Nervous System & Special Senses

Myasthenia gravis: diagnosis and management

Clinical Overview and When to Suspect Myasthenia Gravis

— Antibodies cause receptor cross-linking/internalization, complement-mediated endplate damage, and reduced safety factor for transmission.

— Net result: fatigable, fluctuating weakness that worsens with repeated use and improves with rest.

— Adult with fluctuating ptosis and diplopia that worsens by evening or with sustained upgaze.

— Painless bulbar symptoms: nasal/slurred speech after talking, dysphagia mid-meal, jaw fatigue while chewing gum.

— Proximal limb weakness that improves after rest, with preserved reflexes and no sensory loss.

— Unexplained dyspnea or weak cough in an otherwise alert patient — consider impending myasthenic crisis.

— Postoperative patient with prolonged neuromuscular blockade after nondepolarizing agents.

— Infections (especially respiratory), surgery, pregnancy/postpartum, thyroid disease flare.

— Medications: fluoroquinolones, aminoglycosides, macrolides, beta-blockers, magnesium (IV Mg²⁺ in preeclampsia), procainamide, immune checkpoint inhibitors, D-penicillamine (drug-induced MG).

Board pearl: The combination of purely motor, fatigable weakness with normal sensation, normal reflexes, and ocular involvement should immediately put MG at the top of the differential — pure motor symptoms with bulbar fatigability is the classic Step 3 trigger phrase.

Myasthenia gravis (MG) is an autoimmune disorder of the postsynaptic neuromuscular junction, driven most commonly by IgG antibodies against the nicotinic acetylcholine receptor (AChR), less often against muscle-specific tyrosine kinase (MuSK) or LRP4.

Epidemiology: bimodal — young women (20s–30s) and older men (60s–80s). U.S. prevalence ~20/100,000 and rising as the population ages.

When to suspect on Step 3:

Triggers to ask about (high-yield for stems):

Associated autoimmune conditions: autoimmune thyroid disease (~10–15%), RA, SLE, type 1 DM, pernicious anemia.

Presentation Patterns and Key History

— Asymmetric ptosis that worsens with sustained upgaze (>30 seconds) and binocular diplopia that resolves with monocular cover.

— Pupils are always spared — distinguishes from third-nerve palsy.

— ~50% of ocular-onset cases generalize within 2 years; risk drops sharply after that.

— Bulbar: dysarthria with nasal/hypophonic quality after talking, fatigable chewing ("jaw drops mid-sandwich"), dysphagia for both solids and liquids, nasal regurgitation, weak cough.

— Limb: proximal > distal weakness; difficulty with stairs, brushing hair, lifting groceries. Often asymmetric early.

— Neck flexor weakness is classic — patient props chin with hand ("head drop").

— Respiratory: orthopnea, dyspnea with talking, weak cough — early signs of crisis.

— Predominantly bulbar, neck, respiratory, and facial weakness; tongue atrophy can occur.

— More crises, less ocular predominance, often less responsive to pyridostigmine (and may worsen with it).

— Symptom fluctuation across the day (the single most sensitive historical feature).

— Recent new medications (especially fluoroquinolones, aminoglycosides, beta-blockers).

— Recent infection, surgery, anesthesia exposure, pregnancy.

— Personal/family autoimmune disease, thymoma symptoms (chest pressure, SVC-type complaints).

— Vaccination status and recent immune checkpoint inhibitor use (pembrolizumab, nivolumab).

Key distinction: MG worsens with use and improves with rest; Lambert-Eaton (LEMS) improves transiently with brief exertion (post-exercise facilitation) and has areflexia plus autonomic symptoms (dry mouth, erectile dysfunction). If the stem describes a smoker with proximal weakness and dry mouth, pivot to LEMS, not MG.

Ocular MG (~50% at onset, ~15% remain purely ocular):

Generalized MG:

Diurnal pattern: worst in evening or after sustained activity; better in the morning and after rest or napping.

MuSK-MG phenotype (more often young women, non-white):

Key history elements to extract on the exam:

Physical Exam Findings and Respiratory Assessment

— Sustained upgaze for 60 seconds → progressive ptosis ("curtain sign" as one lid drops, then the other).

— Ice pack test: apply ice to closed ptotic lid for 2 minutes — ≥2 mm improvement in lid height is ~80% sensitive/specific for MG (cold inhibits acetylcholinesterase).

— Cogan lid twitch: look down for 15 seconds, then rapid refixation to primary gaze → upper lid overshoots then settles.

— Extraocular movements: restricted in patterns that don't fit a single cranial nerve; pupils spared.

— Facial weakness: "myasthenic snarl" when attempting to smile; weak eye closure (peek sign — sclera shows after sustained closure).

— Have the patient count aloud from 1 to 100 — voice becomes nasal/hypophonic.

— Inspect palatal elevation; check gag.

— Tongue: MuSK-MG may show triple-furrowed atrophy.

— Fatigable proximal weakness: have patient hold arms abducted at 90° — count seconds to drift.

— Neck flexor weakness (lift head off pillow against resistance) — often profoundly weak.

— Reflexes normal, sensation normal, no fasciculations, no atrophy (except chronic disuse or MuSK).

— Single-breath count: count aloud after one deep breath; <20 suggests significant compromise, <15 is alarming.

