Neuromuscular Junction Disorders

Autoimmune (antibody-mediated) causes

• Anti-AChR myasthenia gravis: complement-fixing IgG1/IgG3 against the postsynaptic receptor; the dominant mechanism in generalized MG
• Anti-MuSK MG: IgG4 antibodies that block agrin–LRP4–MuSK signaling and disrupt receptor clustering; IgG4 does not fix complement, which is why complement inhibitors are less useful in this subgroup
• Anti-LRP4 / seronegative MG: same downstream clustering defect, antibody often undetectable by standard assays
• LEMS: anti-P/Q-type VGCC antibodies, roughly half paraneoplastic from small-cell lung cancer

Non-modifiable risk factors

• Bimodal age/sex distribution: women in the second–fourth decades (thymic hyperplasia, HLA-B8/DR3), men after age 50 (higher thymoma rate)
• Thymic pathology: thymoma in roughly 15% of MG; conversely, a substantial minority of thymoma patients develop MG
• Other autoimmune disease: autoimmune thyroid disease is the classic co-traveler; also RA, SLE, pernicious anemia

Modifiable/precipitating factors examiners plant in the stem

• Drugs: D-penicillamine (causes a true de novo AChR-antibody MG that remits on withdrawal), immune checkpoint inhibitors (MG–myositis–myocarditis overlap), fluoroquinolones, macrolides, aminoglycosides, magnesium, beta blockers, and iodinated contrast
• Smoking: the key modifiable risk for the SCLC that drives LEMS
• Systemic stressors: infection, surgery, pregnancy and the postpartum period, thyroid dysfunction, heat, and abrupt corticosteroid initiation — all recognized crisis triggers in the MGFA International Consensus Guidance

Myasthenia Gravis (Acquired)

• Autoimmune destruction of acetylcholine receptors (AChR): IgG antibodies bind to AChR at the NMJ, activate complement (C1q), and cause destruction of the postsynaptic membrane through the membrane attack complex (MAC), reducing the number of functional receptors by 70-90%
• Antibody-mediated blockade: Anti-AChR antibodies directly block acetylcholine binding to receptors, preventing normal neuromuscular transmission
• Cross-linking and internalization: Antibodies cross-link AChR molecules, promoting receptor internalization and degradation via endocytosis
• Associated autoimmunity: 50% of generalized MG patients have anti-AChR antibodies; anti-muscle-specific kinase (anti-MuSK) antibodies account for ~40% of seronegative cases and cause a different pathophysiology (impaired receptor clustering and stabilization)
• Thymic abnormalities: 15% of MG patients have thymoma; 85% have thymic hyperplasia or other thymic abnormalities; the thymus produces autoreactive B and T cells

Congenital Myasthenic Syndromes (CMS)

• Presynaptic defects: Choline acetyltransferase (ChAT) deficiency or defects in acetylcholine (ACh) synthesis/release (CHAT, SYT2, SLC5A7 mutations)
• Synaptic defects: Deficiency of endplate acetylcholinesterase (AChE) or collagen Q (COL13A1 mutations affecting AChE anchoring)
• Postsynaptic defects: Loss-of-function mutations in AChR subunits (CHRNA, CHRNB, CHRND, CHRNE), AChR-associated protein (RAPSN), or LRP4; reduced receptor number or impaired kinetics
• Result: Decreased safety margin of neuromuscular transmission—the margin between the amplitude of the endplate potential and the threshold needed to trigger an action potential becomes critically reduced

Lambert-Eaton Myasthenic Syndrome (LEMS)

• Anti-voltage-gated calcium channel (VGCC) antibodies: IgG antibodies target P/Q-type calcium channels on presynaptic motor terminals, reduce calcium influx, and decrease acetylcholine release
• Reduced quantal content: Fewer acetylcholine vesicles are released per nerve action potential
• Often paraneoplastic: ~50% associated with small-cell lung cancer (SCLC) due to shared antigen expression

Myasthenia Gravis

• Fatigable ocular weakness (most common initial symptom in 50% of patients): Ptosis, diplopia (typically worsening with sustained upgaze or prolonged reading); symptoms improve with rest or ice pack (ice pack test)
• Bulbar symptoms: Dysarthria (nasal speech quality), dysphagia (difficulty with liquids and solids), facial weakness, jaw claudication; these indicate more severe disease
• Generalized weakness: Proximal limb weakness (hip and shoulder girdle predominantly) worsening with activity and improving with rest; may affect neck flexors and extensors
• Respiratory weakness: Myasthenic crisis with respiratory failure requiring mechanical ventilation; occurs in ~10-15% of patients, typically in first 2 years of disease
• Seronegative presentation: ~10-15% of generalized MG patients lack detectable anti-AChR antibodies; anti-MuSK antibodies more common in this group; seronegative patients may have milder disease or atypical presentations
• Clinical severity classification: Osserman classification (Class I—ocular only; Class II—mild generalized; Class IIb—intermediate; Class III—acute severe; Class IV—late severe) guides prognosis and treatment intensity

