ALS

DEFINITION: Amyotrophic = muscle atrophy (LMN loss); lateral sclerosis = scarring/gliosis of the lateral corticospinal tracts (UMN loss).

EPIDEMIOLOGY: Onset typically age 50–65; slightly male predominance. ~90–95% sporadic; ~5–10% familial.

GENETICS/PATHOPHYSIOLOGY: - SOD1 mutation (Cu/Zn superoxide dismutase, chromosome 21; autosomal dominant, toxic gain of function) – classic board association; ~20% of familial cases. - C9ORF72 hexanucleotide repeat expansion – most common genetic cause overall (familial and some sporadic); associated with frontotemporal dementia (ALS-FTD). - TDP-43 and FUS: protein aggregates/inclusions are the pathologic hallmark in most cases. - Proposed mechanisms: glutamate excitotoxicity, oxidative stress, protein misfolding/aggregation, impaired axonal transport, neuroinflammation.

PATHOLOGY: Loss of anterior horn cells (LMN) in spinal cord, brainstem motor nuclei, and Betz cells in motor cortex (UMN); degeneration of lateral corticospinal tracts.

CLINICAL FEATURES: - LMN signs: weakness, atrophy, fasciculations, hyporeflexia, flaccidity. - UMN signs: spasticity, hyperreflexia, Babinski sign, clonus. - Bulbar involvement: dysarthria, dysphagia, tongue atrophy/fasciculations, pseudobulbar affect (emotional lability). - Asymmetric limb onset (often focal, e.g., hand weakness or foot drop), then spreads. - SPARED: sensation, extraocular movements, bowel/bladder (Onuf nucleus), and usually cognition (though ~15% develop FTD).

DIAGNOSIS: Clinical (El Escorial/Awaji criteria): UMN + LMN signs in multiple regions with progression, after excluding mimics. EMG/NCS shows widespread denervation (fibrillations, fasciculations) with normal sensory nerve studies. MRI to exclude structural lesions (e.g., cervical spondylotic myelopathy). Genetic testing when familial.

DIFFERENTIAL (high-yield): Cervical myelopathy, multifocal motor neuropathy with conduction block (anti-GM1; treat with IVIG), Kennedy disease (X-linked spinobulbar muscular atrophy, CAG repeat in androgen receptor; LMN only with gynecomastia/hypogonadism), spinal muscular atrophy (SMN1; LMN only, infants), poliomyelitis/post-polio syndrome (LMN only), myasthenia gravis (fatigable weakness, no UMN signs), syringomyelia (sensory loss, cape-like), primary lateral sclerosis (UMN only), progressive muscular atrophy (LMN only), vitamin B12 deficiency/subacute combined degeneration (has sensory loss), Lyme and HIV.

TREATMENT: - Riluzole: inhibits presynaptic glutamate release (blocks Na channels); extends survival by ~2–3 months. Monitor LFTs. - Edaravone: free radical scavenger; slows functional decline in selected patients. - Supportive: multidisciplinary care, noninvasive ventilation (BiPAP) improves survival and quality of life, PEG tube for dysphagia, baclofen for spasticity, treatment of sialorrhea, and palliative/advance care planning.

PROGNOSIS: Median survival 3–5 years from onset; death typically from respiratory failure (diaphragm weakness) or aspiration pneumonia.

BOARD PEARLS: "Mixed UMN + LMN signs without sensory loss" = ALS. Fasciculations + hyperreflexia in the same limb is a classic clue. Eye movements and sphincter function are spared. Know riluzole's mechanism and SOD1 association.