— Bedside spirometry: forced vital capacity (FVC) <20 mL/kg, negative inspiratory force (NIF) less negative than −30 cm H₂O, or positive expiratory pressure <40 cm H₂O = the "20/30/40 rule" indicating impending crisis and need for ICU/intubation planning.

— Paradoxical abdominal breathing, inability to lie flat (orthopnea from diaphragmatic weakness), weak cough.

CCS pearl: On a CCS case with suspected MG, order serial NIF and FVC every 2–4 hours; do not rely on pulse oximetry alone — SpO₂ drops late, after CO₂ has already risen. Trending NIF/FVC drives the intubation decision, not ABG.

Cranial nerve exam — the highest-yield bedside maneuvers:

Bulbar exam:

Motor exam:

Respiratory/airway assessment — critical at every encounter:

Diagnostic Workup — Initial Labs, Antibodies, and Imaging

— Anti-AChR antibodies (binding): positive in ~85% of generalized MG and ~50% of pure ocular MG. Highly specific; positive result essentially confirms diagnosis in the right clinical context.

— If AChR negative → send anti-MuSK antibodies (positive in ~40% of AChR-negative generalized MG).

— If both negative ("seronegative MG") → consider anti-LRP4 and anti-agrin antibodies; diagnosis then leans on electrophysiology.

— Striational (anti-titin, anti-RyR) antibodies: associated with thymoma, especially in patients <50 — order if thymoma suspected.

— CT or MRI of the chest with contrast to screen for thymoma (10–15% of MG patients) or thymic hyperplasia (65%).

— Thymoma is more common in older AChR-positive patients; uncommon in MuSK-MG.

— TSH and free T4 (thyroid disease coexists in 10–15%).

— CBC, CMP (baseline before steroids/immunosuppressants).

— HbA1c, lipids, bone density considerations before long-term steroids.

— TB screen (IGRA or PPD), hepatitis B and C serologies, HIV before biologics/immunosuppressants.

— Strongyloides serology in patients from endemic areas before high-dose steroids (risk of hyperinfection).

— Vaccinations updated before immunosuppression (pneumococcal, influenza, COVID, shingles, hepatitis B).

Step 3 management: When confirming new MG, bundle the workup: antibody panel + chest CT + thyroid + infection screen + vaccinations before starting prednisone. Skipping the chest CT is a classic Step 3 trap — undiagnosed thymoma changes management (thymectomy).

Serologic testing — the cornerstone of diagnosis:

Chest imaging — mandatory in every newly diagnosed MG patient:

Baseline labs before initiating immunotherapy:

Avoid routine edrophonium (Tensilon) testing — largely abandoned in U.S. practice due to bradyarrhythmia risk and availability of better tests. Ice pack test is the safer bedside surrogate.

Diagnostic Workup — Electrodiagnostic and Confirmatory Studies

— Low-frequency (2–3 Hz) stimulation of a clinically affected nerve (facial, spinal accessory, ulnar).

— Decremental response of ≥10% in CMAP amplitude between the 1st and 4th–5th stimulus is diagnostic.

— Sensitivity ~75% in generalized MG, lower (~50%) in pure ocular MG.

— More sensitive if performed on a clinically weak muscle and after the patient holds the limb against resistance for a minute.

— Most sensitive test for MG (>95%), but less specific — abnormal in any NMJ disorder, motor neuron disease, neuropathy.

— Measures jitter (variability in interpotential interval between two muscle fibers of the same motor unit) and blocking.

— Reserved for cases where RNS is negative and clinical suspicion remains high.

— Frontalis or extensor digitorum communis are typical muscles tested.

— LEMS: RNS shows decrement at low frequency but >100% facilitation at high frequency (20–50 Hz) or after 10 seconds of maximal voluntary contraction; anti-VGCC antibodies positive.

— Botulism: similar facilitation pattern to LEMS but acute onset with descending paralysis and autonomic features; stool/serum toxin assay.

— Congenital myasthenic syndromes: seronegative with childhood onset, family history — genetic testing.

Board pearl: For a stem with classic fatigable weakness but negative AChR and MuSK antibodies, the next best test is single-fiber EMG, not repeat antibodies. If the case is post-cancer surgery or smoker with proximal weakness and absent reflexes, pivot the workup toward LEMS with high-frequency RNS and VGCC antibodies.

Indicated when: antibodies are negative, diagnosis is uncertain, or to grade severity/distribution.

Repetitive nerve stimulation (RNS):

Single-fiber EMG (SFEMG):

Ice pack test (revisited): rapid, cheap, ~80% sensitive bedside confirmation when ptosis is present.

Pulmonary function for severity: FVC, NIF, MEP — both diagnostic adjuncts and crisis-monitoring tools.

Tests to differentiate mimics:

Risk Stratification and Management Logic

— Ocular vs generalized

— Antibody status: AChR+, MuSK+, seronegative (treatment response differs)

— Severity: MGFA class I (ocular) through class V (intubated/crisis)

— Thymoma present or absent

— Age at onset (early <50 vs late ≥50)

— Achieve "minimal manifestation status" (MMS) or better — patient has no symptoms or functional limits, only minimal weakness on exam.

— Use the lowest effective dose of immunotherapy with tolerable side effects.

1. Symptomatic: pyridostigmine (acetylcholinesterase inhibitor) — first-line for symptom control in AChR+ and seronegative MG; less effective and sometimes worsens MuSK-MG.

