Neuromuscular

Core symptoms include weakness[…], fatigue, exercise intolerance[…], and cramps.

Bulbar or systemic spread can produce dysphagia[…] or dyspnea[…].

Onset hints at etiology: early in life suggests an inherited[…] myopathy (slightly progressive = congenital, more progressive = muscular dystrophy).

Chronic/slowly progressive over time suggests a genetic[…] cause.

Acute weakness with rhabdo suggests infectious, toxic, or metabolic[…] cause.

Subacute is classically immune-mediated[…].

Periodic episodes point to periodic paralysis[…].

Pathognomonic clues: recurrent seizures/stroke → mitochondrial[…] disease; cancer history → paraneoplastic[…]; rheum disease → immune-mediated[…]; malignant hyperthermia with recurrent rhabdo → RYR1 or CACNA1S[…]; pain at rest → myositis or myotonic disorder[…]; exertional pain → metabolic[…] myopathy; cola-colored urine → rhabdo[…]; binocular diplopia → thyroid eye disease or ICI[…]-related myositis.

Myotoxic medications to remember: statins[…], ICI[…], amiodarone[…], hydroxychloroquine[…], and (newer) sertraline[…] associated with MADD.

Labs: CK[…] and aldolase[…] can be elevated but not always.

Check AST/ALT + GGT[…] to rule out a liver source.

Get a CMP[…] to evaluate K+, Ca+2, and Mg+ which can be altered in periodic paralysis.

Order HMGCR[…], snRP, and cavin-4 antibodies to differentiate IMNM[…] in subacute-chronic myopathies not suggestive of other specific diagnoses.

Needle EMG can be normal; hallmark features are myotonic discharges and fibrillation potentials[…] at rest, plus low-amplitude, short-duration, polyphasic[…] motor unit potentials with rapid recruitment on activation.

NCS shows normal sensory[…] responses.

Low-frequency (2-3Hz) repetitive nerve stim[…] may show muscle fiber inexcitability.

Muscle biopsy is required for dermatomyositis[…], IBM (classic finger-flexor + quad weakness), amyloid[…] myopathy, and hydroxychloroquine[…]-induced myopathy.

Other tools: muscle MRI[…] for edema and fatty replacement, genetic[…] testing, plus PFTs[…] for respiratory weakness and EKG/TTE for cardiac involvement.

Initial symptoms: ~80% present with ocular[…] symptoms — ophthalmoplegia with ptosis[…] and binocular diplopia.

Classic signs include Cogan lid twitch[…] (look down, rest, look up → eyelid overshoots then drops), the frontalis sign[…] (frontalis contracts to raise the ptotic eyelid), and the curtain sign[…] (lifting the ptotic lid lowers the good lid).

About 20% present with bulbar[…] symptoms: chewing fatigue, dysphagia to solids, nasal regurgitation, hypophonia[…], dysarthria, weak jaw closure, and sometimes triple-furrowing of the tongue.

Generalization occurs in most patients within 2 years[…]: bulbar, neck, and limb weakness.

Neck flexion[…] weakness > extension causes dropped head.

Limb weakness preferentially affects deltoids, triceps, and wrist/finger extensors[…].

Demographics: early onset (<50yo) mostly women[…] with thymoma and HLA-B8-DR3-DQ2.

Late onset (>50yo) mostly men[…] with thymic atrophy.

About 10-20% have a thymoma[…].

Antibody distribution: ~80[…]% AChR+, ~10% seronegative, ~8% MuSK[…]+ (higher in equatorial populations), ~2% LRP4[…]+ (mild or purely ocular). Crisis triggers: infection, pregnancy, surgery, and medications.

Highest risk meds (CI): botox[…] and D-penicillamine.

Avoid aminoglycosides, fluoroquinolones, macrolides, quinine[…], ICI, hydroxychloroquine, and IV Mg[…]. Use cautiously: statins, beta-blockers, procainamide, and steroids.

Normal physiology: ACh is released into the NMJ → binds AChR[…] on the postsynaptic membrane → voltage-gated Na+ channels open → cations flood in → action potential generated.

Simultaneously, the presynaptic terminal secretes agrin[…] → binds LRP4[…] → phosphorylates MuSK[…] → clusters AChR at the postsynaptic membrane.

AChE[…] terminates the signal. MG core lesion: autoimmune attack delays or blocks the ACh signal.

It begins with loss of self-tolerance[…] in the thymus, where T-regulatory[…] cells normally control autoreactive CD4+ T-cells. In MG, Tregs are impaired → autoreactive CD4+ cells overactivate → release IL-17 and other cytokines → stimulate B-cells → autoantibodies produced.

The thymus develops germinal center[…] hyperplasia.

Subtype-specific lesions: in AChR+ MG, antibodies inactivate AChR[…].

In MuSK+ MG, antibodies bind MuSK and disrupt AChE[…] (explaining cholinergic hypersensitivity).

In LRP4+ MG, antibodies inactivate LRP4[…].

Seronegative cases may reflect assay sensitivity[…] limits.

Ice pack test: apply to a ptotic[…] eyelid for 2 minutes — improvement has >80% sensitivity/specificity for ocular MG.

Mechanism: cooling reduces AChE[…] activity → more ACh available.

EMG/NCS: Repetitive nerve stimulation[…] elicits progressive decrement[…] in CMAP amplitude (normal ~10% between 1st-4th potentials), recorded from clinically weak muscles like nasalis or trapezius; Single-fiber EMG[…] is the most sensitive test, showing increased jitter[…] (proportional to abnormal endplates) and "blocking.".

Blood tests: AChR[…] antibody in 70-85% (early negatives may seroconvert[…] at 6-12 months — retest); MuSK in 7%; LRP4 rarely. Striated muscle Ab is not diagnostic.

Imaging: get Chest CT with and without contrast[…] to rule out thymoma.

Acute/rescue therapies: PLEX[…] removes circulating autoAb, with benefit typically by the 3rd of 5 doses, particularly effective in MuSK[…]+ MG. SE: thrombosis, line infection, PTX.

IVIG[…] uses multiple immunomodulatory mechanisms; effect emerges by 5-7 days and lasts 1-3 months. Standard dose is 2 g/kg over 3-5 days.

