Nervous System & Special Senses

Amyotrophic lateral sclerosis: diagnosis and supportive care

Clinical Overview and When to Suspect ALS

— Incidence ~2/100,000; lifetime risk ~1 in 350

— Peak onset age 55–75; men slightly > women

— ~10% familial (SOD1, C9orf72 most common; C9orf72 also linked to frontotemporal dementia)

— Median survival 3–5 years from symptom onset; bulbar-onset disease portends shorter survival

— Progressive focal limb weakness (foot drop, hand clumsiness, grip weakness) that spreads to contiguous regions

— Bulbar symptoms: dysarthria, dysphagia, tongue fasciculations, sialorrhea

— Mixed UMN/LMN: brisk reflexes in a wasted, fasciculating limb

— Pseudobulbar affect (involuntary laughing/crying)

— Unexplained weight loss and respiratory symptoms (orthopnea, morning headache)

— Sensory loss, bowel/bladder dysfunction, prominent pain, ophthalmoplegia

— Symmetric proximal weakness without UMN signs

— Fluctuating or stepwise course

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of upper motor neurons (UMN) in the motor cortex and corticospinal tracts and lower motor neurons (LMN) in the brainstem and anterior horn cells.

Hallmark = painless, progressive, asymmetric weakness with both UMN and LMN signs in the same body region, without sensory loss, sphincter dysfunction, or significant cognitive impairment in early disease.

Epidemiology

Suspect ALS in a patient ≥40 with:

Red flags AGAINST ALS (rethink the diagnosis):

Step 3 management: A middle-aged patient with painless asymmetric limb weakness + hyperreflexia + fasciculations + atrophy + normal sensation should be referred urgently to neurology for EMG and consideration of a multidisciplinary ALS clinic, which independently prolongs survival.

Board pearl: The combination of UMN and LMN findings in the same myotome without sensory involvement is the single most specific clinical signature of ALS on Step 3 vignettes.

Presentation Patterns and Key History

— Limb-onset (~70%): asymmetric distal weakness — foot drop, tripping, "my hand feels clumsy," buttoning difficulty, weak grip

— Bulbar-onset (~25%): dysarthria (slurred, strained, nasal speech) often precedes dysphagia; choking on liquids; drooling; tongue wasting

— Respiratory-onset (~5%): unexplained dyspnea, orthopnea, morning headaches, daytime somnolence from nocturnal hypoventilation

— Time course: gradual, relentlessly progressive over months, spreading to adjacent regions (a leg → contralateral leg → arm)

— No remissions, no fluctuations (distinguishes from MG, MS)

— Cramps and fasciculations often precede weakness by months

— Weight loss disproportionate to intake — hypermetabolism is characteristic

— Emotional lability / pseudobulbar affect — sudden crying or laughing incongruent with mood

— Family history of ALS, FTD, or early dementia (C9orf72)

— Cognitive screen: ~15% develop frank FTD; up to 50% have subtle executive dysfunction

— Numbness, paresthesias, band-like sensory level

— Urinary urgency/retention, fecal incontinence

— Diplopia, ptosis, fatigable weakness (think myasthenia gravis)

— Pain as a dominant early feature (think radiculopathy, IBM)

— Falls, choking episodes, weight trajectory, speech intelligibility

— Sleep quality, orthopnea, morning headaches (early hypoventilation)

— Caregiver burden, advance directives, code status

Three clinical onset patterns — recognize each:

Critical history elements

What should NOT be in the history (prompts alternative diagnosis):

Functional impact questions to ask at every visit:

Key distinction: ALS is painless and purely motor; MS and cervical myelopathy bring sensory symptoms and sphincter dysfunction; MG brings fluctuation and ocular involvement. Step 3 stems exploit these contrasts.

Board pearl: Bulbar-onset ALS is more common in older women and carries the worst prognosis — early PEG and NIV discussions are appropriate at diagnosis.