2. Chronic immunomodulation: corticosteroids ± steroid-sparing agent (azathioprine, mycophenolate, methotrexate, cyclosporine, tacrolimus).

3. Targeted biologics for refractory disease: rituximab (especially MuSK-MG), eculizumab/ravulizumab (anti-C5, for refractory AChR+ generalized MG), efgartigimod/rozanolixizumab (anti-FcRn, deplete IgG), zilucoplan.

4. Rapid rescue: IVIG or plasma exchange (PLEX) for crisis, severe exacerbation, or pre-thymectomy/pre-op optimization.

5. Thymectomy in selected patients.

— Any patient with thymoma — surgical resection regardless of MG severity (oncologic indication).

— Non-thymomatous generalized AChR+ MG age 18–65: thymectomy improves outcomes and reduces steroid burden (MGTX trial). Less clear benefit in MuSK-MG and pure ocular MG.

Step 3 management: First decision after diagnosis is "Does this patient have a thymoma?" — drives surgical referral. Second is "Symptomatic only or immunomodulation needed?" — most generalized patients need both pyridostigmine and a steroid-sparing plan from the outset.

Classify the patient before choosing therapy:

Goals of therapy (per MGFA/international consensus):

Treatment ladder:

Thymectomy indications:

Pharmacotherapy — First-Line Regimens in Detail

— Start 30–60 mg PO every 4–6 hours while awake; titrate to symptom control, typical max 60–90 mg every 4 hours (~360–480 mg/day).

— Onset 15–30 min, peak 2 h, duration 3–4 h. Time doses before meals to maximize chewing/swallowing strength.

— Cholinergic side effects: abdominal cramping, diarrhea, hypersalivation, lacrimation, bradycardia, fasciculations. Coadminister glycopyrrolate or hyoscyamine if GI side effects limit dosing.

— Cholinergic crisis (rare) at very high doses — paradoxical worsening from receptor desensitization plus muscarinic excess.

— Prednisone: in mild/moderate disease, start low (10–20 mg/day) and titrate up by 5 mg every few days to 0.75–1 mg/kg/day (typical target 40–60 mg/day) to avoid the well-described early steroid-induced worsening (occurs in up to 50%, peaks ~5–10 days).

— In severe or hospitalized patients, start high-dose with concurrent IVIG/PLEX coverage.

— Once stable for several weeks, taper slowly to lowest effective alternate-day dose.

— Side-effect mitigation: calcium 1200 mg + vitamin D 800 IU daily, DEXA at baseline, bisphosphonate if indicated, PJP prophylaxis (TMP-SMX) if ≥20 mg prednisone for ≥4 weeks, glucose monitoring, BP control.

— Azathioprine 2–3 mg/kg/day — check TPMT activity before starting; monitor CBC and LFTs.

— Mycophenolate mofetil 1–1.5 g BID — well-tolerated, teratogenic (counsel contraception).

— Tacrolimus, cyclosporine, methotrexate — alternatives.

— IVIG 2 g/kg over 2–5 days or PLEX 5 exchanges over 7–10 days — equivalent efficacy in crisis; PLEX may act faster (within days).

— Use for crisis, severe exacerbation, pre-thymectomy bridging, or refractory disease.

Board pearl: When starting prednisone in MG, warn the patient about transient worsening in the first 1–2 weeks and have a low threshold to admit moderate-to-severe patients for monitoring or coadminister IVIG/PLEX as a "bridge."

Pyridostigmine (Mestinon):

Corticosteroids — backbone of chronic immunomodulation:

Steroid-sparing agents (start early, expect 6–12 month onset of effect):

Rescue therapy:

Advanced Pharmacotherapy, Thymectomy, and Drugs to Avoid

— Eculizumab / ravulizumab (anti-C5 monoclonal): for refractory AChR+ generalized MG. Requires meningococcal vaccination ≥2 weeks before initiation (boxed warning). Ravulizumab dosed every 8 weeks.

— Efgartigimod, rozanolixizumab (anti-FcRn): reduce circulating IgG including pathogenic antibodies; cyclic IV/SC dosing.

— Zilucoplan (SC complement inhibitor): also needs meningococcal vaccination.

— Rituximab (anti-CD20): especially effective in MuSK-MG; reasonable second-line. Check hepatitis B before infusion.

— Transsternal or robotic/VATS approach; refer to high-volume center.

— Benefits unfold over 1–3 years post-op (reduced steroid dose, higher remission rate).

— Optimize patient first — FVC, NIF; consider IVIG or PLEX preoperatively if bulbar/respiratory weakness.

— Communicate with anesthesia: avoid or minimize nondepolarizing neuromuscular blockers; if needed, reduce rocuronium dose and have sugammadex available; succinylcholine response is variable.

— Antibiotics: fluoroquinolones (FDA boxed warning), aminoglycosides, macrolides (especially azithromycin, erythromycin, telithromycin), clindamycin, ketolides.

— Cardiovascular: beta-blockers, procainamide, quinidine, calcium channel blockers (less commonly).

— Neuromuscular: magnesium sulfate IV (avoid in eclampsia if possible — use alternatives), neuromuscular blockers, botulinum toxin.

— Immune/other: immune checkpoint inhibitors (can unmask or trigger MG), D-penicillamine (drug-induced MG, usually reversible), chloroquine/hydroxychloroquine, interferon-alfa, statins (occasional worsening).