Preferred in children or patients with poor IV access[…].

Thymectomy is performed in all patients with thymoma, ideally within the first 2 years[…] of MG when well controlled.

It is the only path to drug-free remission in nonthymomatous AChR[…]+ generalized MG.

Cholinesterase inhibitors like pyridostigmine (Mestinon)[…] provide symptomatic relief but do not alter natural history.

Overdose causes cholinergic crisis[…] with increased secretions and aspiration risk.

Steroids are very effective but commonly cause early exacerbation[…] lasting up to a week — do not discontinue.

High-risk patients (elderly, severe bulbar) should receive IVIG or PLEX[…] first.

Oral nonsteroidal immunosuppressants: Azathioprine[…] — n/v/fever reaction requires discontinuation; MMF[…] — GI upset and teratogenic; Cyclosporine and tacrolimus — inhibit IL-2; watch for nephrotoxicity[…]; MTX[…] inhibits DHFR.

Biologics: B-cell depletion: Rituximab[…] (anti-CD20, especially effective in MuSK+) and Inebilizumab[…] (anti-CD19, broader depletion).

Complement inhibitors Eculizumab, Ravulizumab, Zilucoplan[…] block C5 cleavage to prevent MAC formation.

SE: N. meningitidis[…] infection risk.

Neonatal FcRn[…] inhibitors (Efgartigimod, Rozanolixizumab, Nipocalimab) increase lysosomal degradation of IgG. Selective compared to PLEX.

CAR-T[…] therapy — risk of cytokine release syndrome and ICANS. Anti-IL-6 therapies (satralizumab, tocilizumab) in trials as of 2025.

Core lesion: autoimmune disease with ~90% having autoantibodies against presynaptic P/Q-type voltage-gated Ca+2 channels[…] (contrast with MG, which is postsynaptic[…]).

Normally these VGCCs mediate Ca+2 influx after the action potential reaches the terminal → vesicle docking and ACh[…] release.

In LEMS, autoAb cause channel internalization[…] → decreased ACh release.

Classifications: SCLC[…]-related LEMS accounts for most cases, predominantly male[…]; Nontumor[…] LEMS has a genetic (HLA) predisposition, bimodal age, predominantly female[…], often with other autoimmune diseases; ICI[…]-associated LEMS; Pediatric LEMS is rare, lacks autonomic dysfunction, and rarely linked to cancer.

The DELTA-P[…] score helps differentiate SCLC vs nontumor LEMS.

Pattern: starts as fatigueable proximal lower extremity[…] weakness → ascends to proximal upper extremity → late oculobulbar[…] involvement (contrast with MG, where this happens first). Within a limb the pattern is proximal-to-distal.

Faster progression in SCLC-related[…] LEMS than nontumor.

Hyporeflexia or areflexia that improves transiently with activity[…] — called "postexercise facilitation[…]." Test reflexes after a rest period.

Autonomic[…] dysfunction in most: dry mouth, constipation, erectile dysfunction.

Diagnostics: VGCC antibody[…] is positive in >85% (can be false-positive in SCLC); EMG/NCS shows low-amplitude CMAPs[…] at baseline, jitter and blocking on single-fiber EMG; Repetitive nerve stim[…]: low-frequency (1-5 Hz) shows >10% decrement (like MG); high-frequency (~50 Hz) shows >60% facilitation[…] after maximum voluntary contraction (the LEMS-defining finding).

First-line: 3,4-DAP (diaminopyridine)[…].

Mechanism: blocks presynaptic K+[…] channels → prolongs CMAP duration, and directly targets the β-subunit of VGCC[…] → both increase ACh release into the NMJ.

SE: perioral and distal paresthesias[…]; high doses can cause seizures or arrhythmias.

Next agents: rescue with IVIG or PLEX[…]; long-term prednisone, rituximab, or azathioprine[…].

Always treat the underlying SCLC[…] when present (analog of thymectomy in MG) and avoid trigger medications.

Location: LEMS is presynaptic[…] (P/Q-type VGCC autoAb); MG is postsynaptic[…] (AChR/MuSK/LRP4).

Association: LEMS with SCLC[…]; MG with thymoma[…].

Clinical pattern: LEMS starts proximal LE[…] → distal within limb → ascends to UE → late oculobulbar, with autonomic[…] involvement. MG starts with oculobulbar early and rarely has autonomic dysfunction.

Diagnostic hallmark: LEMS has post-exercise facilitation[…] (>60% RNS increment); MG has decrement.

Baseline CMAPs are low[…] in LEMS and normal/low in MG.

Definition: Facio-Scapulo-Humeral[…] Dystrophy is a gain-of-function[…] mutation in transcription factor DUX4[…] on the D4Z4 repeat array at chromosome 4q35[…].

Mechanism: D4Z4 hypomethylation[…] → under-suppression of the gene + 4qA[…] haplotype stabilizes DUX4 mRNA → overactivated DUX4 in skeletal muscle → apoptosis[…].

Larger D4Z4 repeats produce milder[…] disease.

Subtypes: FSHD1 is AD[…]; FSHD2 is digenic[…], often from SMCHD1[…] mutations. Clinically identical.

Pattern: slow, progressive, asymmetric[…] weakness starting in face[…] → shoulder girdle → upper arms → legs — a descending[…] pattern. Facial involvement (orbicularis oculi/oris): difficulty with eye closure, smiling, lip pursing, cheek puffing.

Scapular involvement (trapezius + serratus anterior): "Poly-Hill[…]" sign (upper back muscle wasting elevation) and "scapular winging[…]."

Humeral involvement (biceps/triceps): "Popeye arms[…]" with preserved forearm and distal deltoid muscle bulk.

Truncal involvement: rectus abdominis wasting → "Beevor sign[…]" with upward umbilical movement on neck flexion.

Lower extremity: tibialis anterior weakness → foot drop, but distinguish from neurogenic foot drop because the EDB[…] is preserved.

Extramuscular: pain, fatigue, hearing[…] loss, retinal[…] disease, cardiopulmonary issues. Lifespan is typically normal.

