Demyelinating, Peripheral Nerve and Neuromuscular Junction Disorders

Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, immune-mediated demyelinating disease of the central nervous system (CNS), affecting the brain, optic nerves, and spinal cord. The key pathology is formation of sharply demarcated plaques of demyelination with relative axonal preservation early, followed by gliosis and neurodegeneration. Because oligodendrocytes myelinate CNS axons, MS is a disorder of oligodendrocytes, not Schwann cells.

Pathogenesis and Immunology

MS is primarily a T-cell–mediated autoimmune disease directed against CNS myelin antigens such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein. Autoreactive CD4⁺ Th1 and Th17 cells cross the blood–brain barrier, secrete inflammatory cytokines, and recruit macrophages. IFN-γ activates macrophages, while IL-17 promotes neutrophil and monocyte recruitment and blood–brain barrier disruption. B cells also contribute through antigen presentation and antibody production; this explains the efficacy of anti-CD20 therapies.

Inflammatory demyelination causes saltatory conduction failure. Normally, myelin increases membrane resistance and decreases capacitance, allowing rapid impulse propagation between nodes of Ranvier. Demyelination exposes internodal axonal membrane, causing slowed conduction or conduction block. This explains symptoms that worsen with heat or exercise, called Uhthoff phenomenon, because elevated temperature further impairs conduction in demyelinated axons.

Epidemiology and Risk Factors

• Typical onset: age 20–40 years.
• Sex: female predominance, approximately 2–3:1.
• Geography: more common at higher latitudes, linked partly to lower ultraviolet exposure and vitamin D levels.
• Genetics: associated with HLA-DRB1*1501.
• Environmental risks: Epstein–Barr virus infection, smoking, obesity in adolescence, and low vitamin D.

Clinical Manifestations

MS causes neurologic deficits that are disseminated in time and space. Lesions commonly involve periventricular white matter, optic nerves, brainstem, cerebellum, and spinal cord.

Manifestation	High-Yield Features
Optic neuritis	Painful monocular vision loss, decreased visual acuity, impaired color vision, afferent pupillary defect.
Internuclear ophthalmoplegia	Lesion of the medial longitudinal fasciculus; impaired ipsilateral adduction with contralateral abducting nystagmus.
Sensory or motor deficits	Numbness, paresthesias, weakness, spasticity, hyperreflexia, Babinski sign.
Cerebellar involvement	Ataxia, intention tremor, dysarthria.
Spinal cord lesions	Lhermitte sign: electric shock-like sensation down the spine with neck flexion.
Autonomic symptoms	Urinary urgency, retention, constipation, sexual dysfunction.

Clinical Courses

Subtype	Description
Relapsing-remitting MS	Most common initial form, approximately 85%; attacks followed by partial or complete recovery.
Secondary progressive MS	Gradual neurologic decline after an initial relapsing-remitting course.
Primary progressive MS	Progressive disability from onset; approximately 10–15% of cases.
Clinically isolated syndrome	First demyelinating episode suggestive of MS but not yet meeting full diagnostic criteria.

Diagnosis

Diagnosis relies on the McDonald criteria, demonstrating lesions disseminated in space and time while excluding better explanations. MRI is the most important test. Typical MRI findings include ovoid periventricular plaques perpendicular to the ventricles, called Dawson fingers, reflecting inflammation along medullary veins. Active lesions enhance with gadolinium, whereas older lesions do not; simultaneous enhancing and nonenhancing lesions demonstrate dissemination in time.

• CSF: oligoclonal IgG bands in approximately 85–95% of patients; elevated IgG index. Normal CSF has no unique oligoclonal bands restricted to CSF.
• Evoked potentials: delayed visual evoked potentials reflect slowed conduction after optic nerve demyelination.
• Important mimics: neuromyelitis optica spectrum disorder with aquaporin-4 IgG, MOG-antibody disease, vitamin B12 deficiency, CNS vasculitis, Lyme disease, sarcoidosis, and HIV.

Pathology

Grossly, plaques are firm gray-tan areas in white matter, classically near the lateral ventricles. Microscopically, active plaques show perivascular lymphocytic inflammation, macrophages containing myelin debris, and loss of myelin with relative preservation of axons. Chronic plaques show astrocytic gliosis. This distinction is high-yield: MS affects CNS myelin made by oligodendrocytes, whereas Guillain–Barré syndrome affects peripheral myelin made by Schwann cells.