— Iodinated contrast: rare exacerbation; not absolute contraindication — use when indicated.

CCS pearl: Before any inpatient antibiotic or perioperative order set in an MG patient, screen the med list against the MG-exacerbating drug list. Order "avoid fluoroquinolones, aminoglycosides, IV magnesium" as a written alert — this is patient safety gold for CCS scoring.

Targeted biologics for refractory generalized MG:

Thymectomy details:

Drugs that exacerbate MG — must memorize:

Special Populations — Elderly and Renal/Hepatic Impairment

— Increasingly common; often AChR+ with male predominance.

— Lower incidence of thymoma than middle-aged onset but still requires chest imaging in every patient.

— Higher burden of comorbidities — diabetes, osteoporosis, cardiovascular disease — affects steroid choice and dosing.

— Greater risk of crisis and aspiration; lower physiologic reserve.

— Start at lower dose (30 mg every 4–6 hours) and titrate cautiously; bradycardia and syncope more common.

— Watch for urinary retention, bronchospasm, and GI cramping; consider glycopyrrolate adjunct.

— Renal clearance ~75% — reduce dose in CKD stages 3–5.

— Higher risk of hyperglycemia, osteoporotic fractures, cataracts, infection, hypertension, mood disturbance.

— Aggressive bone health: DEXA at baseline and every 1–2 years; calcium/vit D; bisphosphonate if T-score ≤−1.5 or fragility fracture or chronic ≥7.5 mg/day prednisone.

— Steroid-sparing strategy is even more important — favor mycophenolate (well-tolerated) or azathioprine.

— Azathioprine: check TPMT first; reduce dose in renal/hepatic impairment; monitor LFTs and CBC monthly initially.

— Mycophenolate: dose reduce in severe renal disease; teratogenic, but in elderly less relevant — still counsel female partners of childbearing potential if applicable.

— Methotrexate: avoid if CrCl <30; hepatotoxicity in alcohol use; not preferred in chronic liver disease.

— Cyclosporine/tacrolimus: nephrotoxic, watch BP and renal function; many drug interactions (CYP3A4).

— Beta-blockers for HTN/HF — may need to switch to ACEi/ARB.

— Statin-induced myalgia can confound MG assessment.

— Avoid sedating anticholinergics that compound bulbar symptoms.

Step 3 management: In an elderly MG patient on prednisone, layer the prophylaxis order set: PPI if NSAID/anticoagulant use, calcium/vit D, DEXA, TMP-SMX for PJP if high-dose chronic steroids, vaccinations updated before immunosuppression, and BP/glucose monitoring at each visit.

Late-onset MG (age ≥50):

Pyridostigmine in elderly:

Corticosteroids:

Steroid-sparing agents and organ dysfunction:

Polypharmacy red flags in elderly MG:

Special Populations — Pregnancy, Neonatal, and Pediatric MG

— Course is unpredictable: roughly one-third improve, one-third stable, one-third worsen; postpartum exacerbation is common.

— Preconception counseling: optimize disease control, switch teratogenic immunosuppressants (mycophenolate, methotrexate, cyclophosphamide are contraindicated) to pregnancy-compatible agents (azathioprine and cyclosporine are acceptable when benefits outweigh risks; prednisone is generally safe at lowest effective dose).

— Pyridostigmine PO is safe in pregnancy; avoid IV pyridostigmine (can induce uterine contractions).

— Manage exacerbations with IVIG or PLEX rather than escalating immunosuppression.

— Vaginal delivery preferred; second stage may be prolonged because expulsive (voluntary striated muscle) effort fatigues — assisted vaginal delivery (forceps/vacuum) often needed. Smooth uterine muscle is unaffected.

— Cesarean reserved for obstetric indications.

— Avoid magnesium sulfate for preeclampsia — can precipitate crisis. Use alternatives (levetiracetam, phenytoin) for seizure prophylaxis after consultation with neurology and OB.

— Regional anesthesia (epidural) preferred over general; communicate with anesthesia regarding neuromuscular blocker sensitivity.

— Maternal IgG antibodies cross the placenta → hypotonia, weak cry, poor suck, respiratory distress within first 1–4 days of life.

— Self-limited, resolves over 2–4 weeks as maternal antibodies clear.

— Supportive care; pyridostigmine if needed; rarely IVIG/PLEX.

— Distinct from arthrogryposis multiplex congenita (rare, due to in-utero antibody effects on fetal AChR).

— Prepubertal onset more often ocular, often seronegative or low-titer, higher spontaneous remission rate.

— Postpubertal juvenile MG resembles adult disease.

— Thymectomy can be considered in generalized AChR+ juvenile MG.

Board pearl: A pregnant MG patient developing preeclampsia — do not give IV magnesium. Switch to alternative seizure prophylaxis and treat hypertension with labetalol or hydralazine (note: monitor for beta-blocker MG effect, but labetalol is generally tolerated).

Pregnancy and MG:

Labor and delivery:

Neonatal transient MG (~10–20% of infants of MG mothers):

Juvenile MG:

Complications and Adverse Outcomes

— Affects ~15–20% of patients at some point; peak incidence in first 2 years of disease.

— Triggers: infection (most common), surgery, aspiration, medication changes (steroid initiation, MG-exacerbating drugs), pregnancy/postpartum, tapering immunotherapy, emotional stress.