DDX to exclude: limb-girdle muscular dystrophy, Emery-Dreifuss[…], and mitochondrial myopathy.

Diagnostics: get genetic[…] testing for D4Z4 repeat size and 4qA haplotype (Southern blot, optical genome mapping, or advanced sequencing).

If FSHD1 is negative but suspicion remains, sequence SMCHD1[…] or do methylation analysis for D4Z4 hypomethylation. Prenatal testing via CVS or amniocentesis is available. CK may be normal up to 5x ULN; a normal value does not exclude. EMG is not routinely used. Muscle MRI is sensitive for selective involvement.

Screenings: baseline PFTs[…], audiology, ophthalmology (retinal), and cardiac if symptomatic.

Treatment: mostly supportive care[…], NSAIDs for pain, surgery for severe scapular winging. Trials underway in CRISPR epigenetic editing and microRNA interference against DUX4.

Clinical core: slowly progressive, symmetric[…] weakness of proximal[…] muscles (pelvic > shoulder[…] girdle), with distal involvement later.

Oculobulbar[…] or facial weakness is absent.

CK[…] is usually elevated but variable; some patients have rhabdo[…]. Unlike congenital muscular dystrophy, patients must achieve independent walking before symptom onset.

2017 (current) classification: LGMD-D[…]: autosomal dominant, often lower CK (may be normal); LGMD-R[…]: autosomal recessive, more common, faster progression, CK typically >1000[…].

α-Dystroglycanopathies: abnormal glycosylation of α-dystroglycan → sarcolemma dysfunction. Variable severity; may have calf pseudohypertrophy, cardiopulmonary[…] involvement, cognitive impairment, and transient post-febrile[…] weakness in kids. Defective membrane repair: failure of annexin/dysferlin-mediated repair.

Causes asymmetric[…] weakness with calf atrophy and difficulty walking on toes.

Classic signs: "boule de biceps[…]," "diamond on quadriceps[…]," "calf heads on a trophy[…]." Biopsy may show inflammatory infiltrates and amyloidosis. Sarcoglycanopathies: failure to assemble the sarcoglycan complex → sarcolemma instability.

Childhood-onset weakness with wheelchair use by teens (DMD-like) plus dilated cardiomyopathy[…]. Biopsy shows decreased sarcoglycan immunoreactivity.

Calpainopathy (most common in many countries): defective calpain-3[…]. FSHD-like pattern — hip/knee weakness with facial weakness and scapular winging.

DDX: IBM[…]: quadriceps + finger flexor weakness (not LGMD pattern); IMNM[…]: same weakness pattern and similar biopsy (necrotic fibers, endomysial fibrosis), but positive HMGCR or SRP[…] antibodies and responds to immunotherapy; Dystrophinopathy[…] (DMD/Becker): X-linked, cardiopulmonary and cognitive involvement, onset <5yo, wheelchair by teens.

Serum tests: IMNM antibodies[…] to exclude IMNM; CK; and genetic[…] testing which has replaced muscle biopsy as first-line.

Always check for statin, ICI, or steroid[…] drug-induced causes. EMG may show myotonic discharges, fibrillation potentials, and myopathic changes. Muscle biopsy is reserved for genetic-test-negative or VUS cases. Treatment: supportive care and PT.

Definition: Inclusion Body Myositis[…] is the most common myopathy in adults.

Pattern: slowly progressive, asymmetric[…] weakness of finger flexors and knee extensors (quadriceps)[…] in older males[…] (other IIMs favor females), and does not respond[…] to immunotherapy (other IIMs do). Bedside tests: have the patient supinate forearms and make a fist (finger flexors); have them kneel on one knee and stand without arms (quadriceps).

Atypical presentations: isolated dysphagia[…] or foot drop; in females, facial diplegia. Most atypical cases eventually develop the typical pattern.

Treatment: supportive[…] care; avoid corticosteroids and immunosuppressants — associated with worse outcomes.

Pathology hallmarks: endomysial cytotoxic T cells[…] + rimmed vacuoles[…] and protein aggregates (disrupted protein homeostasis) + mitochondrial dysfunction with cytochrome c oxidase[…]-negative fibers. Contrast with other IIMs which are primarily inflammatory.

EMG/NCS: mixed neuropathic and myopathic[…] features — long-duration, high-amplitude MUPs (neuropathic) plus short-duration, low-amplitude MUPs (myopathic) — with occasional myotonic discharges and fibrillations.

Muscle biopsy (cornerstone) shows three major features: endomysial CD8 T cells[…] invading non-necrotic fibers; rimmed vacuoles[…] + protein aggregates (amyloid, TDP43) detected on Congo red stain or EM; and mitochondrial dysfunction with COX-negative fibers and ragged red[…]/blue fibers. Imaging: muscle MRI or ultrasound of vastus or medial calf can help guide biopsy.

Serum: ~50% have nonspecific cN1A[…] antibody; CK <10-15x ULN. T-cell LGL clone (flow cytometry) seen in RA/Sjögren co-occurrence.

Five major IIMs: dermatomyositis[…], antisynthetase syndrome[…], IMNM[…], polymyositis[…], and IBM (covered separately, doesn't respond to immunotherapy).

Non-IBM symptom pattern: symmetric, proximal > distal[…] weakness primarily of neck flexors, shoulder girdle, and hip girdle → difficulty rising, climbing stairs, holding arms overhead. Later distal involvement.

Ocular[…] muscles spared but bulbar and respiratory[…] muscles can be involved. Sensation and reflexes preserved.

Trigger: usually a viral infection[…] activates the type I interferon[…] pathway, especially perifascicular[…]ly.

Increased dendritic cells in muscle, plus MAC[…] attacks on capillaries.

Symptoms: subacute-to-chronic weakness in the standard IIM pattern, plus characteristic skin findings: Heliotrope[…] rash (periorbital); Gottron papules[…] (hands); V, Shawl, and Holster[…] signs (rashes on neck/chest, shoulder/back, and hips); Poikiloderma[…] (hyper/hypopigmentation on back and extensors); Calcinosis cutis[…].

Other organs: cardiopulmonary (ILD[…]), GI motility, joint arthralgias.

