Amyotrophic Lateral Sclerosis

• Excitotoxicity via glutamate dysregulation: Excessive glutamate accumulation in the synaptic cleft overstimulates NMDA and AMPA receptors on motor neurons, leading to calcium influx-mediated neuronal injury. This occurs through decreased expression of the excitatory amino acid transporter 2 (EAAT2) on astrocytes, which normally clears glutamate from the extracellular space. The resulting calcium overload activates proteases, endonucleases, and pro-apoptotic pathways. This mechanism explains why riluzole, which inhibits glutamate release, provides modest survival benefit.

• Protein misfolding and aggregation: Misfolded proteins, particularly SOD1 (superoxide dismutase 1) in familial ALS and TDP-43 (TAR DNA-binding protein 43) in both sporadic and familial forms, accumulate intracellularly as inclusions. These aggregates sequester functional protein, impair proteasomal and autophagosomal clearance, and trigger proteotoxic stress. TDP-43 pathology represents the neuropathological hallmark in ~97% of ALS cases and is thought to cause disease through loss of normal RNA-binding function and gain of toxic function through aggregation.

• Mitochondrial dysfunction and bioenergetic failure: Motor neurons are metabolically demanding cells highly vulnerable to mitochondrial dysfunction. Accumulation of misfolded proteins in mitochondria, particularly SOD1 and TDP-43, impairs oxidative phosphorylation, reduces ATP production, and increases reactive oxygen species (ROS) generation. This bioenergetic crisis is compounded by impaired mitochondrial calcium buffering, exacerbating excitotoxic injury. Mitochondrial DNA abnormalities and decreased PGC-1α (master regulator of mitochondrial biogenesis) further perpetuate this cycle.

• Neuroinflammation and glial dysfunction: Both microglia and astrocytes become activated and contribute to motor neuron death through multiple mechanisms. Activated microglia produce pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and neurotoxic factors. Astrocytes lose their supportive function, producing less neurotrophic factors and failing to clear glutamate and potassium. This non-cell-autonomous mechanism is supported by evidence that expression of mutant SOD1 in microglia and astrocytes—but not motor neurons alone—causes disease, and by the therapeutic benefit observed with anti-inflammatory approaches in animal models.

• Impaired axonal transport: ALS-associated mutations in proteins involved in axonal transport (KIF5A, DCTN1, UNC13A) or in RNA-binding proteins that regulate axonal transport machinery disrupt the delivery of essential proteins and organelles to distal axons. This leads to axonal degeneration beginning distally (dying-back hypothesis) and accumulation of protein aggregates. Defective retrograde transport of neurotrophic factors further compromises neuronal survival.

• RNA dysmetabolism: TDP-43 and FUS (fused in sarcoma), which are RNA-binding proteins, normally localize to the nucleus and regulate mRNA splicing, stability, and localization. In ALS, these proteins are sequestered in cytoplasmic aggregates, causing loss of nuclear function and aberrant cytoplasmic accumulation. This leads to dysregulation of hundreds of transcripts involved in neuronal survival, axonal maintenance, and protein homeostasis.

• Oxidative stress: Impaired antioxidant defenses (particularly in SOD1-related disease, though mutations may impair dismutase function) combined with mitochondrial ROS production and neuroinflammation create a pro-oxidant environment. This oxidative stress damages lipids, proteins, and DNA, further perpetuating neuronal injury.

• Genetic mutations (Familial ALS, ~10% of cases): Multiple genes have been identified in fALS, with C9orf72 repeat expansions (most common in European populations, ~30-40% of fALS), SOD1 mutations (~20% of fALS), FUS mutations (~5% of fALS), and TARDBP (encoding TDP-43) mutations (~5% of fALS) being the most frequent. Over 25 genes have been implicated, with newer discoveries including UNC13A, KIF5A, and ATXN2. These genes encode proteins involved in protein handling, axonal transport, RNA metabolism, and stress granule dynamics. Autosomal dominant inheritance predominates, though autosomal recessive (particularly SOD1, DCTN1) and X-linked patterns exist. C9orf72 expansions are notable for association with frontotemporal dementia (FTD) in addition to motor neuron disease, highlighting the ALS-FTD spectrum.