Treatment Principles and Pharmacology

For Step 1, know the mechanism and major toxicities of disease-modifying therapies rather than detailed treatment algorithms. Acute relapses are often treated with high-dose corticosteroids, commonly IV methylprednisolone 1 g/day for 3–5 days, which suppresses inflammatory cytokine transcription via glucocorticoid receptor signaling.

Drug/Class	Mechanism	High-Yield Adverse Effects
Interferon-β	Decreases T-cell activation and trafficking across the blood–brain barrier.	Flu-like symptoms, depression, hepatotoxicity, leukopenia.
Glatiramer acetate	Myelin basic protein mimic; shifts immune response toward anti-inflammatory T-cell phenotype.	Injection-site reactions, flushing, chest tightness.
Fingolimod	Sphingosine-1-phosphate receptor modulator; sequesters lymphocytes in lymph nodes.	Bradycardia after first dose, macular edema, infections.
Natalizumab	Monoclonal antibody against α4-integrin; blocks leukocyte adhesion and CNS entry.	Progressive multifocal leukoencephalopathy due to JC virus reactivation.
Ocrelizumab	Anti-CD20 monoclonal antibody causing B-cell depletion.	Infusion reactions, infections; used in relapsing MS and primary progressive MS.

The Expanded Disability Status Scale (EDSS) ranges from 0 to 10, where 0 is normal neurologic examination, 6 indicates need for unilateral walking assistance, and 10 indicates death due to MS. It is commonly used in clinical trials to quantify disability progression. Landmark disease-modifying therapy trials showed reduced relapse rates and MRI lesion burden, supporting the concept that inflammatory activity drives early relapsing disease, whereas later progressive disease reflects accumulated axonal loss and neurodegeneration.

Guillain–Barré Syndrome

Core definition and pathogenesis

Guillain–Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy of the peripheral nervous system, classically causing rapidly progressive, symmetric, ascending weakness with areflexia. Unlike multiple sclerosis, which involves oligodendrocyte myelin in the CNS, GBS primarily targets Schwann cell myelin, peripheral nerve axons, or both. The typical time course is monophasic: symptoms progress to a nadir within 4 weeks; progression beyond 8 weeks suggests chronic inflammatory demyelinating polyneuropathy rather than GBS.

The major mechanism is molecular mimicry after infection. Antibodies generated against microbial antigens cross-react with peripheral nerve gangliosides, activating complement and macrophage-mediated injury. The most classic trigger is Campylobacter jejuni gastroenteritis, especially associated with anti-GM1 antibodies and axonal variants. Other triggers include cytomegalovirus, Epstein–Barr virus, Mycoplasma pneumoniae, HIV, influenza-like illness, surgery, and rarely vaccination. The neurologic syndrome usually begins 1–3 weeks after the antecedent illness.

Major clinical variants

Variant	Primary pathology	High-yield associations
AIDP: acute inflammatory demyelinating polyradiculoneuropathy	Segmental demyelination of peripheral nerves and roots	Most common form in North America and Europe; slowed conduction velocity, prolonged distal latencies, conduction block
AMAN: acute motor axonal neuropathy	Motor axonal injury at nodes of Ranvier	Often post-Campylobacter; anti-GM1; pure motor weakness with preserved sensation
AMSAN: acute motor-sensory axonal neuropathy	Motor and sensory axonal degeneration	More severe; slower recovery because axonal regeneration is required
Miller Fisher syndrome	Variant involving cranial/peripheral nerves	Triad: ophthalmoplegia, ataxia, areflexia; strongly associated with anti-GQ1b antibodies

Clinical presentation and localization

GBS typically begins with paresthesias in the feet followed by symmetric weakness that ascends from legs to arms and face. Deep tendon reflexes are reduced or absent early. Sensory findings are often mild relative to weakness because motor roots are heavily affected. Pain, especially back or radicular pain, is common. Cranial nerve involvement may cause bilateral facial weakness, dysphagia, or ophthalmoplegia. Autonomic dysfunction may produce tachycardia, bradyarrhythmias, labile blood pressure, urinary retention, or ileus.

The most dangerous complication is respiratory failure from diaphragmatic and intercostal muscle weakness. Approximately 20–30% of hospitalized patients require mechanical ventilation. Bedside respiratory thresholds commonly used to trigger ICU-level monitoring or intubation concern include forced vital capacity <20 mL/kg, maximal inspiratory pressure less negative than −30 cm H₂O, or maximal expiratory pressure <40 cm H₂O. These numbers are not Step 1 management minutiae to memorize in isolation, but they reinforce that GBS is a peripheral nerve disorder that can kill by neuromuscular respiratory failure.