High malignancy risk, especially with TIF1-γ[…] antibody.

Key antibodies: anti-Mi2[…] (classic, good prognosis), anti-TIF1-γ[…] (malignancy), anti-MDA-5[…] (rapid ILD).

Biopsy: perifascicular atrophy[…] (specific), MHC-1 + MxA reactivity, perivascular/perimysial inflammation, and MAC[…] deposition on small vessels (specific).

Mechanism: activation of type II[…] interferon → antibodies against aminoacyl-tRNA synthetase[…], most commonly anti-Jo1[…].

Clinical triad: subacute-chronic myositis[…] (proximal > distal weakness) + ILD[…] + nonerosive arthritis[…], often with Raynaud's or mechanic's hands[…] rash that can lead to misdiagnosis as dermatomyositis.

Biopsy: perivascular and perimysial[…] inflammation (similar to DM) but with much less MxA, plus perimysial fragmentation and alkaline phosphatase[…]+ staining.

Pathophysiology: unknown. Symptoms: acute[…] weakness, often with myalgias[…].

Antibodies: Anti-HMGCR[…]: suspect in patients with statin[…] use, persistently elevated CK after stopping the statin, and elevated malignancy risk; Anti-SRP[…]: more treatment-resistant and often with cardiopulmonary[…] involvement; ~1/3 are antibody-negative.

Biopsy: scattered necrotic[…] fibers with sparse inflammation. No perifascicular atrophy. Endomysial inflammation with CD8 T cells invading non-necrotic fibers.

Polymyositis: diagnosis is decreasing with newer tools. HLA Ag-specific[…] response against muscle fibers, with subacute-chronic, symmetric proximal > distal weakness predominantly in females[…]. Many cases are now reclassified as IBM, antisynthetase syndrome, IMNM, or muscular dystrophies.

Overlap syndromes: inflammatory myopathy + well-established CTD (SLE, RA, Sjögren's, MCTD[…]), sometimes with myositis-associated antibodies.

Serum markers: CK[…] usually elevated, extremely high (>10,000) in IMNM[…]; Aldolase[…] may be high with normal CK — marker of perimysial inflammation (DM or antisynthetase syndrome); LFTs may be high but check GGT[…] which should be normal in myopathy and high in liver disease; Specific antibodies per diagnosis.

EMG/NCS: short-duration, low-amplitude, polyphasic MUAPs[…] with rapid recruitment, plus fibrillations (active disease), complex repetitive discharges, and myotonic discharges. NCS usually normal. Muscle MRI: fatty atrophy and muscle/fascial edema (nonspecific) — often used to select a biopsy target.

Screenings: CT chest[…] for ILD if dyspnea; cancer screening especially in TIF1-γ DM and HMGCR IMNM.

First-line: Corticosteroids[…]: first-line for most except DM and IMNM. Prednisone 0.75 mg/kg/day or IVMP 1g daily × 3-5 days with taper.

Monitor CK reduction[…] in IMNM; monitor exam in DM/antisynthetase/polymyositis.

IVIG[…]: first-line for DM and add-on for HMGCR IMNM. Dosed at 2 g/kg over 3-5 days, then monthly × ≥3 months then taper. SE: flu-like symptoms, thrombosis, hyponatremia.

Second-line: MTX[…]: coadminister with folate 1 mg/day. SE: pulmonary fibrosis and hepatotoxicity — caution in DM (ILD risk). Azathioprine — infusion reaction. MMF — GI issues.

Rituximab[…] — infection risk including PML.

Prophylaxis: Bactrim[…] for PJP, TB screen, DEXA scan for steroids, glucose monitoring.

Dermatomyositis: Mi2, TIF1-γ[…] antibodies; skin involvement; ILD; high malignancy[…] risk (TIF1-γ); biopsy = perifascicular atrophy + MAC on vessels + tubuloreticular inclusions; type 1 IFN pathway; first-line IVIG[…].

Antisynthetase syndrome: Jo1[…] antibody; mechanic's hands; ILD; biopsy = perimysial inflammation + alkaline phosphatase staining; type 2 IFN pathway; first-line steroids[…].

IMNM: HMGCR, SRP[…] antibodies; malignancy risk (HMGCR); biopsy = necrotic fibers with sparse inflammation; first-line steroids ± IVIG[…].

Polymyositis: no specific antibody; slight malignancy risk; biopsy = endomysial CD8 T cells invading non-necrotic fibers; first-line steroids[…].

Three categories: Nondystrophic myotonias[…]: Cl- and Na+ channelopathies; Periodic paralyses[…]: Na+, K+, and Ca+2 channelopathies; Rhabdomyolysis[…]: metabolic myopathies, muscular dystrophies, and other genetic issues.

Most channelopathies are autosomal dominant[…], starting early in life.

Mechanisms by syndrome: Myotonia congenita[…] → loss of function in CLCN1[…] chloride channels → increased depolarization → myofiber hyperexcitability (myotonia[…]); Paramyotonia congenita[…] → SCN4A[…] sodium channels → abnormal depolarization → hyperexcitability; Hypo/Hyperkalemic periodic paralysis[…] → CACNA1S[…] voltage-sensor calcium channels → channel leakage → paralysis; Andersen-Tawil[…] syndrome → KCNJ2 potassium channel loss of function → abnormal depolarization → myotonia.

Myotonia congenita (CLCN1): AD form is Thomsen[…], AR form is Becker[…].

Classic finding is delayed muscle relaxation[…] after forceful contraction that improves with repetition[…] ("warm-up" phenomenon). Muscle hypertrophy present.

EMG: generalized myotonic[…] discharges and post-exercise amplitude drop.

Treatment: mexiletine[…] (Na+ channel blocker), Na+-channel-blocking ASMs, and acetazolamide[…] (CA inhibitor).

Note: succinylcholine[…] is contraindicated.

Paramyotonia congenita (SCN4A): "paradoxical[…] myotonia" — worsens with repetition (e.g., exercise) and cold[…].

Exam: lid-lag[…] phenomenon or ocular myotonia. EMG: CMAP decrement (short exercise pattern 1) — does not return to baseline. Treatment: same as myotonia congenita.