Congenital Myasthenic Syndromes

• Infantile presentation: Feeding difficulties, weak cry, hypotonia, ptosis, and ophthalmoplegia in the neonatal period or early infancy
• Developmental delay and learning difficulties: Variable intellectual involvement depending on genetic subtype
• Episodic weakness exacerbations: Triggered by infection, fever, or medication (certain antibiotics); absence of ocular signs in some CMS subtypes (e.g., AChR deficiency presenting primarily with limb weakness)
• Pathognomonic signs by subtype: AChE deficiency presents with apnea episodes; AChR deficiency or anti-MuSK disease may present with predominantly cervical and respiratory weakness

Lambert-Eaton Myasthenic Syndrome

• Proximal lower limb weakness: More prominent in legs than arms (opposite of MG), leading to difficulty rising from chairs or climbing stairs
• Autonomic dysfunction: Dry mouth, constipation, impotence, blurred vision, reduced sweating; autonomic symptoms often precede motor symptoms
• Diminished deep tendon reflexes (DTRs) with post-tetanic potentiation: Reflexes are initially hyporeflexic but normalize temporarily after brief voluntary contraction or electrical stimulation of the nerve (pathognomonic finding)
• Lack of ocular involvement: Eyes are typically spared, distinguishing LEMS from MG
• Pain: Often present (back, shoulder, legs)
• Paraneoplastic association: Screen for occult SCLC; malignancy may develop months to years after LEMS onset

Clinical Testing for Myasthenia Gravis

• Ice pack test (ice water immersion test): Patient applies ice to affected eye for 2 minutes; improvement in ptosis or diplopia has 90% sensitivity and specificity for ocular MG; most sensitive for ocular symptoms, less reliable for generalized MG
• Edrophonium (Tensilon) challenge test: Acetylcholinesterase inhibitor given IV; produces dramatic temporary improvement in weakness if MG present (sensitivity 60-95% depending on disease severity and ocular vs. generalized); largely replaced by antibody testing due to risk of cholinergic crisis; rarely used in modern practice
• Repetitive nerve stimulation (RNS): Electrical stimulation of a motor nerve with recording of muscle action potentials; decremental response (>10% decline in compound muscle action potential amplitude across successive stimuli) seen in 70% of generalized MG but only 50% of pure ocular MG; non-specific but helps confirm neuromuscular junction dysfunction
• Single-fiber electromyography (SFEMG): Gold standard diagnostic test with highest sensitivity (~95% sensitivity even in seronegative MG); detects increased "jitter" (variability in time interval between action potentials of muscle fiber pairs) and blocking; most specific and sensitive but not widely available and requires expertise; reserved for diagnostic confirmation in seronegative or equivocal cases
• Serum antibody testing: Anti-acetylcholine receptor (anti-AChR) antibodies present in 80% of generalized MG and 50% of ocular MG; anti-muscle-specific kinase (anti-MuSK) antibodies found in ~40% of seronegative MG patients and correlate with oculobulbar-predominant weakness; high specificity when present

Imaging and Additional Workup

• CT or MRI chest: Identify thymoma in all MG patients (perform in all patients with generalized MG regardless of age); thymic abnormalities present in ~75% of generalized MG
• **Pulmonary function testing (

Immediate stabilization (myasthenic crisis)

• Airway assessment first: serial forced vital capacity and negative inspiratory force, not pulse oximetry or ABG — hypercapnia is a late finding. The classic 20/30/40 rule (VC <20 mL/kg, NIF less negative than −30 cmH₂O, maximal expiratory pressure <40 cmH₂O) prompts elective intubation
• Rapid immunotherapy: plasma exchange or IVIG; MGFA International Consensus Guidance treats them as comparable, with PLEX often favored for bulbar/respiratory crisis and IVIG when vascular access or hemodynamics are limiting
• Hold pyridostigmine while intubated to reduce secretions and to avoid masking cholinergic crisis; withdraw the offending drug or treat the triggering infection