Diagnosis

Diagnosis is primarily clinical, supported by cerebrospinal fluid and electrodiagnostic testing. The classic CSF finding is albuminocytologic dissociation: elevated protein with normal or near-normal leukocyte count. CSF protein is often >45 mg/dL, while WBC count is typically <10 cells/mm³. This may be absent during the first week and becomes more sensitive after 7–10 days. A CSF pleocytosis above 50 cells/mm³ should prompt consideration of alternatives such as HIV, Lyme disease, malignancy, or infectious polyradiculitis.

Nerve conduction studies in AIDP show demyelination: slowed conduction velocity, prolonged distal motor latencies, prolonged or absent F waves, and conduction block. Axonal forms show reduced compound muscle action potential amplitudes. MRI is not required for classic cases but may show enhancement of nerve roots due to inflammation and breakdown of the blood-nerve barrier.

Severity scoring and prognosis

A commonly used functional staging system is the GBS Disability Scale: 0 = healthy; 1 = minor symptoms, able to run; 2 = able to walk 10 m independently; 3 = able to walk 10 m with aid; 4 = bedbound or chairbound; 5 = requires assisted ventilation; 6 = death. Mortality is approximately 3–7%, usually from respiratory failure, autonomic instability, infection, or thromboembolism. Most patients improve, but recovery may take months; about 80% can walk independently by 6 months.

Treatment principles and high-yield pharmacology

Two disease-modifying therapies are effective: intravenous immunoglobulin (IVIG) and plasma exchange. IVIG is commonly given as 0.4 g/kg/day for 5 days. Plasma exchange is typically 4–6 exchanges over 7–14 days. They are similarly effective and are not combined routinely, because combination therapy has not shown additional benefit. Glucocorticoids are not effective in GBS, a classic examination contrast with many other autoimmune neurologic diseases.

Evidence-based guidelines from the American Academy of Neurology support plasma exchange for nonambulatory patients within 4 weeks of onset and consider it for ambulatory patients within 2 weeks. IVIG is recommended for patients who require assistance walking and present within about 2 weeks of weakness onset. The landmark North American plasma exchange trial showed faster improvement with plasma exchange, and subsequent randomized trials demonstrated IVIG to be comparably effective.

Key differentials for Step 1

• Botulism: descending paralysis, dilated pupils, impaired acetylcholine release.
• Myasthenia gravis: fluctuating fatigable weakness, ocular involvement, normal reflexes and sensation.
• Lambert–Eaton syndrome: proximal weakness improves with use, autonomic symptoms, associated with small cell lung carcinoma.
• Tick paralysis: acute ascending paralysis; improves after tick removal; no albuminocytologic dissociation.
• Poliomyelitis or West Nile anterior horn cell disease: asymmetric flaccid paralysis with fever and CSF pleocytosis.

Acute Disseminated Encephalomyelitis

Core definition and epidemiology

Acute disseminated encephalomyelitis (ADEM) is an acute, immune-mediated, inflammatory demyelinating disorder of the CNS characterized by multifocal neurologic deficits plus encephalopathy, typically occurring after an infection or, rarely, vaccination. It primarily affects children, with a typical age of 5–8 years and an incidence of approximately 0.2–0.8 per 100,000 children per year. For USMLE Step 1, the key contrast is that ADEM is usually monophasic, postinfectious, and associated with encephalopathy, whereas multiple sclerosis is classically relapsing and usually lacks encephalopathy at onset.

Pathogenesis and pathology

ADEM is thought to result from molecular mimicry: infectious antigens trigger T-cell and antibody responses that cross-react with CNS myelin proteins, including myelin basic protein, proteolipid protein, and, in some patients, myelin oligodendrocyte glycoprotein (MOG). The disorder often appears 1–3 weeks after viral illness such as measles, varicella, influenza, Epstein-Barr virus, or after nonspecific upper respiratory or gastrointestinal infection. Vaccination-associated ADEM is rare and far less common than postinfectious ADEM.