Sodium channel myotonia (SCN4A): stiffness after exercise[…] or K+-rich foods (bananas, avocados); no weakness.

Neonates may have hypotonia or severe laryngospasm[…]. EMG: myotonic discharges with no decrement on short exercise (pattern 3).

Treatment: Na+ channel blockers; IV dantrolene[…] for severe myotonic crisis.

Hypo/HyperKPP (SCN4A): episodic weakness (partial or whole body, minutes to hours), areflexia[…] during attacks, can progress to permanent proximal weakness after decades.

Screen with TFTs and EKG[…] (rule out systemic causes and Andersen-Tawil). HyperKPP triggers: K+-rich foods, fasting, cold (may coexist with paramyotonia). Labs normal between, high during. EMG silent during attack.

Treatment: avoid triggers + treat acute attacks (Ca gluconate, albuterol, insulin); acetazolamide[…] or dichlorphenamide + thiazide for prevention.

HypoKPP: subtypes CACNA1S[…] (Ca+2) and SCN4A (Na+). No myotonia.

Progressive fatty replacement[…] of muscle independent of attacks. Triggers: carb-rich foods, hypoK states, stress (epinephrine). Treatment: K+ supplementation acutely; acetazolamide + K-sparing diuretics for prevention.

Andersen-Tawil syndrome (KCNJ2 K+ channel): classic triad of skeletal muscle[…] involvement (episodic weakness triggered by exercise/rest), cardiac[…] involvement (syncope, arrhythmias, may need PPM/AICD), and dysmorphic features[…] (micrognathia, scoliosis, low-set ears, short stature).

MRI shows fatty[…] replacement of calf/thigh. May see cognitive issues. Treatment: avoid triggers, cardiology referral with Holter monitoring, ± acetazolamide/dichlorphenamide.

Rhabdomyolysis: recurrent weakness, cramps/myalgias, exercise intolerance, swelling[…] with CK >5-10,000, sometimes with AKI from myoglobinuria[…].

Metabolic myopathies include McArdle[…] disease (myophosphorylase[…] deficiency) with classic "second-wind[…]" phenomenon — exercise becomes easier after ~10 min. Forearm exercise test shows lactate and ammonia rise.

MADD[…] (multiple acyl-CoA dehydrogenase deficiency) is responsive to riboflavin[…]. Diagnostics: genetic testing first → whole exome/genome + mitochondrial testing if negative.

Muscular dystrophies can also cause rhabdo ("pseudometabolic" presentation) but with elevated baseline CK and persistent weakness between[…] episodes.

Definition: delayed muscle relaxation[…] after contraction.

Mechanism: missplicing of CLCN1[…] → defective Cl- channel → impaired repolarization → repetitive depolarization → myotonia.

Often not bothersome[…] to patients.

Exacerbated by rest after exercise, cold, and pregnancy[…]; improves with repetitive movement[…] ("warm-up" phenomenon) — test before strength exam.

Testing types: grip[…] myotonia (clench fist), eyelid[…] myotonia (force closure), percussion[…] myotonia (reflex hammer tap), and electrical[…] myotonia on EMG (trains of PSWs[…]).

EMG patterns: DM1 = waxing/waning[…]; DM2 = waning only or absent[…] (test in vastus).

Can also be seen in myotonic dystrophies, nondystrophic myotonic disorders, other myopathies, neurogenic disease, and MuSK[…]+ MG.

Genetics: CTG[…] trinucleotide expansion in the 3' UTR of the DMPK[…] gene.

Genetic features include anticipation[…] (earlier and longer in subsequent generations) and mosaicism[…]. Congenital form: most severe, high mortality early in life, maternally inherited.

Severe generalized hypotonia, but no myotonic[…] discharges yet.

Adult-onset symptoms: Distal[…] muscle and facial[…] muscle weakness; toe extensors are spared (distinguishes from neurogenic foot drop); CNS: ptosis, central sleep apnea[…], fatigue (very common, unlike DM2); Early cataracts[…]; Myotonia is prominent (unlike DM2); GI[…] issues more common in DM1 (DM2 has more vascular risk factors).

EMG: waxing/waning[…] myotonic discharges.

Genetics: CCTG[…] tetranucleotide expansion in the CNBP[…] gene.

No anticipation[…] but has mosaicism (unlike DM1).

Symptoms: axial and proximal[…] weakness (contrast with DM1 distal) with muscle pain/stiffness, often initially misdiagnosed as fibromyalgia[…].

Myotonia is not[…] a prominent feature.

Vascular[…] risk factors more common (DM1 has more GI involvement).

EMG: waning[…] pattern only.

Pathophysiology of both: gene mutation → abnormal DNA → abnormal RNA → sequestered RNA-binding proteins → gene missplicing[…] in multiple organs.

Biopsy (both): abundant internal/central nuclei[…]; type 1 fiber atrophy in DM1, type 2 fiber atrophy in DM2.

Multiorgan involvement (more common in DM1[…]): Cardiopulmonary: arrhythmias[…] and central sleep apnea; Ophthalmic: early cataracts[…] ("Christmas tree"), ptosis; Endocrine: insulin resistance[…]; GI dysmotility; Cancer screening important (skin, heme, uroGYN). Treatment: if not bothersome, none.

For bothersome myotonia: mexiletine[…] unless arrhythmias; some Na+ channel-blocking ASMs.

Modafinil[…] for daytime sleepiness/sleep apnea. Nondystrophic myotonic disorders (CLCN1 or SCN4A): myotonia without multiorgan involvement or dystrophic biopsy. Normal lifespan.

Elevated risk of malignant hyperthermia[…] with general anesthesia.

Mechanism: X-linked[…] disorders from DMD[…] gene mutations → defective dystrophin.

Subtypes: Duchenne (DMD)[…] — severe form from frameshift[…] mutation → unstable mRNA → absent/nonfunctional protein; Becker (BMD)[…] — milder form from in-frame[…] mutation → partially functional protein.

Onset and prognosis: DMD onset 2-5yo[…], wheelchair by 12-13yo[…]. BMD onset >5yo, wheelchair >16yo.