— Features: increasing bulbar weakness, dyspnea, orthopnea, weak cough, FVC <20 mL/kg or NIF less negative than −30, paradoxical breathing.

— Overdose of pyridostigmine → muscarinic excess (SLUDGE: salivation, lacrimation, urination, defecation, GI cramps, emesis) plus weakness from nicotinic receptor desensitization.

— Key distinction from myasthenic crisis: muscarinic features prominent (miosis, hypersalivation, bradycardia, diarrhea, fasciculations).

— Treat by holding pyridostigmine, supportive care, atropine for muscarinic symptoms.

— Steroids: osteoporotic fracture, diabetes, infection, weight gain, cataracts, avascular necrosis, mood/psychosis.

— Azathioprine: myelosuppression, hepatotoxicity, flu-like idiosyncratic reaction, ↑ NMSC and lymphoma risk long-term.

— Mycophenolate: GI intolerance, leukopenia, teratogenicity.

— Rituximab: infusion reactions, hypogammaglobulinemia, PML (rare), HBV reactivation.

— Complement inhibitors: meningococcal infection.

— IVIG: headache, aseptic meningitis, thromboembolism, AKI, volume overload, hemolysis.

— PLEX: central line complications, citrate hypocalcemia, hypotension, coagulopathy.

Key distinction: When an MG patient on pyridostigmine deteriorates, ask: fasciculations + diarrhea + miosis + hypersalivation = cholinergic crisis (hold drug); clear lungs without those features but with respiratory fatigue = myasthenic crisis (treat with IVIG/PLEX and intubate as needed). When in doubt, hold pyridostigmine and treat as myasthenic crisis with airway support.

Myasthenic crisis — life-threatening respiratory failure from MG weakness:

Cholinergic crisis (now rare):

Aspiration pneumonia: bulbar weakness → silent aspiration; swallow evaluation indicated whenever bulbar symptoms present.

Iatrogenic complications:

Psychosocial: depression, fatigue beyond weakness, occupational disability, falls from leg weakness.

When to Escalate Care — ICU, Consults, and Inpatient Triage

— FVC <20 mL/kg, NIF less negative than −30 cm H₂O, or MEP <40 cm H₂O ("20/30/40 rule").

— Single-breath count <15–20.

— Severe bulbar dysfunction with inability to handle secretions, weak cough, recurrent aspiration.

— Paradoxical abdominal breathing, tachypnea, accessory muscle use.

— Rising PaCO₂ (late and ominous sign — do not wait for hypercapnia to intubate).

— Anticipate intubation rather than crash-intubate; pre-oxygenate carefully.

— Avoid succinylcholine if possible (variable response — may need higher dose); prefer rocuronium at reduced dose with sugammadex for reversal.

— Consider non-invasive ventilation (BiPAP) as a bridge in selected awake, cooperative patients without severe bulbar weakness — may avert intubation.

— Admit to ICU; serial NIF/FVC every 2–4 hours.

— IVIG 2 g/kg over 2–5 days or PLEX × 5 sessions — choose based on availability, comorbidities (PLEX faster but requires central access; IVIG avoid in renal failure, hypercoagulable state).

— Hold pyridostigmine while intubated (reduces airway secretions; resume during weaning).

— Continue or initiate corticosteroids alongside rescue therapy (under IVIG/PLEX cover to mitigate early worsening).

— Identify and treat trigger (cultures, CXR, medication review).

— DVT prophylaxis, stress ulcer prophylaxis, nutrition (NG if dysphagia).

— Neurology for diagnosis, antibody and EMG workup, treatment optimization.

— Thoracic surgery for thymectomy planning.

— Pulmonology/critical care for ventilatory support.

— Speech-language pathology for swallow evaluation.

— Anesthesia preop consultation for any surgery.

CCS pearl: On a CCS crisis case, the high-scoring sequence is: ICU admit → serial NIF/FVC → IVIG or PLEX → hold pyridostigmine if intubated → continue/initiate steroids → identify trigger → SLP swallow eval → DVT/PPI prophylaxis. Don't forget to update location to ICU and stop offending drugs (fluoroquinolone, magnesium, etc.).

Immediate ICU admission criteria in MG exacerbation/crisis:

Airway management:

Inpatient management bundle for crisis:

Consultations:

Key Differentials — Other Neuromuscular Junction and Muscle Disorders

— Presynaptic disorder; antibodies to voltage-gated calcium channels (VGCC).

— ~50% are paraneoplastic — small cell lung cancer in older smokers; screen with chest CT, repeat if initially negative.

— Proximal leg-predominant weakness, areflexia (reflexes return after brief exercise — "post-exercise facilitation"), autonomic features (dry mouth, erectile dysfunction, constipation).

— RNS: low-amplitude baseline CMAP with >100% facilitation at high-frequency stimulation.

— Treat underlying cancer; symptomatic therapy with amifampridine (3,4-DAP); IVIG/immunosuppression for refractory.

— Acute, descending, symmetric paralysis with prominent autonomic signs (fixed dilated pupils, dry mouth, ileus, urinary retention).

— Food-borne, wound (IV drug use, "skin popping"), infant (honey).

— RNS resembles LEMS; treat with equine antitoxin.

— Polymyositis/dermatomyositis/inclusion body myositis — proximal weakness, elevated CK, myopathic EMG, no fatigability or ocular involvement (IBM affects finger flexors and quads).