Histologically, ADEM shows perivenular inflammation and demyelination. Small veins are surrounded by sleeves of lymphocytes and macrophages, with loss of myelin around vessels and relative preservation of axons. This contrasts with MS plaques, which are often sharply demarcated and of different ages. ADEM resembles experimental autoimmune encephalomyelitis, an animal model of T-cell-mediated demyelination.

Clinical presentation

ADEM typically has an acute to subacute onset over hours to days. The defining feature is encephalopathy, meaning altered mental status, irritability, confusion, lethargy, or coma not explained by fever alone. Multifocal CNS findings reflect widespread lesions in white matter, deep gray nuclei, brainstem, cerebellum, spinal cord, or optic nerves.

• Constitutional prodrome: fever, malaise, headache, nausea, or vomiting may precede neurologic deficits.
• Cerebral findings: encephalopathy, seizures, behavioral change.
• Motor deficits: weakness, pyramidal signs, hyperreflexia, Babinski sign.
• Cerebellar/brainstem findings: ataxia, dysarthria, cranial nerve palsies.
• Spinal cord involvement: transverse myelitis with sensory level, weakness, and bladder dysfunction.
• Optic nerve involvement: optic neuritis may cause painful visual loss, often bilateral in pediatric demyelination.

Diagnostic criteria and investigations

International pediatric criteria emphasize: first polyfocal clinical CNS event presumed inflammatory demyelination, encephalopathy, brain MRI abnormalities during the acute phase, and no new clinical or MRI findings after 3 months. The “3-month” rule helps separate monophasic ADEM from relapsing disorders such as MS or MOG antibody-associated disease.

Test	Typical ADEM finding	High-yield interpretation
MRI brain/spine	Large, bilateral, asymmetric, poorly marginated T2/FLAIR hyperintense lesions; often >1–2 cm; may involve subcortical/deep white matter, basal ganglia, thalami, brainstem, cerebellum, and spinal cord	Lesions are often of the same age; deep gray involvement favors ADEM over MS
CSF	Mild lymphocytic pleocytosis, usually <100 cells/µL; mildly elevated protein; glucose usually normal	Supports inflammation but is nonspecific; must exclude infection
Oligoclonal bands	Absent or transient in most cases	Persistent oligoclonal bands favor MS
MOG-IgG	Positive in a subset, especially children with ADEM phenotype	Suggests MOG antibody-associated demyelination; may predict recurrence

Classification and important variants

Form	Definition	Exam-relevant feature
Monophasic ADEM	Single demyelinating episode with no new symptoms or MRI lesions after 3 months	Classic form; common in children
Multiphasic ADEM	New ADEM-like episode occurring >3 months after initial event and >1 month after completing steroids	Raises concern for MOG-associated disease
ADEM with optic neuritis	ADEM phenotype plus optic nerve inflammation	May overlap with MOG-IgG disease
Acute hemorrhagic leukoencephalitis	Hyperacute, severe hemorrhagic variant also called Hurst disease	More fulminant; may show necrosis, hemorrhage, edema, high mortality

Differential diagnosis

The most important Step 1 differential is multiple sclerosis. ADEM favors younger age, postinfectious onset, encephalopathy, monophasic course, large poorly demarcated lesions, and deep gray matter involvement. MS favors young adults, optic neuritis or internuclear ophthalmoplegia without encephalopathy, relapsing course, periventricular ovoid plaques perpendicular to ventricles called Dawson fingers, and persistent CSF oligoclonal bands.

Other mimics include viral encephalitis, bacterial meningitis, CNS vasculitis, leukodystrophies, metabolic encephalopathies, acute transverse myelitis, and neuromyelitis optica spectrum disorder. Infectious encephalitis is particularly important because both ADEM and infection can present with fever, seizures, CSF lymphocytes, and altered mental status.

Treatment principles and prognosis

Treatment is immunosuppression after reasonable exclusion of infection. Common first-line therapy is high-dose corticosteroid treatment, such as IV methylprednisolone 20–30 mg/kg/day, maximum 1 g/day, for 3–5 days, often followed by an oral prednisone taper over 4–6 weeks. Steroid-refractory cases may receive IV immunoglobulin total dose 2 g/kg over 2–5 days or plasma exchange, commonly 5–7 exchanges over 10–14 days. Evidence is largely observational rather than based on large randomized landmark trials.