Cardiac findings may precede weakness in BMD[…].

Neurodevelopmental/behavioral[…] disorders more prevalent in DMD — any child with autism should have a CK checked.

Symptoms: proximal weakness with delayed walking (normal 14-18 months), toe walking[…], frequent falls, difficulty climbing stairs.

Dilated cardiomyopathy[…] or arrhythmia are major causes of morbidity/mortality.

Respiratory[…] failure mitigated by regular PFTs and BIPAP.

Exam signs: calf pseudohypertrophy[…], neck flexion weakness, and the Gowers[…] sign (child uses arms to "march up" legs to stand).

Diagnostic algorithm: 1. Screen with CK[…] in boys with motor delay; usually >1000[…] by 2-3yo (much higher in DMD, sometimes tens of thousands), then decreases as muscle is replaced by fibrofatty tissue. Normal CK essentially rules out. 2.

If elevated → genetic[…] testing for DMD via next-gen sequencing. 3.

If inconclusive → muscle biopsy[…] showing dystrophic changes (near-absent in DMD[…], reduced sarcolemmal staining in BMD), >95% reduction on Western blot in DMD vs variable in BMD.

If AST/ALT elevated, check GGT[…] — normal GGT means muscle (not liver) source.

DDX: don't miss SMA[…] Type 3 (would have hyporeflexia and neurogenic EMG, vs preserved reflexes and myopathic EMG in dystrophinopathy).

Treatment: Steroids[…] (prednisone 0.75 mg/kg/day, deflazacort, or vamorolone[…]) starting 3-5yo delay loss of ambulation, respiratory failure, and cardiomyopathy.

Givinostat[…] (HDAC inhibitor) — first non-steroidal FDA-approved for ambulatory boys >6yo on stable steroids. SE: thrombocytopenia, hypertriglyceridemia.

Exon-skipping antisense oligonucleotides[…] (suffix "-lirsen") for ~1/3 of patients — restore reading frame. Weekly IV. Europe-only: stop-codon readthrough drugs. Gene therapy and CRISPR/Cas9 are options with serious risks, not curative.

Lesion of the anterior interosseous[…] nerve (a purely motor[…] branch of the median[…] nerve) causes weakness of distal phalangeal flexion[…] of the thumb and index[…] fingers.

Abduction[…] and extension of the thumb are mediated by the radial[…] nerve.

Hypoglossal palsy from carotid dissection presents with ipsilateral tongue[…] deviation, ipsilateral Horner[…] syndrome, and possible dysarthria.

UMN lesions cause contralateral[…] tongue deviation; peripheral XII lesions are always ipsilateral[…].

Labor-related right leg weakness with impaired hip flexion[…], knee extension[…], absent patellar reflex[…], and medial leg sensory loss is classic for femoral nerve[…] injury from prolonged lithotomy.

Medial lower leg sensation is supplied by the saphenous[…] branch of the femoral nerve.

Progressive symmetric demyelinating neuropathy with severe tremor[…], sensory ataxia, and poor IVIG response is classic for anti-neurofascin 155 (NF155)[…] IgG4[…] antibody-associated CIDP. Anti-CNTN1 and anti-CASPR1 can also cause CIDP, but only NF155 is strongly linked to high-amplitude tremor and sensory ataxia.

The reaction to peripheral nerve transection is Wallerian[…] degeneration: the distal[…] segment of the axon degenerates and is cleared by Schwann cells and macrophages. Death of the cell body, onion bulb formation, rimmed vacuoles, and endomysial inflammation are not typical.

In painful diabetic neuropathy with BPH, duloxetine[…] is first-line because it is FDA-approved, effective, and lacks strong anticholinergic[…] effects (preferable to TCAs in BPH).

Spontaneous fasciculations are produced by disorders of motor axons or the lower motor neuron cell body[…], not by autonomic axons, dorsal root ganglia, muscle fibers, or the postsynaptic[…] membrane.

Progressive weakness, severe head lag, tongue fasciculations[…], preserved finger movement, areflexia, and normal eye[…] movements in a 5-month-old are diagnostic for SMA Type 1[…].

For myasthenia gravis patients requiring antibiotics, azithromycin[…] is the safest choice (<2% risk of exacerbation).

Avoid gentamicin, ciprofloxacin, and telithromycin[…] due to high risk of respiratory failure[…] or crisis.

Infantile botulism causes reduced CMAP amplitude from inhibition of ACh vesicle release[…] from the presynaptic[…] nerve terminal. Conduction velocity usually stays normal.

For acute cranial and diffuse weakness, pupillary[…] dilation is the most specific finding for botulism[…], reflecting autonomic cholinergic blockade. Other findings overlap with myasthenia and GBS.

The most common inherited cause of exercise-induced rhabdomyolysis and myoglobinuria in adolescents is CPT II[…] deficiency.

CPT I deficiency affects the liver[…].

Carnitine transporter deficiency causes cardiomyopathy[…] and hypotonia.

General carnitine deficiency causes persistent weakness[…], not episodic myoglobinuria.

Rapidly progressive symmetric weakness with CK >20× ULN and normal reflexes/sensation is best evaluated with muscle biopsy[…] to confirm the specific myopathy[…] and guide treatment. EMG is supportive but not diagnostic for subtype.

A 2-month-old with poor feeding, hypotonia, hyporeflexia, respiratory distress, and cardiomegaly[…] most likely has acid maltase (Pompe)[…] deficiency, a rapidly progressive infantile-onset glycogen storage[…] disorder. SMA, myasthenia, and myotonic dystrophy do not present with early cardiomegaly.

The most common gene underlying autosomal dominant, early-onset Alzheimer[…] disease in families with multiple affected members in their 40s is presenilin 1 (PSEN1)[…].

APP[…] and PSEN2[…] can also cause EOAD but are less common.

Foot drop with weak dorsiflexion and eversion[…], preserved inversion[…] (tibial nerve), and sensory loss over the lateral leg and dorsum of the foot[…] localizes to the common peroneal[…] nerve at the fibular head.

Posterior thigh/lateral ankle pain, sole and pinky-toe paresthesias, weak plantarflexion[…], and absent ankle jerk[…] localize to a S1[…] radiculopathy.