• Sporadic ALS (sALS, ~90% of cases): The majority of ALS cases are sporadic, arising from de novo mutations, epigenetic modifications, or gene-environment interactions. Genome-wide association studies (GWAS) have identified common genetic variants with modest effect sizes in genes implicated in fALS (SOD1, C9orf72, ATXN2), as well as immune-related and RNA-binding protein genes. This suggests a common genetic architecture between sALS and fALS with different penetrance thresholds.

• Environmental factors: Proposed environmental risk factors include exposure to heavy metals (particularly lead), pesticides (organophosphates, herbicides), and electric shocks. The evidence remains inconsistent and largely epidemiological. Military service has been weakly associated with ALS, potentially related to environmental exposures or strenuous physical activity. However, the attributable risk from any single environmental factor is modest, suggesting gene-environment interactions rather than obligate causation.

• Physical trauma and repetitive injury: Some evidence suggests that focal motor neuron injury from physical trauma or repetitive strain may precede ALS onset at that anatomical level (focal-onset ALS). Repeat mild head trauma may increase risk, though causation is unclear. Professional athletes, particularly in contact sports, show slightly increased incidence in some studies.

• Smoking and alcohol use: Smoking history shows inconsistent associations with ALS in epidemiological studies, with some meta-analyses suggesting modest increased risk. Alcohol use has not been consistently associated with increased ALS risk.

• Metabolic factors: Elevated BMI and hyperglycemia may have protective effects in some studies (reverse causality with pre-symptomatic weight loss cannot be excluded), while metabolic syndrome and diabetes show variable associations. These relationships remain incompletely understood.

• Age and sex: Incidence increases steadily with age, peaking in the 7th-8th decade. Males are affected 1.5 times more frequently than females, with unclear mechanistic basis (possibly X-linked protective factors, hormonal factors, or occupational exposure differences).

• Progressive muscle weakness and atrophy: The cardinal feature is asymmetrical, progressive weakness beginning focally and spreading to contiguous muscle groups. Spinal-onset ALS (60-70% of cases) typically presents with distal lower extremity weakness (foot drop, difficulty climbing stairs) or upper extremity weakness (difficulty with fine motor tasks, hand grip). Bulbar-onset ALS (25-30%) presents with dysarthria (speech impairment, nasal quality), dysphagia (difficulty swallowing), tongue atrophy, and fasciculations. Weakness progresses distally to proximally and to contralateral limbs. Accompanying muscle atrophy (wasting) becomes apparent over weeks to months and reflects denervation. Early focal weakness may be subtle (mild foot drag, slight hand weakness, jaw tremor), requiring careful examination for detection.

• Fasciculations: Visible, involuntary muscle twitching representing spontaneous firing of motor units is a characteristic but non-specific finding. Fasciculations are often most prominent in weak muscles and in the tongue. While ALS is associated with fasciculations, benign fasciculation syndrome (often in anxious patients) causes fasciculations without weakness or denervation on EMG.

• Cramps and spasticity: Painful muscle cramps, particularly at night and in lower extremities, affect >60% of patients and may precede weakness. These reflect motor neuron hyperexcitability. Spasticity (velocity-dependent increased muscle tone) develops due to UMN loss and relative preservation of LMN function initially, contributing to increased stiffness, reduced range of motion, and painful contractures. Hyperreflexia is characteristic when UMN disease predominates.

• Dysarthria and dysphagia: Progressive bulbar involvement causes slurred, nasal, or harsh speech (dysarthria) and difficulty swallowing (dysphagia). Early dysphagia may manifest as coughing with liquids, difficulty clearing secretions, or food residue in the mouth. Later, aspiration risk increases substantially, necessitating dietary modification or feeding tube placement. These symptoms reflect weakness of muscles innervated by CN IX, X, and XII.