Prognosis is generally favorable: most children improve substantially, and many recover fully, though residual cognitive, motor, visual, or seizure-related deficits can occur. Mortality in typical ADEM is low, generally <5%, but acute hemorrhagic leukoencephalitis has a much worse prognosis. Recurrence or new lesions after the expected monophasic window should prompt reconsideration of MS, MOG antibody-associated disease, or neuromyelitis optica spectrum disorder.

Peripheral Neuropathies

Peripheral neuropathy refers to dysfunction of peripheral nerves distal to the brainstem and spinal cord, including sensory, motor, and autonomic fibers. Step 1 questions often require localization by distribution and identification of whether the primary lesion is axonal or demyelinating. Peripheral nerves contain axons wrapped by Schwann cells; one Schwann cell myelinates one internode of one axon, unlike CNS oligodendrocytes, which myelinate multiple axons.

Pathophysiologic Classification

Pattern	Mechanism	Electrodiagnostic Finding	Classic Causes
Axonal neuropathy	Primary degeneration of axon; distal axons are most vulnerable because of high metabolic demand and long transport distance	Reduced compound muscle action potential or sensory nerve action potential amplitudes; conduction velocity relatively preserved	Diabetes mellitus, alcohol, uremia, toxins, vitamin B12 deficiency, chemotherapy
Demyelinating neuropathy	Schwann cell or myelin injury causing impaired saltatory conduction	Markedly slowed conduction velocity, prolonged distal latency, conduction block, temporal dispersion	Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease type 1
Neuronopathy/ganglionopathy	Damage to dorsal root ganglia or motor neurons	Non-length-dependent sensory loss or motor neuron signs	Paraneoplastic anti-Hu, Sjögren syndrome, toxins

Normal motor nerve conduction velocities are approximately >50 m/s in upper limbs and >40 m/s in lower limbs. Demyelinating disease often slows conduction to <70% of the lower limit of normal. In contrast, axonal loss primarily decreases signal amplitude because fewer functioning axons remain.

Clinical Patterns and Localization

• Distal symmetric polyneuropathy: the most common pattern; produces “stocking-glove” sensory loss because the longest axons are affected first. Symptoms begin in toes, ascend, and later involve fingers.
• Mononeuropathy: single nerve lesion, often from compression or trauma. Examples include median nerve compression in carpal tunnel syndrome and common fibular nerve injury causing foot drop.
• Mononeuritis multiplex: asymmetric, painful involvement of multiple individual nerves due to ischemic injury of the vasa nervorum. Classically associated with vasculitides such as polyarteritis nodosa, granulomatosis with polyangiitis, and diabetes.
• Small-fiber neuropathy: pain and temperature loss with burning dysesthesias; strength, reflexes, and routine nerve conduction studies may be normal because unmyelinated C fibers and thinly myelinated Aδ fibers are poorly assessed.
• Autonomic neuropathy: orthostatic hypotension, resting tachycardia, gastroparesis, erectile dysfunction, bladder dysfunction, and abnormal sweating.

High-Yield Etiologies

Diabetic Peripheral Neuropathy

Diabetes mellitus is the most common cause of distal symmetric polyneuropathy in developed countries. Mechanisms include nonenzymatic glycation of proteins, oxidative stress, microvascular ischemia, and activation of the polyol pathway: excess glucose is converted by aldose reductase to sorbitol, which accumulates and causes osmotic and oxidative injury, especially in Schwann cells. Typical findings include decreased vibration and proprioception, reduced ankle reflexes, burning pain, and loss of protective sensation. Screening uses a 10-g monofilament, vibration testing with a 128-Hz tuning fork, pinprick, and ankle reflexes. Diabetes diagnostic thresholds include fasting plasma glucose ≥126 mg/dL, random glucose ≥200 mg/dL with symptoms, 2-hour oral glucose tolerance test ≥200 mg/dL, or HbA1c ≥6.5%.

Vitamin and Metabolic Neuropathies

Vitamin B12 deficiency causes peripheral neuropathy plus subacute combined degeneration involving dorsal columns and lateral corticospinal tracts. Laboratory clues include macrocytosis, elevated methylmalonic acid, and elevated homocysteine. Serum B12 is often considered low at <200 pg/mL. Thiamine deficiency may cause dry beriberi with peripheral neuropathy, often in alcohol use disorder or malnutrition. Uremic neuropathy is typically distal symmetric and axonal.