After CABG, medial arm/hand sensory loss with weak intrinsic hand muscles (ulnar ADM + median APB) reflects a lower brachial plexus (C8-T1)[…] injury — classic for sternal retractor traction.

Severe unilateral proximal lower extremity pain[…] and weakness after pelvic surgery suggest a postsurgical inflammatory[…] lumbosacral radiculoplexus neuropathy.

For distal symmetric polyneuropathy, SPEP[…] is the highest-yield single lab (monoclonal gammopathy).

Amyloid[…] is most likely to cause abnormal heart rate variability.

The earliest cardiovascular autonomic finding is elevated resting heart rate[…] (vagal dysfunction).

Lack of paresthesia[…] (numbness without positive sensory symptoms) suggests a genetic[…] cause of polyneuropathy.

Anti-GQ1b[…] antibody is the marker of Miller Fisher[…] syndrome (ophthalmoplegia, ataxia, areflexia).

The most common arrhythmia in GBS is sinus tachycardia[…].

IgM gammopathy accounts for ~75[…]% of paraprotein-related neuropathies.

Anti-MAG[…] DADS neuropathy shows severely prolonged distal motor latencies[…] — a length-dependent demyelinating pattern.

Progressive ataxia, ophthalmoplegia, severe sensory loss, areflexia, IgM gammopathy, and IVIG-unresponsiveness define CANOMAD[…] — a demyelinating polyneuropathy variant.

POEMS[…] syndrome distinguishes from CIDP by polyneuropathy + organomegaly, endocrinopathy, M-protein, and skin changes[…].

Cardiomyopathy + neuropathic pain + dysautonomia + IVIG-unresponsive "CIDP" should trigger TTR gene[…] testing for hereditary amyloidosis.

Treatment includes patisiran[…], an siRNA that lowers TTR production.

An HbA1c drop of >4[…]% over 3 months confers >80% absolute risk of treatment-induced neuropathy of diabetes.

Cisplatin and other platinum[…] chemotherapies are classically associated with "coasting" (worsening after drug stops).

Per ASCO, duloxetine[…] is first-line for chemotherapy-induced peripheral neuropathy.

B6[…] toxicity causes sensory neuronopathy.

Nitrous oxide[…] inactivates B12 and mimics B12 deficiency.

Anti-intrinsic factor[…] antibody is most specific for pernicious anemia.

Severe thiamine[…] deficiency can mimic GBS.

Sjögren[…] syndrome can cause a sensory ganglionopathy with gait ataxia, proprioception loss, low SNAP amplitudes, and normal strength.

ANNA-1 (anti-Hu)[…] antibodies suggest underlying SCLC[…].

Tender, beaded, thickened peripheral nerves should raise suspicion for Mycobacterium leprae[…] (leprosy).

Distal symmetric polyneuropathy[…] is the most common PNS disorder in HIV.

In advanced HIV, CMV[…] polyradiculopathy presents with urinary retention, paralysis, and neutrophilic[…] CSF pleocytosis.

HNPP shows prolonged distal motor latencies[…] and conduction block[…] at compressible sites — recurrent painless mononeuropathies after mild pressure.

HSAN type I results from serine palmitoyltransferase[…] mutations and causes skin ulcerations[…], absent pain perception, and autonomic dysfunction.

SOD1[…] mutations are the only ALS subtype with FDA-approved gene-specific therapy — tofersen[…] (antisense oligonucleotide).

C9orf72[…] hexanucleotide expansion causes ALS-FTD. FUS, TARDBP, and ATXN2 currently have no targeted Rx.

Riluzole[…] requires monitoring of LFTs/transaminases[…].

A cough peak flow <270 L/min[…] is the threshold to start mechanical insufflation-exsufflation.

PLS[…] more often involves bulbar/spastic dysarthria (pseudobulbar palsy); HSP[…] is largely spinal with predominant lower extremity spasticity.

Nusinersen[…] is given by intrathecal injection into the CSF and modifies SMN2 splicing.

Onasemnogene abeparvovec (Zolgensma)[…] delivers the SMN1 gene by AAV9. Patellar reflex is lost first in SMA1; CK is normal or only mildly elevated.

Kennedy disease (spinobulbar muscular atrophy) is a X-linked[…] disorder of the androgen receptor (AR) gene[…] → gynecomastia, testicular atrophy, and androgen-insensitivity features alongside slowly progressive bulbar/proximal LMN weakness.

In an older patient with a "MND" picture but focal findings (calf atrophy, low tibial CMAPs, chronic reinnervation), consider a focal tibial mononeuropathy[…] mimicking motor neuron disease — neuropathy that is treatable should not be missed.

High-risk medications for MG exacerbation include aminoglycosides, fluoroquinolones, telithromycin[…], and (especially) ICIs (anti-PD-1/PD-L1/CTLA-4)[…], which cause the most de novo MG and worst exacerbations. ACEi, cephalosporins, GLP-1 agonists, and TCAs are not classically implicated.

Safe in pregnancy: prednisone, pyridostigmine, IVIG, PLEX[…].

Teratogenic — avoid: MMF, MTX, cyclophosphamide[…]. Nipocalimab has insufficient pregnancy data.

MuSK MG features facio-pharyngeal and neck[…] weakness with bulbar/respiratory crises, treatment resistance, and ocular sparing.

MuSK antibody is IgG4[…] → does not activate complement → no benefit from C5 inhibitors (eculizumab/ravulizumab/zilucoplan) or thymectomy.

Rituximab[…] is highly effective. Pyridostigmine often causes cholinergic hypersensitivity in this subtype.

In ocular MG, lifting the more ptotic lid causes the contralateral lid to drop (curtain sign[…]) — explained by Hering's law[…] of equal innervation to the levator palpebrae.

LEMS classically presents with proximal weakness, hyporeflexia, and autonomic symptoms[…] (dry mouth, erectile dysfunction, palpitations).

Anti-P/Q-type VGCC[…] antibody is positive in >85%.

EMG shows low CMAP at rest and >100% increment[…] after 2-3 Hz/exercise (facilitation). Avoid neuromuscular blockers and risky antibiotics due to respiratory failure risk.