— Chronic progressive external ophthalmoplegia (CPEO): mimics ocular MG with ptosis and ophthalmoplegia but is progressive, symmetric, and without fatigability; ragged-red fibers on biopsy.

Key distinction: Ocular MG vs CPEO — both show ptosis and limited EOM; MG fluctuates and responds to ice/edrophonium; CPEO is steady and progressive over years with normal antibodies, normal RNS, and family history. MG diplopia, CPEO usually no diplopia (symmetric ophthalmoplegia).

Lambert-Eaton myasthenic syndrome (LEMS):

Botulism:

Congenital myasthenic syndromes: childhood onset, family history, seronegative; genetic testing.

Inflammatory myopathies:

Mitochondrial / metabolic myopathies:

Periodic paralyses (hypo/hyperkalemic): episodic, triggered by exercise/carbs, normal between episodes.

Key Differentials — Brainstem, Peripheral, and Systemic Mimics

— Can cause ophthalmoplegia and bulbar symptoms but typically with central signs (crossed deficits, ataxia, hemiparesis, sensory loss, hyperreflexia, Babinski).

— MRI brain with contrast clarifies.

— Third nerve palsy: ptosis + "down and out" eye, may include pupil involvement (compressive — aneurysm, herniation). MG spares the pupil.

— Internuclear ophthalmoplegia (MS in young, lacunar stroke in older): adduction deficit with contralateral abducting nystagmus — distinct pattern, no fatigability.

— Bilateral facial nerve palsies: consider Lyme, sarcoidosis, GBS.

— Ascending weakness with areflexia and sensory complaints; Miller Fisher has ophthalmoplegia + ataxia + areflexia (anti-GQ1b).

— CSF: albuminocytologic dissociation; NCS: demyelinating features.

— Mixed UMN + LMN findings, fasciculations, atrophy, brisk reflexes with weakness, no sensory loss.

— Bulbar onset ALS can mimic bulbar MG, but the presence of tongue fasciculations, atrophy, and UMN signs distinguishes.

— Proptosis, lid retraction (not ptosis), restrictive ophthalmoplegia. TSH/TRAb abnormal; orbital CT/MRI shows enlarged extraocular muscles.

— Inconsistent exam, give-way weakness, distractibility (Hoover sign); diagnosis of exclusion.

— Statins (myopathy), organophosphates (cholinergic toxidrome), aminoglycosides (transient NMJ blockade), immune checkpoint inhibitor myasthenia/myositis (treat with steroids + holding ICI).

Board pearl: Pupillary involvement, sensory deficits, hyperreflexia, fasciculations, or proximal CK elevation argue strongly against MG. A "fatigable, fluctuating, pure motor, areflexia-absent or normal-reflex" picture without sensory loss is the MG fingerprint.

Brainstem stroke / multiple sclerosis:

Cranial nerve palsies:

Guillain-Barré syndrome / Miller Fisher variant:

ALS (amyotrophic lateral sclerosis):

Thyroid eye disease (Graves orbitopathy):

Functional/psychogenic weakness:

Medication/toxin-induced:

Long-Term Plan, Discharge Medications, and Secondary Prevention

— Pyridostigmine at optimized dose with clear instructions on timing relative to meals and activity.

— Prednisone with explicit taper plan (typical taper: reduce by 5 mg every 2–4 weeks once stable; transition to alternate-day dosing when feasible).

— Steroid-sparing agent started in parallel (mycophenolate or azathioprine) with monitoring labs scheduled.

— PJP prophylaxis (TMP-SMX) if on ≥20 mg prednisone for ≥4 weeks or on combination immunosuppression.

— Calcium 1200 mg + vitamin D 800–1000 IU, ± bisphosphonate based on DEXA/fracture risk.

— PPI if NSAID or anticoagulant use; glucose monitoring if diabetes/prediabetes; BP control.

— Annual influenza (inactivated), COVID-19 boosters, pneumococcal (PCV20 or PCV15+PPSV23), shingles (Shingrix — inactivated, safe), hepatitis B, Tdap, meningococcal (mandatory before complement inhibitors).

— Medical alert bracelet noting MG and drug allergies.

— Wallet card listing drugs to avoid (fluoroquinolones, aminoglycosides, IV magnesium, beta-blockers, neuromuscular blockers).

— Emergency action plan for crisis symptoms.

— Notify all providers (dentist, anesthesiologist) of MG diagnosis before procedures.

— Sleep hygiene, paced activity, avoid extreme heat (worsens conduction).

— Aggressive infection prevention; early treatment of respiratory infections (avoiding fluoroquinolones).

— Stress management; mental health screening.

Step 3 management: Build a longitudinal MG care plan at discharge: schedule neurology follow-up at 2–4 weeks, labs at 2 weeks (CBC, CMP for immunosuppressants), PCP for steroid-comorbidity monitoring, ophthalmology yearly for cataracts/IOP, DEXA at baseline, and SLP if any bulbar symptoms persist.

Discharge medication checklist after MG exacerbation or new diagnosis:

Vaccinations (give before immunosuppression when possible; avoid live vaccines during immunosuppression):

Patient-issued safety items:

Lifestyle and trigger avoidance:

Follow-Up, Monitoring Parameters, and Counseling

— First 1–3 months: neurology every 2–4 weeks while titrating immunotherapy.