Toxic and Drug-Induced Neuropathies

Common toxic causes include alcohol, arsenic, lead, and chemotherapy. Step 1–relevant drugs include isoniazid, which causes pyridoxine depletion and sensory neuropathy; prevention is pyridoxine 25–50 mg/day. Vincristine disrupts microtubule-dependent axonal transport. Cisplatin and taxanes can cause dose-dependent sensory neuropathy.

Hereditary Neuropathies

Charcot-Marie-Tooth disease is a hereditary motor and sensory neuropathy with distal weakness, foot deformities such as pes cavus, and “stork-leg” calves. Type 1 is demyelinating and commonly due to PMP22 gene duplication on chromosome 17; nerve conduction velocities are markedly reduced. Type 2 is primarily axonal and has relatively preserved velocities with reduced amplitudes.

Neuropathic Pain Pharmacology

Drug Class	Examples and Typical Adult Doses	Mechanism	Key Adverse Effects
SNRIs	Duloxetine 30–60 mg daily	Increases descending inhibitory serotonin and norepinephrine signaling	Nausea, insomnia, hypertension, serotonin syndrome risk
Gabapentinoids	Gabapentin commonly titrated from 300 mg nightly to 300–1200 mg three times daily; pregabalin 50–100 mg three times daily	Bind α2δ subunit of voltage-gated calcium channels, decreasing excitatory neurotransmitter release	Sedation, dizziness, edema; renal dose adjustment
Tricyclic antidepressants	Amitriptyline 10–25 mg nightly, titrated as tolerated	Blocks serotonin and norepinephrine reuptake; also anticholinergic and antihistaminic effects	Dry mouth, urinary retention, orthostatic hypotension, QT prolongation

On pathology, severe axonal injury distal to a lesion produces Wallerian degeneration: breakdown of axon and myelin distal to the injury, macrophage clearance, and possible regeneration along intact endoneurial tubes at roughly 1–3 mm/day. This explains why recovery after peripheral nerve injury is slow and depends on lesion distance from the target muscle or sensory receptor.

Myasthenia Gravis

Myasthenia gravis (MG) is an autoimmune disorder of the postsynaptic neuromuscular junction characterized by fluctuating, fatigable skeletal muscle weakness that worsens with use and improves with rest. It is high-yield because it links immunology, synaptic physiology, pharmacology, and mediastinal pathology. Prevalence is approximately 15–25 per 100,000; classic epidemiology is women age 20–40 and men age >50.

Neuromuscular Junction Physiology and Pathogenesis

At the normal neuromuscular junction, a motor neuron action potential opens presynaptic voltage-gated Ca²⁺ channels, causing acetylcholine (ACh) vesicle release. ACh binds nicotinic ACh receptors on the folded postsynaptic motor end plate, producing an end-plate potential. The normal junction has a safety factor: the end-plate potential is larger than the threshold needed to trigger a muscle action potential. MG reduces this safety factor, so repeated activity causes transmission failure and fatigable weakness.

• Anti-ACh receptor antibodies: present in approximately 80–85% of generalized MG and 50% of purely ocular MG. They are usually IgG1/IgG3, activate complement, destroy postsynaptic folds, and cross-link receptors, accelerating internalization.
• Anti-MuSK antibodies: present in about 5–8% of MG. MuSK is required for clustering ACh receptors via agrin–LRP4 signaling. These antibodies are often IgG4, less complement-fixing, and are associated with prominent bulbar, facial, neck, and respiratory weakness.
• Anti-LRP4 antibodies: less common; interfere with agrin-mediated ACh receptor organization.

The thymus is central to AChR-positive MG. Approximately 65–75% have thymic follicular hyperplasia, and 10–15% have a thymoma. Therefore, a patient with MG should be evaluated for an anterior mediastinal mass. Histologically, the disease is a type II hypersensitivity process, but unlike Graves disease, the antibody effect is destructive/blocking rather than stimulatory.

Clinical Features

The hallmark is weakness without sensory loss. Deep tendon reflexes are typically normal, distinguishing MG from many neuropathies. Extraocular muscles are commonly affected because they fire frequently and have small motor units.

• Ocular symptoms: fluctuating ptosis and diplopia; pupils are spared because pupillary constriction uses autonomic smooth muscle, not skeletal neuromuscular junctions.
• Bulbar symptoms: dysarthria, dysphagia, nasal speech, chewing fatigue, facial weakness.
• Limb weakness: usually proximal greater than distal.
• Respiratory involvement: may cause myasthenic crisis, defined clinically by respiratory failure requiring ventilatory support.