First-line chronic therapy

• Acetylcholinesterase inhibitors: pyridostigmine — symptomatic only, no effect on the autoimmune process; notably less effective in anti-MuSK disease
• Corticosteroids: prednisone is the first-line immunotherapy per MGFA guidance; start low and titrate up, since high-dose initiation can transiently worsen weakness

Escalation / steroid-sparing

• Antimetabolites/calcineurin inhibitors: azathioprine (check TPMT/NUDT15 first), mycophenolate, tacrolimus
• Anti-CD20: rituximab — the preferred escalation in anti-MuSK MG
• Complement inhibitors: eculizumab, ravulizumab, zilucoplan for refractory AChR-antibody-positive generalized MG
• FcRn antagonists: efgartigimod, rozanolixizumab, which accelerate IgG catabolism

Disease-related

• Myasthenic crisis (emergency): respiratory muscle and bulbar failure, usually triggered by infection, surgery, or an offending drug. Signals are rising respiratory rate, staccato speech, inability to count to 20 on one breath, paradoxical abdominal motion, and a falling FVC/NIF — normal oxygen saturation does not exclude it
• Aspiration pneumonia: pharyngeal and tongue weakness with impaired cough; a new infiltrate plus worsening weakness creates a vicious cycle, since infection itself worsens transmission
• Neonatal transient myasthenia (emergency in the nursery): maternal IgG crosses the placenta; hypotonic newborn with weak cry and poor suck, resolving over weeks as antibody clears. Rarely, fetal AChR blockade causes arthrogryposis
• Occult malignancy: thymoma (may cause local compression or red cell aplasia) and, in LEMS, SCLC that can appear months to years after the neurologic syndrome

Treatment-related

• Cholinergic crisis (emergency): excess pyridostigmine causes depolarizing blockade; muscarinic excess gives SLUDGE, miosis, bradycardia, bronchorrhea, and fasciculations — the pupils and secretions distinguish it from myasthenic crisis, in which pupils are normal
• Steroid-induced early worsening: high-dose prednisone can transiently deepen weakness in the first one to two weeks; chronic use brings hyperglycemia, infection, and glucocorticoid-induced osteoporosis, for which the ACR recommends calcium, vitamin D, and risk-stratified bisphosphonate
• Azathioprine: myelosuppression and hepatotoxicity, exaggerated in TPMT/NUDT15-deficient patients; mycophenolate is teratogenic
• Rituximab: hypogammaglobulinemia, hepatitis B reactivation, rare PML
• Complement inhibitors: boxed warning for meningococcal disease — ACIP-recommended meningococcal vaccination before initiation
• IVIG: thrombosis, aseptic meningitis, acute kidney injury. PLEX: hypocalcemia, coagulopathy, catheter complications

• Fatigability is the signature: ptosis worsening on sustained upgaze and diplopia at the end of the day. The ice pack test is the cheap bedside confirmation for ptosis — cooling slows acetylcholinesterase.
• Exercise direction separates MG from LEMS: MG weakness worsens with repeated use (decremental RNS response); LEMS strength and reflexes transiently improve after brief maximal contraction (post-tetanic facilitation, incremental response on high-frequency RNS). Autonomic symptoms — dry mouth, constipation — plus areflexia in a smoker means LEMS and a hunt for SCLC.
• The single association examiners test: every patient with newly diagnosed MG needs CT or MRI of the chest for thymoma, regardless of age or symptoms.
• Best next step in suspected crisis: measure FVC and NIF at the bedside and intubate on trend, then give PLEX or IVIG. Do not wait for hypoxemia or a rising PaCO₂, and do not order a chest CT before securing the airway.
• Anti-MuSK is the exception subtype: oculobulbar and neck-extensor predominant, frequently AChR-negative, often poorly responsive to and even intolerant of pyridostigmine, and preferentially responsive to rituximab.
• Drug triggers are a favorite stem device: aminoglycosides, fluoroquinolones, macrolides, IV magnesium (classically in a pregnant patient treated for preeclampsia), and beta blockers. D-penicillamine causes drug-induced MG that remits after withdrawal.
• Common distractors to avoid: the edrophonium (Tensilon) test is historical, not the modern first test — serologies come first. A new pupillary abnormality argues against MG, since MG spares pupils; dilated pupils with descending flaccid paralysis in an infant points to botulism. Steroids may transiently worsen weakness at initiation, which is expected, not treatment failure.
• Thymectomy helps AChR-positive generalized non-thymomatous MG (MGTX) and is mandatory for thymoma — but it is not indicated for LEMS.