— Stable phase: every 3–6 months; annually once at minimal manifestation status on stable regimen.

— Use validated tools: MG-ADL (activities of daily living) patient-reported, QMG (Quantitative MG) clinician-performed, MGFA postintervention status for documentation of remission/MMS.

— Reassess pulmonary function (FVC, NIF) in patients with bulbar/respiratory history.

— Azathioprine: CBC and LFTs every 1–2 weeks for first 8 weeks, then monthly × 3, then every 3 months.

— Mycophenolate: CBC monthly first 3 months, then every 3 months; LFTs periodically.

— Methotrexate: CBC/LFTs/Cr every 4–8 weeks; folate supplementation.

— Cyclosporine/tacrolimus: BP, Cr, electrolytes, drug levels.

— Rituximab: check CD19/CD20, immunoglobulins, HBV serologies periodically.

— Long-term steroids: glucose/HbA1c, lipid panel, BP, DEXA every 1–2 years, annual eye exam.

— Trigger recognition (infection, drugs, heat, stress).

— Drugs to avoid — give patient a printed list; review at every visit.

— Importance of taking pyridostigmine before meals if dysphagia.

— Pregnancy planning — switch off teratogenic agents 6 months pre-conception.

— Driving safety with diplopia or limb weakness — temporary restrictions may apply; review state reporting rules.

— Mental health — depression and fatigue are common; screen with PHQ-9.

— Energy conservation, paced activity, low-resistance aerobic exercise when stable.

— PT/OT consultation; SLP for swallow strategies and voice therapy.

Board pearl: The MG-ADL score change of ≥2 points is the validated threshold for clinically meaningful improvement or worsening — frequently used in trials and increasingly in clinical practice to guide therapy adjustments.

Routine outpatient follow-up cadence:

Disease-activity tracking:

Lab monitoring by therapy:

Counseling priorities:

Rehabilitation:

Ethical, Legal, and Patient Safety Considerations

— Thymectomy decision-making requires discussion of unclear short-term benefit (effects manifest over 1–3 years), surgical risks, and that surgery is recommended even with mild generalized MG in age 18–65 — patients may decline if expecting immediate relief. Document shared decision-making.

— Complement inhibitors (eculizumab/ravulizumab/zilucoplan): require informed consent regarding meningococcal infection risk; document vaccination ≥2 weeks before initiation, or coverage with antibiotic prophylaxis if therapy must start sooner. REMS program enrollment is mandatory.

— Pregnancy and immunosuppression: counsel about teratogenic risk of mycophenolate and methotrexate; document contraception plan in women of reproductive age (REMS for mycophenolate).

— Hospital-to-home: ensure pyridostigmine dose is reconciled, steroid taper schedule documented, follow-up scheduled, drug-avoidance list given.

— ED handoffs: communicate MG diagnosis and forbidden drugs to triage; flag in EHR.

— Perioperative: written communication to anesthesia regarding neuromuscular blocker sensitivity, avoidance list, and post-op respiratory monitoring plan.

— Diplopia and limb weakness may impair driving; counsel and document; state-specific reporting requirements (e.g., California, Pennsylvania, New Jersey) for conditions causing lapses of consciousness or motor impairment.

— Reasonable accommodations under ADA (rest breaks, modified schedule, reduced lifting); document functional limitations to support FMLA/disability claims.

— Frail elderly or refractory crisis patients should have goals-of-care discussions regarding intubation, tracheostomy, and long-term ventilation. Document advance directives.

— Add drug allergy/intolerance alerts for fluoroquinolones, aminoglycosides, IV magnesium, neuromuscular blockers — prevents inadvertent ordering in subsequent admissions.

Step 3 management: A patient hospitalized for pneumonia with MG receives a fluoroquinolone from a covering hospitalist and crashes — this is a preventable adverse event. The systems-based fix is EHR allergy alerts plus a problem-list flag plus patient-carried wallet card. Step 3 frequently tests this exact safety scenario.

Informed consent edge cases:

Transitions of care — the highest-risk safety zone in MG:

Mandatory reporting and driving:

Workplace and disability:

End-of-life and advance care planning:

EHR safety bundling:

High-Yield Associations and Rapid-Fire Clinical Facts

— Younger women, often non-white; prominent bulbar, neck, and respiratory weakness; tongue atrophy; less ocular; thymus usually normal; poor response to pyridostigmine (may worsen); excellent response to rituximab.

Board pearl: If the stem mentions a young woman with bulbar weakness, tongue atrophy, negative AChR antibodies, and poor response to pyridostigmine — the answer is MuSK-MG, and the high-yield treatment is rituximab.

MG is associated with thymic abnormalities: ~65% thymic hyperplasia, ~10–15% thymoma. Always image the chest at diagnosis.

Thymoma + MG → check anti-titin and anti-ryanodine receptor (RyR) antibodies; often older patients with more severe disease.

MuSK-MG profile:

Autoimmune comorbidities (think when stem mentions MG): autoimmune thyroid disease, RA, SLE, pernicious anemia, type 1 DM, vitiligo.

Drug-induced MG: D-penicillamine (classic), interferon-alfa, immune checkpoint inhibitors (can cause MG, myocarditis, and myositis as a triad — 3M syndrome, high mortality).