Symptoms often worsen with infection, surgery, pregnancy/postpartum state, emotional stress, and drugs that impair neuromuscular transmission. High-yield offending drugs include aminoglycosides, fluoroquinolones, macrolides, magnesium, beta-blockers, procainamide, quinidine, and penicillamine.

Classification and Severity

MGFA Class	Definition
I	Purely ocular weakness
II	Mild generalized weakness; IIa limb/axial predominant, IIb bulbar/respiratory predominant
III	Moderate generalized weakness; IIIa or IIIb by distribution
IV	Severe generalized weakness; IVa or IVb by distribution
V	Intubation, with or without mechanical ventilation

The Quantitative Myasthenia Gravis score ranges from 0–39, assessing ocular, bulbar, limb, and respiratory strength; higher scores indicate worse disease. Respiratory danger is suggested by forced vital capacity <15–20 mL/kg or negative inspiratory force weaker than about −20 to −30 cm H₂O.

Diagnosis

• Serology: AChR-binding antibody is the first-line test; specificity is very high, generally >95%. If negative, test MuSK and sometimes LRP4 antibodies.
• Ice pack test: improvement of ptosis after 2–5 minutes of cooling supports MG; reported sensitivity is about 80–90% for ocular MG, with high specificity.
• Repetitive nerve stimulation: a >10% decrement in compound muscle action potential amplitude at low-frequency stimulation, classically 2–3 Hz, supports a postsynaptic transmission defect.
• Single-fiber EMG: most sensitive test, often >95%, showing increased jitter due to variable neuromuscular transmission.
• Edrophonium test: historical; edrophonium is a short-acting acetylcholinesterase inhibitor with onset in seconds and duration about 5–10 minutes. A typical test dose was 2 mg IV followed by 8 mg IV if tolerated, with atropine available for bradycardia. It is now used less commonly due to adverse effects and better antibody/EMG testing.

Treatment Principles and Pharmacology

For Step 1, understand the mechanisms rather than specialty algorithms. Pyridostigmine, a reversible acetylcholinesterase inhibitor, increases ACh in the synaptic cleft and improves strength without altering autoimmunity. A typical adult dose is 30–60 mg orally every 4–6 hours; onset is about 30–60 minutes, and duration is 3–4 hours. Adverse effects are cholinergic: diarrhea, abdominal cramping, sweating, salivation, bronchospasm, bradycardia, miosis, and fasciculations.

Corticosteroids and steroid-sparing immunosuppressants such as azathioprine, mycophenolate, cyclosporine, or tacrolimus reduce autoantibody-mediated disease. Rapid therapies for severe exacerbation include IVIG, commonly 2 g/kg total over 2–5 days, or plasma exchange, which removes circulating antibody. In myasthenic crisis, weakness results from undertreated MG; in cholinergic crisis, excessive acetylcholinesterase inhibition causes muscarinic symptoms plus weakness. This distinction is classic for exams.

Thymectomy is indicated for thymoma and benefits selected AChR-positive generalized MG. The landmark MGTX trial showed that extended transsternal thymectomy plus prednisone improved time-weighted Quantitative MG scores and reduced prednisone requirements compared with prednisone alone in nonthymomatous AChR-positive generalized MG, especially in patients age 18–65 years with disease duration less than about 5 years.

Transient neonatal MG can occur because maternal IgG crosses the placenta; symptoms usually resolve as antibody is cleared. This differs from congenital myasthenic syndromes, which are inherited defects of neuromuscular transmission and are not autoimmune.

Lambert–Eaton Syndrome

Core mechanism and pathophysiology

Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the presynaptic neuromuscular junction. IgG autoantibodies target P/Q-type voltage-gated calcium channels (VGCCs) on the motor nerve terminal. Normally, an arriving action potential depolarizes the presynaptic membrane, opens VGCCs, permits Ca²⁺ influx, and triggers synaptic vesicle fusion with release of acetylcholine (ACh). In LEMS, reduced Ca²⁺ entry causes decreased quantal ACh release, producing a low end-plate potential that may fail to reach threshold for muscle action potentials.

The classic physiologic clue is facilitation: with repeated muscle use, residual Ca²⁺ accumulates in the nerve terminal, partially overcoming impaired Ca²⁺ entry and increasing ACh release. Thus, strength and reflexes may transiently improve after exercise, unlike many other neuromuscular disorders.