• Respiratory insufficiency: Progressive weakness of the diaphragm and intercostal muscles leads to restrictive ventilatory physiology. Initial symptoms include dyspnea on exertion, orthopnea (shortness of breath when lying flat due to loss of accessory muscle contribution), and sleep-disordered breathing (particularly REM sleep hypoventilation). Paradoxical abdominal breathing (abdomen moves inward during inspiration) indicates diaphragmatic weakness. Advanced respiratory compromise requires mechanical ventilation; ~10-20% of ALS patients pursue noninvasive ventilation long-term.

• Emotional lability and cognitive change: Pseudobulbar affect (involuntary laughing or crying inappropriate to emotional context) occurs in ~50% of patients due to bilateral UMN involvement of emotional motor pathways. Cognitive and behavioral changes occur in ~5-15% of patients with ALS as part of the ALS-FTD spectrum, manifesting as executive dysfunction, behavioral disinhibition, or apathy. These changes suggest C9orf72 repeat expansions or other genetic variants.

• Preserved sensory function and ocular motility: Sensory examination remains normal—sensory symptoms suggest alternative diagnosis. Extraocular muscles (CN III, IV, VI) are characteristically spared, preserving eye movements and blinking even in advanced disease (locked-in syndrome can develop with preserved cognition but complete paralysis). This preserved extraocular function helps distinguish ALS from some mimics.

• Classic ALS variants:
• Primary lateral sclerosis (PLS): Slowly progressive UMN-predominant disease without LMN findings; average survival >15 years. ~5-10% eventually develop LMN signs (ALS-PLS conversion).
• Progressive muscular atrophy (PMA): LMN-predominant disease without overt UMN signs; slower progression than typical ALS.
• Flail arm syndrome: Predominantly upper extremity weakness with relatively preserved lower extremity function; better prognosis.
• Flail leg syndrome: Predominantly lower extremity weakness; intermediate prognosis between bulbar and typical spinal-onset.
• Progressive bulbar palsy: Bulbar-onset with early speech and swallowing difficulties; worse prognosis.
• ALS-FTD spectrum: Concurrent motor and cognitive/behavioral symptoms with frontotemporal dementia features.

• Clinical diagnostic criteria (Revised El Escorial criteria, now termed Awaji criteria): Diagnosis requires evidence of LMN degeneration (clinical, electrophysiological, or neuropathological evidence in one region) plus UMN degeneration (clinical or electrophysiological evidence in one region, in the same region preferred but not required), with progressive spread of signs (clinical or electrophysiological) to other regions over time. Importantly, LMN and UMN signs do not need to occur in the same region—a patient with lower extremity weakness showing LMN signs and upper extremity weakness showing UMN signs fulfills criteria. Key diagnostic requirement: The disease must be progressive clinically or electrophysiologically over at least 3 months, distinguishing ALS from static motor neuropathies. The Awaji criteria (2008) gave equivalent weight to electrophysiological evidence of denervation alongside clinical signs, improving early diagnostic sensitivity. Diagnosis is typically clinical; no serum biomarkers are currently standard clinical tools, though phosphorylated tau (p-tau) and neurofilament light chain (NfL) show promise as research biomarkers.

• Electromyography (EMG) findings: EMG is essential for diagnosis and shows neurogenic pattern with acute and chronic denervation changes. Acute denervation appears as fibrillations (spontaneous action potentials of individual muscle fibers) and positive sharp waves in weak muscles—these indicate active denervation from motor neuron loss. Chronic denervation manifests as large-amplitude, long-duration motor unit action potentials (MUAPs) with reduced interference pattern, reflecting collateral reinnervation from surviving motor neurons. Reduced recruitment (inability to recruit normal number of motor units at maximal effort) is characteristic. Importantly, motor nerve conduction studies show normal conduction velocities and normal compound muscle action potential (CMAP) amplitudes until late disease, helping exclude primary demyelinating neuropathies. Sensory nerve conduction studies are normal, which is critical—sensory involvement suggests alternative diagnosis. EMG abnormalities may precede clinical signs, supporting early diagnosis. The number of muscle groups showing denervation correlates with disease severity.