Ice pack test: ~80% sensitive for ocular MG; place ice over a ptotic lid for 2 minutes; ≥2 mm improvement is positive.

Edrophonium (Tensilon) test: historical; rarely used in U.S. due to bradyarrhythmia risk.

20/30/40 rule for crisis: FVC <20 mL/kg, NIF less negative than −30, MEP <40 → ICU and prepare to intubate.

Pyridostigmine doesn't cross BBB; minimal CNS effects.

IVIG vs PLEX in crisis: roughly equivalent efficacy; PLEX faster onset (days), IVIG easier logistics (no central line).

Eculizumab/ravulizumab/zilucoplan: mandatory meningococcal vaccination at least 2 weeks pre-treatment.

Pregnancy: avoid mycophenolate, methotrexate, cyclophosphamide; azathioprine and prednisone acceptable; avoid IV magnesium for eclampsia.

Neonatal MG: transient, 2–4 weeks, supportive.

Anesthesia: sensitivity to nondepolarizing NMB; have sugammadex available; avoid succinylcholine when possible.

Driving: counsel about diplopia/weakness; state-specific reporting.

Board Question Stem Patterns

— Best next step: Anti-AChR antibodies + ice pack test; chest CT regardless of result.

— Best management: pyridostigmine + start low-dose prednisone with up-titration + steroid-sparing agent (mycophenolate or azathioprine) + chest CT for thymoma + vaccinations + bone/PJP prophylaxis as appropriate.

— Best next step: ICU admission, hold fluoroquinolone (switch to azithromycin? No — also exacerbates! Use a non-MG-aggravating agent like ceftriaxone), IVIG or PLEX, hold pyridostigmine if intubated, serial NIF/FVC.

— Diagnosis: cholinergic crisis. Action: hold pyridostigmine, supportive care, atropine for muscarinic features.

— Best response: avoid magnesium; use alternative (levetiracetam) and treat hypertension; consult neurology.

— Best management: offer thymectomy based on MGTX trial — improves outcomes and reduces steroid burden in non-thymomatous AChR+ generalized MG age 18–65.

— Best next test: Anti-MuSK antibodies. If positive, rituximab is the high-yield therapy.

— Best plan: optimize disease (consider preop IVIG/PLEX if bulbar/respiratory weakness), communicate with anesthesia (reduce rocuronium, have sugammadex available, avoid succinylcholine when possible), continue pyridostigmine through morning of surgery, plan post-op monitored bed.

CCS pearl: On any MG crisis CCS case, change location to ICU early, order serial NIF and FVC, start IVIG or PLEX, identify and remove the trigger drug, and consult neurology, pulmonology, and SLP.

Stem 1 — Classic ocular onset: Middle-aged woman with several weeks of intermittent double vision and droopy lids that worsen by evening; exam shows fatigable ptosis; pupils normal.

Stem 2 — Generalized MG with new diagnosis: Patient with AChR+ generalized MG, FVC normal, mild bulbar symptoms.

Stem 3 — Crisis trigger: MG patient admitted for community-acquired pneumonia receives levofloxacin and within 24 hours has worsening dyspnea, dysphagia, weak cough, NIF −20.

Stem 4 — Cholinergic vs myasthenic crisis: Patient on high-dose pyridostigmine with worsening weakness, miosis, hypersalivation, fasciculations, diarrhea.

Stem 5 — Pregnant patient with preeclampsia and MG: OB wants to give magnesium sulfate.

Stem 6 — Thymectomy candidate: 35-year-old with new AChR+ generalized MG, chest CT shows thymic hyperplasia (no thymoma).

Stem 7 — Seronegative young woman with prominent bulbar disease: AChR negative, fails pyridostigmine.

Stem 8 — Preop anesthesia clearance: MG patient for elective cholecystectomy.

One-Line Recap

Myasthenia gravis is an antibody-mediated postsynaptic neuromuscular junction disorder producing fatigable, fluctuating, purely motor weakness with ocular and bulbar predominance — diagnosed by AChR/MuSK antibodies (and chest CT for thymoma), treated symptomatically with pyridostigmine and longitudinally with corticosteroids plus a steroid-sparing immunosuppressant, with IVIG or PLEX rescue and ICU airway support driven by the 20/30/40 rule during crisis.

Diagnose: fatigable ptosis/diplopia/bulbar/proximal weakness with normal reflexes and sensation → AChR antibodies first, MuSK if negative, single-fiber EMG if both negative; chest CT in every patient to rule out thymoma.

Treat: pyridostigmine for symptoms, prednisone with slow up-titration plus azathioprine or mycophenolate for steroid sparing; rituximab for MuSK-MG; complement or FcRn inhibitors for refractory disease; thymectomy for thymoma always, and for AChR+ generalized MG age 18–65.

Rescue and crisis: 20/30/40 rule (FVC <20 mL/kg, NIF less negative than −30, MEP <40) drives ICU admission and intubation planning; IVIG or PLEX are equivalent rescue; hold pyridostigmine while intubated; identify trigger (infection, fluoroquinolone, aminoglycoside, beta-blocker, IV magnesium).

Safety net: vaccinate before immunosuppression; meningococcal vaccine before complement inhibitors; avoid teratogens (mycophenolate, methotrexate) in pregnancy; avoid magnesium in pregnant MG patients with preeclampsia; medical alert bracelet and EHR drug-avoidance flagging at every transition of care.