Neuromuscular Junction Disorders
Alexis Lizarraga
James Berry
Neuromuscular junction (NMJ): Composed of presynaptic, synaptic, & postsynaptic regions. Dzs affect one of these three → failure of transmission across NMJ. Fluctuating symptoms are common in NMJ dz.
DIFFERENTIAL DIAGNOSIS OF NMJ DYSFUNCTION
Presynaptic: Lambert-Eaton myasthenic syndrome, congenital myasthenic syndromes (CMS), botulism, tick paralysis, some drugs, & venoms.
Synaptic: CMS of end-plate AChE deficiency, cholinesterase-inhibiting drugs, organophosphates.
Postsynaptic: MG, transient neonatal MG, CMS, drugs/venoms.
MYASTHENIA GRAVIS
Epidemiology: Prevalence ˜1/5,000 to 1/50,000. Annual incidence ˜1/50,000-1/200,000. For age <50 yo, F > M incidence; for age >50 yo, M > F incidence.
Pathophysiology: Autoimmune (AI) d/o of synaptic transmission. Abs interfere w/fxn, placement, or survival of nicotinic AChRs. Muscarinic receptors not affected → pupillary/autonomic responses spared. Abnormalities at the level of the thymus (intrathymic autosensitization against AChR) &/or peripheral immunoregulatory system (antigenic mimicry) lead to anti-AChR ab, disaggregation of AChR (anti-MuSK/anti-LRP4 ab), & simplification of nl, highly infolded NMJ surface. This loss of functional AChRs → decrease in end-plate potential amplitudes → muscle fiber not depolarized to threshold → NM transmission failure. Muscle-specific tyrosine kinase (MuSK) mediates postsynaptic clustering of AChR, maintains presynaptic structures (Lancet Neurol 2009;8:475-490).
Presentation: Pt history: Variable or fatigable wkns, 20% p/w pharyngeal wkns or hoarse voice, diplopia (blurred vision in subtle cases), orthopnea 2/2 diaphragmatic wkns. Neurologic exam: Nl pupillary reflexes, + ptosis (usu asymmetric & fatigues w/upgaze), asymmetric ophthalmoparesis, hypercontracted frontalis to maintain eye opening, Cogan lid twitch, “myasthenic snarl,” transverse pucker. Wkns of jaw closure, bulbar muscles, palate, axial & prox limbs, neck flex > ext. Tachypnea & shallow respirations, intact sensation, variably depressed reflexes.
Other subtypes: (1) Anti-MuSK: Young F w/prominent oculobulbar, neck, shoulder, & ventilatory muscle wkns, frequent crises, & typically not assoc w/thymoma, +/- triple furrowing of tongue. (2) Ocular: Sx limited to ocular wkns for >2 yr → 90% do not generalize; electrodiagnostic challenge; mono-Rx w/AChEIs may be sufficient; immunosuppression may have a role. (3) Anti-LRP4 (low-density lipoprotein receptorrelated protein): Effects on AChR clustering & agrin-LRP4 interaction could lead to the identification of a new MG subtype. Pts appear to respond to immune suppression. Anti-agrin also under investigation (Arch Neurology 2012;69:445-451; Neuromuscul Disord 2013;23:568-570). (4) Double Ab negative (AChR & MuSK): Classic presentation, neg ab tests.
Ddx: Motor neuron dz (MND), Lambert-Eaton myasthenic syndrome (LEMS), GBS, diphtheria, tick paralysis, thyroid ophthalmopathy, mitochondrial d/os, CMS, botulism, organophosphate & other toxins, inflammatory myopathy, skull-based tumors, cholinergic crisis, oculopharyngeal muscular dystrophy, AIDP.
Dx: (1) Ab testing. (1a) AChR abs: Binding Ab: Se 80%-85% in generalized MG, Se 55% in ocular MG. Blocking Ab: + in isolation in ˜1% of MG. Modulating ab: + in 3%-4%
MG in isolation, ↑ freq w/thymoma. At presentation, AChR Ab can be negative and then become detectable later in the course of dz. Ab level does not indicate severity. (1b) Anti-muscle-specific tyrosine kinase abs (Anti-MuSK): Present in 40%-50% of MG pts w/o AChR Abs. (1c) Striated muscle ab: Se 75%-95% for MG w/thymoma; often present in older MG pts w/o thymoma; utility limited by poor Sp. (1d) Anti-LRP4: 7-33% of double seronegative (MuSK/AChR) pts are +. Not yet commercially available. (2) EMG/NCS: Repetitive nerve stimulation: Low rates of rep stim (2-5 Hz) deplete ACh → decrement >10% (Se 30%-98% for generalized MG & 10%-40% for ocular MG). SFEMG: + blocking &/or increased jitter (variation in contraction time b/n muscle fibers) (Se 80%-99%) (Muscle Nerve 1992;15:720-724). (3) Bedside evaluation. (3a) Tensilon test (edrophonium, an AChEI): IV test dose 2 mg, if no response after 30 s, administer 2 mg at a time up to 10 mg every 10-15 s. Follow clinically observable deficit & only accept unequivocal improvement as (+). Abort if side effects. Onset 30 s, lasts 5-10 min. Side effects: Salivation, sweating, nausea, cramping, fasciculations, bradycardia, ↓ BP, & resp distress. AMBU bag/code cart & atropine at bedside, telemetry. Utility: Se ˜90%. (3b) Ice test: Put ice pack on closed eye × 3 min—ptosis improves by at least 2 mm (Se 80%-97% in pts w/ptosis, use in pts w/contraindication to Tensilon test) (Neuromuscul Disord 2006;16:459-467; Muscle Nerve 2013;48:902-904).
