicore Disease
• Oculopharyngeal muscular dystrophy
• Oculopharyngodistal myopathy
Q2
• Anasthetic agents : • Antibiotics:
• Neuromuscular blocking agents • Aminoglycosides
• Lidocaine, procaine • Erythromycin
• Cardiovascular drugs: • Tetracyclins
• Beta blockers • Penicillins
• Qinidine • Sulfonamides
• Procainamide • Floroquinilones
• Clindamycin
• Anti-convulsants:
• Phenytoin