Botulism causes descending[…] flaccid paralysis with no sensory involvement. GI symptoms (nausea/vomiting/constipation) are more typical than in MG.

Acute diplopia followed by dysarthria/dysphagia and flaccid paralysis after contaminated food → urgent antitoxin[…].

Negative AChR/MuSK/LRP4/VGCC antibodies, no response to mestinon or steroids → suspect congenital myasthenic syndrome (CMS)[…] and pursue genetic[…] testing.

CMS is typically autosomal recessive[…], infancy onset, with fluctuating fatigability.

DOK7[…] variants are common.

RAPSN[…] subtype features respiratory crises with illness, responsive to pyridostigmine.

For acute neuromuscular respiratory failure, get FVC then NIF[…] as the emergent bedside tests to guide ventilatory support.

Anti-TIF1-γ[…] antibody confers the strongest cancer association in dermatomyositis (OR ~9.37). Cancer screening is required at diagnosis.

Dermatomyositis biopsy shows perifascicular sarcoplasmic MxA[…] staining — a marker of type I interferon[…] pathway activation.

ICI-related[…] myositis is the only inflammatory myopathy commonly with extraocular muscle[…] involvement, plus myocarditis[…] and lymphopenia.

IBM can present with isolated dysphagia[…], especially in women[…], sometimes with a cricopharyngeal bar[…].

Cardiomyopathy[…] is a red flag against IBM. LDB3 myofibrillar myopathy can mimic IBM. cN-1A antibody is not specific.

IMNM mimics LGMD: persistent very high CK, proximal weakness, and biopsy with necrotic/regenerating fibers. Statin[…] use suggests anti-HMGCR.

Treatment includes IVIG ~2 g/kg[…] and malignancy screening.

Distinguish from LGMD-R9 when only a single heterozygous FKRP[…] variant is found.

Female DMD carriers can develop dilated cardiomyopathy[…] from skewed X-inactivation.

They need cardiology[…] referral and screening.

Becker MD: late childhood onset, ambulation loss in late adolescence, calf hypertrophy, high CK, and cardiomyopathy. Dystrophin shows normal sarcolemmal distribution but reduced amount[…].

In DMD, ACEi or ARB[…] should start before age 10 to delay dilated cardiomyopathy.

Beta-blockers and MRAs[…] are added when LV dysfunction develops.

Deflazacort[…] causes more cataracts than prednisone but has favorable growth profile.

DMD gene-targeted therapies: exon-skipping antisense oligonucleotides[…] restore reading frame (gene modulation).

Delandistrogene moxeparvovec[…] is the FDA-approved AAV gene therapy. Biopsy IHC for diagnosis: control = normal staining, DMD = absent, Becker = reduced.

Emery-Dreifuss MD: classic scapuloperoneal pattern with scapular winging, foot dorsiflexion weakness, and prominent elbow contractures[…] in children/adolescents.

LGMD-R12 (ANO5)[…] causes asymmetric biceps + quadriceps weakness, difficulty toe-walking, and recurrent rhabdomyolysis.

LGMD-R9 (FKRP)[…] causes limb-girdle weakness with hamstring > quadriceps involvement and reduced α-dystroglycan on biopsy.

Initial workup is a NGS panel[…].

A middle-aged adult with progressive dysphagia[…], cricopharyngeal bar, mild neck flexion weakness, and rimmed vacuoles[…] on distal vastus biopsy is classic for OPMD[…].

DM1 features distal-predominant[…] weakness, grip myotonia with warm-up, facial/temporalis wasting, flaccid dysarthria, pilomatrixomas[…], and sleep apnea.

Pathomechanism: RNA foci sequester MBNL[…] → missplicing.

Cold, rest, and pregnancy[…] worsen myotonia. Childhood-onset DM1 commonly shows ADHD/anxiety.

Long-term statin therapy, proximal weakness, clinical myotonia, and Christmas tree cataracts[…] → confirm with EMG showing myotonic discharges → suspect DM2 (PROMM)[…].

Mexiletine[…] is the most effective treatment for handgrip myotonia.

Paramyotonia congenita causes paradoxical[…] myotonia (worsens with repetition, opposite of warm-up) and worsens in cold[…].

Caused by SCN4A[…] pathogenic variants. Adult presentation is often leg stiffness after rest; ocular involvement uncommon.

HypoPP type 2 is loss-of-function SCN4A[…]; during attacks limbs are flaccid and areflexic with normal sensation.

Acute treatment for hyperkalemic[…] PP: carbohydrate snack → insulin → drives K+ intracellular.

Negative SCN4A/CACNA1S/KCNJ2 panel testing → consider RYR1[…].

Mild proximal weakness, scapular winging, and a family history of malignant hyperthermia[…] should prompt RYR1[…] testing.

VCP[…] variants cause an autosomal dominant multisystem proteinopathy with IBM, ALS, and Paget disease of bone[…].

Fatty acid oxidation disorders cause post-exercise pain and myoglobinuria with febrile illness. Diagnose with the serum acylcarnitine[…] profile.

Treatment: triheptanoin[…].

MADD[…] (riboflavin-responsive) can mimic polymyositis.

Cramps with "second wind" phenomenon[…] after ~10 min of exercise, chronic CK elevation, and exercise intolerance = myophosphorylase[…] deficiency (GSD V, McArdle).

Pompe disease (acid maltase deficiency) shows early respiratory/diaphragm[…] weakness preceding limb weakness — a feature that distinguishes it from DMD[…].

MADD biopsy shows large nonrimmed lipid-filled vacuoles[…] with Oil Red O positivity.

Caused by ETF/ETFDH[…] mutations.

Often riboflavin[…]-responsive.

Side-to-side pelvic instability with a waddling gait reflects hip abductor weakness — specifically the gluteus medius[…] muscle.

For haploinsufficiency disorders, gene supplementation[…] raises functional protein.

Exon-skipping antisense oligonucleotides[…] are gene modulation.

CRISPR/Cas9[…] is limited in skeletal muscle because muscle is non-dividing (poor homology-directed repair).