MG in isolation, ↑ freq w/thymoma. At presentation, AChR Ab can be negative and then become detectable later in the course of dz. Ab level does not indicate severity. (1b) Anti-muscle-specific tyrosine kinase abs (Anti-MuSK): Present in 40%-50% of MG pts w/o AChR Abs. (1c) Striated muscle ab: Se 75%-95% for MG w/thymoma; often present in older MG pts w/o thymoma; utility limited by poor Sp. (1d) Anti-LRP4: 7-33% of double seronegative (MuSK/AChR) pts are +. Not yet commercially available. (2) EMG/NCS: Repetitive nerve stimulation: Low rates of rep stim (2-5 Hz) deplete ACh → decrement >10% (Se 30%-98% for generalized MG & 10%-40% for ocular MG). SFEMG: + blocking &/or increased jitter (variation in contraction time b/n muscle fibers) (Se 80%-99%) (Muscle Nerve 1992;15:720-724). (3) Bedside evaluation. (3a) Tensilon test (edrophonium, an AChEI): IV test dose 2 mg, if no response after 30 s, administer 2 mg at a time up to 10 mg every 10-15 s. Follow clinically observable deficit & only accept unequivocal improvement as (+). Abort if side effects. Onset 30 s, lasts 5-10 min. Side effects: Salivation, sweating, nausea, cramping, fasciculations, bradycardia, ↓ BP, & resp distress. AMBU bag/code cart & atropine at bedside, telemetry. Utility: Se ˜90%. (3b) Ice test: Put ice pack on closed eye × 3 min—ptosis improves by at least 2 mm (Se 80%-97% in pts w/ptosis, use in pts w/contraindication to Tensilon test) (Neuromuscul Disord 2006;16:459-467; Muscle Nerve 2013;48:902-904).
Additional testing: TFTs, Chest CT, or MRI to eval thymoma.
Prognosis: Prognosis varies & depends on underlying dz distribution & severity. Early in course, exacerbations are often severe, but w/Rx remissions lasting many months are common. Max dz severity reached in 2 yr in 66% pts. Spontaneous & durable remission in 10%-15%. On avg, active dz lasts 7 yr followed by 10 yr of relative quiescence, then finally “burned-out” phase characterized by some degree of fixed deficit. 15%-40% of pts w/an isolated ocular presentation will not develop generalized MG. Of those that do, transition to generalized MG is usually within 2 yr (Ann Neurol 1983;14:516-519).
TREATMENT: ACUTE EXACERBATIONS/CRISIS
Definitions: Myasthenic crisis—Acute flare of wkns generally w/respiratory failure, often requiring intubation & ICU admission or delay of extubation ≥24 h after surgery.
Causes: (1) Dz progression, (2) Infxn/stressor, (3) withdrawal/↓ in MG Rx, (4) contraindicated medication.
Plasma exchange (PE): Requires large-bore catheter & performed qod. Potential side effects: Line infection, cardiovascular instability, pneumothorax, electrolyte shifts, bleeding.
IVIg: 2 g/kg in divided doses over 2-5 days. Potential side effects: Aseptic meningitis, flulike symptoms (n/v, myalgias, fevers, chills), ARF, CHF exacerbation, allergic Rxn (test IgA levels prior to r/o IgA deficiency), headache common, very rare thrombotic events (MI/stroke).
Pyridostigmine: In intubated pts, might avoid due to increase in secretions. If not intubated, initial adult dose 15-30 mg tid-qid; gradually titrate as necessary (max 360 mg daily). Onset ˜30-60 min—pts w/dysphagia can take 30 min before meal.
Steroids: In intubated pts, can start IV methylprednisolone together w/PE or IVIg at 500-1,000 mg/day for 5 days followed by 0.8 mg/kg IV daily until able to take PO steroids. If not intubated, initiate prednisone at a dose of 1-1.5 mg/kg/day × 2-4 wk (max 100 mg/day), then taper by 5-10 mg q2-4 wk to lowest tolerated dose. May worsen exacerbation acutely; thus, should use caution & consider hospitalization for monitoring and/or starting PE or IVIg prior to initiating steroids during an exacerbation. Onset of action ≥2 wk.
Supportive care: Aspiration precautions, temporary NPO or NG tube feeding, close resp monitoring w/NIF & VC, ventilatory support if necessary.
Differential: Cholinergic crisis (salivation, lacrimation, diarrhea, bradycardia). Rx: hold or ↓ AChE meds.
CHRONIC TREATMENT
Principles
Time to benefit: (1) Immediate = cholinesterase inhibitors. (2) Very rapid (days) = plasma exchange, IVIg. (3) Short term (2-6 wk) = corticosteroids. (4) Long term (2-12 mo) = mycophenolate mofetil, azathioprine, rituximab, thymectomy.
Prior to initiation of immunosuppression: Negative PPD, baseline CBC w/diff, CMP, HbA1c, bone density prior to prednisone.
Nonimmune modulatory: Pyridostigmine. Dosing adjusted PRN. Ocular symptoms: Prism glasses.
Immune modulatory: Steroids, steroid-sparing agents, & thymectomy (Amato AA, Russell JA. Neuromuscular Disorders. McGraw Hill, 2008:457-528).
Steroids: Initiate at a dose of 1-1.5 mg/kg/d × 2-4 wk (max 100 mg/day). Once in remission or improvement plateaus, ↓ dose &/or administration interval (e.g., decrease by 5-10 mg q2-4 wk) to lowest tolerated. Side effects: Cataracts, HTN, osteoporosis, immune suppression, ↑ wt, mood d/o, psychosis, skin sensitivity to sun, glucose intolerance/DM, peptic ulcers, avascular necrosis, steroid myopathy, growth stunting in children.Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