• Magnetic resonance imaging (MRI) of brain and spinal cord: MRI is performed primarily to exclude alternative diagnoses (structural lesions, tumors, compressive myelopathy, demyelinating disease). In ALS, conventional MRI is often normal. However, research MRI techniques show motor cortex atrophy and T2 hyperintensity in the motor cortex (rarely helpful clinically) and corticospinal tract hyperintensities on T2/FLAIR sequences in ~20-30% of patients (non-specific and not required for diagnosis). MRI is valuable for ruling out spinal cord compression, syrinx, stroke, or structural lesions that mimic ALS.

• Laboratory evaluation: Routine blood work (CBC, CMP, TSH, vitamin B12, paraneoplastic panel) and CSF analysis are normal in ALS but are obtained to exclude alternative diagnoses. Creatine kinase (CK) may be mildly elevated (typically <300 U/L) from muscle damage but is rarely markedly elevated. Markedly elevated CK (>1000 U/L) suggests myopathy rather than ALS. Hexosaminidase A activity should be checked if young-onset ALS with rapid progression to exclude Tay-Sachs disease (juvenile-onset form mimics ALS). Genetic testing is indicated when: (1) family history of ALS or dementia, (2) young-onset ALS (<50 years), (3) atypical phenotype, or (4) rapid progression. C9orf72 repeat expansion testing is most commonly pursued initially, particularly in European ancestry populations with family history; most labs screen for expansions >30 repeats.

• Differential diagnosis considerations:
• Multifocal motor neuropathy (MMN): Presents with asymmetrical focal weakness, but motor conduction blocks are present (slowing/amplitude reduction on motor studies), sensory nerves are spared, and disease is typically more indolent and responsive to IVIG
• Kennedy disease (X-linked bulbospinal muscular atrophy): Bulbar symptoms with gynecomastia, diabetes, elevated CK; trinucleotide repeat disorder; slower progression
• Cervical myelopathy: Weakness is associated with sensory level, bowel/bladder involvement, and structural findings on MRI
• Myasthenia gravis: Fa

Immediate stabilisation

• Acute hypercapnic respiratory failure or aspiration: support ventilation (non-invasive first if the patient can protect the airway) and clarify goals of care before intubating — extubation may be impossible.

Disease-modifying therapy (first-line)

• Glutamate release inhibitor — riluzole: the only oral agent with a mortality benefit, extending survival/time to tracheostomy by a few months. Mechanism ties to the excitotoxicity pathway; monitor LFTs and CBC (hepatotoxicity, rare neutropenia).
• Free-radical scavenger — edaravone: IV or oral; FDA-approved on slowing functional decline (ALSFRS-R) in a selected early-disease population, not on survival.
• Antisense oligonucleotide — tofersen: intrathecal, restricted to *SOD1*-mutation ALS; FDA accelerated approval based on neurofilament light chain reduction. Genetic confirmation is required first.

Symptomatic and supportive escalation

• Non-invasive ventilation (NIV/BiPAP): the single intervention with the largest survival and quality-of-life benefit (AAN); start for orthopnea, symptomatic hypoventilation, or declining FVC/sniff nasal pressure — do not wait for daytime hypercapnia.
• Secretion management: anticholinergics (glycopyrrolate, amitriptyline) for sialorrhea; mechanical insufflation–exsufflation (cough assist) for weak cough.
• Pseudobulbar affect: dextromethorphan/quinidine.
• Spasticity and cramps: baclofen or tizanidine; depression/anxiety: SSRIs.

Definitive/procedural

• Percutaneous endoscopic gastrostomy: for dysphagia and weight loss; AAN advises placing it early, while forced vital capacity is still relatively preserved, since procedural sedation late in disease is hazardous.
• Tracheostomy with invasive ventilation: an option, but leads to prolonged dependence and possible locked-in state — requires advance-directive discussion.

Avoid

• Succinylcholine: denervation upregulates extrajunctional ACh receptors → hyperkalemic cardiac arrest.
• Diaphragmatic pacing in ALS with respiratory insufficiency: trial evidence showed harm rather than benefit.
• Over-sedation without ventilatory support; steroids, IVIG, and plasma exchange have no role (they belong to the mimics).