Etiology and clinical associations

LEMS is strongly associated with malignancy, especially small cell lung carcinoma (SCLC), a neuroendocrine tumor that can express VGCC-like antigens and trigger a paraneoplastic immune response. Approximately 50%–60% of LEMS cases are paraneoplastic; among these, SCLC accounts for most cases. LEMS may precede cancer diagnosis by months to years, so unexplained LEMS should prompt evaluation for occult malignancy, particularly in older patients with a smoking history.

• Paraneoplastic LEMS: typically older adult, smoking history, weight loss or pulmonary symptoms may be present.
• Autoimmune/non-tumor LEMS: often younger, may coexist with other autoimmune diseases such as thyroid disease, type 1 diabetes, or pernicious anemia.

Clinical presentation

The Step 1 pattern is proximal muscle weakness, autonomic symptoms, and decreased reflexes that improve with use. Weakness often begins in the hips and thighs, causing difficulty rising from a chair or climbing stairs. Ocular and bulbar symptoms can occur but are generally less prominent than in myasthenia gravis.

• Motor: symmetric proximal lower limb weakness; later shoulder girdle involvement.
• Reflexes: diminished or absent deep tendon reflexes at rest; may transiently return after brief exercise.
• Autonomic dysfunction: dry mouth is classic; also erectile dysfunction, constipation, impaired sweating, orthostatic symptoms, and blurred vision from pupillary dysfunction.
• Sensation: usually normal, helping distinguish LEMS from peripheral neuropathies.

Diagnosis: antibodies and electrophysiology

Serologic testing detects antibodies against P/Q-type VGCCs in approximately 85%–90% of patients with LEMS and in an even higher proportion of paraneoplastic cases. Electrophysiology demonstrates a presynaptic transmission defect.

Test	High-yield finding in LEMS	Mechanistic explanation
Low-frequency repetitive nerve stimulation, 2–3 Hz	Low baseline compound muscle action potential (CMAP) with decrement	Insufficient ACh release at rest
High-frequency stimulation, 20–50 Hz, or brief maximal exercise	Incremental CMAP response, often >100%	Ca2+ accumulation increases vesicular ACh release
Serology	P/Q-type VGCC antibodies positive in most cases	Autoimmune attack on presynaptic Ca2+ channels

Differentiation from myasthenia gravis

Feature	Lambert–Eaton syndrome	Myasthenia gravis
Target	Presynaptic P/Q-type VGCC	Postsynaptic ACh receptor or MuSK
ACh release/receptors	Decreased ACh release	Reduced functional postsynaptic receptors
Effect of repeated use	Strength improves	Strength worsens with fatigue
Reflexes	Decreased; improve after exercise	Usually normal
Autonomic symptoms	Common, especially dry mouth	Uncommon
Cancer association	Small cell lung carcinoma	Thymoma, thymic hyperplasia

Treatment principles and pharmacology

For Step 1, treatment is best understood mechanistically. Treating the underlying SCLC can improve paraneoplastic LEMS by reducing antigenic stimulation. Symptomatic therapy aims to increase presynaptic ACh release or prolong ACh action.

Therapy	Typical adult dosing concept	Mechanism and key adverse effects
Amifampridine 3,4-diaminopyridine	Often started at 5–10 mg orally 3–4 times/day; titrated, commonly up to 60–80 mg/day depending on formulation and guidance	Blocks presynaptic voltage-gated K+ channels, prolonging depolarization and increasing Ca2+-dependent ACh release. Half-life is short, about 2–3 hours. Risks include paresthesias, insomnia, seizures at high exposure, and QT-related cautions.
Pyridostigmine	Commonly 30–60 mg orally every 4–6 hours	Acetylcholinesterase inhibitor; prolongs ACh in the synaptic cleft. Often less effective alone than in myasthenia gravis because the primary defect is reduced ACh release. Cholinergic effects include diarrhea, cramping, salivation, and bradycardia.
Immunotherapy	IVIG often 2 g/kg total over 2–5 days; plasma exchange used in severe cases	Reduces pathogenic antibody effect; useful for significant weakness or rapid symptomatic control.

High-yield summary: LEMS is a presynaptic autoimmune Ca²⁺ channel disorder causing decreased ACh release, proximal weakness, autonomic symptoms, and hyporeflexia. It is classically associated with small cell lung carcinoma. The most testable electrophysiologic finding is an incremental CMAP response after exercise or high-frequency stimulation.