Respiratory (the usual cause of death)

• Neuromuscular respiratory failure — emergency: diaphragm and intercostal denervation produce restrictive physiology. Signalled by orthopnea, paradoxical abdominal breathing, morning headache and hypersomnolence (nocturnal hypoventilation), falling FVC/sniff nasal inspiratory pressure, and rising PaCO₂ on ABG. Pulse oximetry is insensitive — hypercapnia precedes desaturation.
• Aspiration pneumonia — emergency: bulbar weakness plus ineffective cough. Signalled by coughing on thin liquids, wet voice, fever with a new infiltrate.
• Mucus plugging/laryngospasm: sudden stridor or choking spells from weak cough and thickened secretions.

Bulbar and nutritional

• Malnutrition and cachexia: dysphagia plus hypermetabolism; signalled by progressive weight loss, an independent adverse prognostic marker prompting gastrostomy.
• Sialorrhea: not overproduction but failure to swallow saliva; drooling with aspiration risk.

Immobility-related

• Venous thromboembolism: stasis from paralysis; unilateral leg swelling or unexplained hypoxemia — pulmonary embolism is an emergency.
• Pressure ulcers, joint contractures, adhesive capsulitis, falls with fracture.

Neuropsychiatric

• Frontotemporal dementia/executive dysfunction (ALS–FTD spectrum, especially C9orf72): impairs adherence to NIV and decision-making capacity.
• Pseudobulbar affect and reactive depression.

Treatment-related

• Riluzole: transaminase elevation (dose-limiting hepatotoxicity), rarely neutropenia and interstitial lung disease — check LFTs periodically.
• Edaravone: infusion reactions; the formulation contains sodium bisulfite, a hazard in sulfite-sensitive asthmatics.
• Gastrostomy placement: procedural sedation in a patient with low vital capacity can precipitate respiratory arrest — emergency risk, hence early placement.
• NIV: mask pressure ulcers, aerophagia, gastric distension.
• Tracheostomy/invasive ventilation: ventilator-associated pneumonia, tracheal stenosis, and progression to a totally locked-in state with preserved cognition.
• Succinylcholine exposure: hyperkalemic cardiac arrest from extrajunctional ACh receptor upregulation — emergency.

• The defining pattern: upper and lower motor neuron signs in the same patient, often the same limb, with completely normal sensation. A wasted, fasciculating hand with a brisk reflex in that same arm, or atrophic legs with upgoing toes, is the stem's giveaway.
• Buzzwords to recognize: tongue fasciculations with tongue atrophy, brisk jaw jerk, foot drop that spread to the other leg, pseudobulbar affect (uncontrollable crying), split hand (thenar wasting out of proportion to hypothenar).
• Single best next step after the history and exam: EMG/nerve conduction studies — showing fibrillations, positive sharp waves, and large-amplitude long-duration MUAPs with normal sensory studies. MRI is ordered to exclude a compressive/structural mimic, not to make the diagnosis.
• The one drug association tested: riluzole, a glutamate-release inhibitor, is the classic answer for modest survival benefit; monitor LFTs. NIV is the intervention with the greatest survival gain overall.
• What ALS spares: extraocular movements, bowel/bladder sphincters, sensation, and (in most patients) cognition. If the stem includes a sensory level, bladder incontinence, or ophthalmoplegia, it is not ALS.
• Genetics: C9orf72 hexanucleotide repeat is the most common familial cause and links ALS to frontotemporal dementia — the ALS–FTD spectrum stem.
• Anesthesia trap: never give succinylcholine — denervation-induced extrajunctional receptors cause hyperkalemic arrest.
• Common distractors: multifocal motor neuropathy (pure LMN, conduction block, anti-GM1, responds to IVIG — treatable, so it must be excluded); cervical spondylotic myelopathy (sensory level, neck pain, MRI lesion); Kennedy disease (bulbar signs with gynecomastia, X-linked CAG repeat, high CK); myasthenia gravis (fatigable, ptosis/diplopia — eyes are spared in ALS); benign fasciculation syndrome (twitching without weakness or EMG denervation).