Physical Exam Findings and Respiratory Assessment

— Fasciculations (best seen in tongue, deltoid, thigh) — pathognomonic when widespread

— Atrophy — intrinsic hand muscles ("split hand" with thenar/first dorsal interosseous wasting sparing hypothenar), tongue scalloping

— Flaccid weakness, hyporeflexia in severely wasted muscles

— Cramps

— Hyperreflexia in an atrophic, weak limb (highly suggestive)

— Spasticity, clonus, Hoffman sign, Babinski

— Pseudobulbar affect, brisk jaw jerk, hyperactive gag

— Spastic dysarthria (strained, slow)

— Tongue: atrophy + fasciculations (LMN) and slow, spastic movement (UMN)

— Palatal weakness, nasal speech, weak cough

— Sialorrhea from impaired swallowing (not increased production)

— Forced vital capacity (FVC) — upright and supine; >10% drop supine suggests diaphragmatic weakness

— Maximal inspiratory pressure (MIP/NIF) — more sensitive early

— Sniff nasal inspiratory pressure (SNIP)

— Resting SpO₂, overnight oximetry, ABG for CO₂ retention

— Observe for accessory muscle use, paradoxical abdominal breathing, orthopnea

— Sensory level, vibratory loss, proprioceptive deficits

— Extraocular muscle weakness, ptosis

— Cerebellar signs, parkinsonism (suggests ALS-plus or alternative dx)

The defining exam: coexisting UMN and LMN signs in the same region, with sensory exam completely normal.

Lower motor neuron signs

Upper motor neuron signs

Bulbar exam

Respiratory assessment — do at EVERY visit:

Exam findings that should NOT be present:

Step 3 management: Initiate noninvasive ventilation (NIV) when FVC <50% predicted, MIP <60 cm H₂O, symptomatic orthopnea, or nocturnal hypoventilation — NIV is the single intervention with the largest survival benefit in ALS (adds ~7–13 months).

Board pearl: The "split hand" sign — disproportionate wasting of thenar eminence and first dorsal interosseous with relatively preserved hypothenar — is highly specific for ALS.

Diagnostic Workup — Initial Labs, Imaging, and Exclusion Testing

— CBC, CMP (electrolytes, Ca, Mg, renal, hepatic)

— TSH, free T4 (thyrotoxic myopathy)

— Vitamin B12, folate, copper, vitamin E (myelopathy mimics)

— CK — often mildly elevated (<1000); markedly high CK suggests myopathy/IBM

— HIV, RPR — treatable causes of motor syndromes

— SPEP/IFE, free light chains — paraproteinemic neuropathy / MMN

— Anti-GM1 antibodies if multifocal motor neuropathy (MMN) is on differential (pure LMN, conduction block)

— AChR and MuSK antibodies if bulbar/fluctuating — rule out myasthenia

— Heavy metals (lead) if exposure history

— Hexosaminidase A in young patients (late-onset Tay-Sachs)

— MRI brain and cervical spine with contrast is essential to exclude:

– Cervical spondylotic myelopathy (UMN legs + LMN arms — classic mimic)

– Foramen magnum lesion, syringomyelia, MS, tumor

— Add lumbar MRI if leg-predominant LMN signs

— Subtle corticospinal tract T2 hyperintensity may be seen in ALS but is nonspecific

— FVC (sitting and supine), MIP, SNIP, SpO₂

— Establishes trajectory; repeated every 3 months

— Weight, BMI, swallowing evaluation; >10% weight loss is a poor prognostic marker

ALS remains a clinical diagnosis supported by EMG; initial workup is largely aimed at excluding mimics.

Baseline laboratory panel

Imaging

Pulmonary baseline

Nutritional baseline

CCS pearl: On CCS-style cases, the first orders in a suspected ALS workup are: MRI cervical spine, EMG/NCS, CBC, CMP, TSH, B12, CK, SPEP, HIV — then refer to neuromuscular neurology. Do NOT order genetic testing or muscle biopsy as initial steps unless specific features mandate.

Key distinction: Cervical spondylotic myelopathy causes UMN legs + LMN arms but spares bulbar function and tongue — a normal tongue exam in this pattern favors spine; tongue fasciculations favor ALS.

Diagnostic Workup — EMG, Genetic Testing, and Diagnostic Criteria

— Motor amplitudes (CMAPs) reduced in weak muscles

— Sensory studies normal — a critical feature; abnormal sensory NCS argues against ALS

— No conduction block (its presence suggests MMN, which is treatable with IVIG)

— Conduction velocities preserved or only mildly slowed

— Acute denervation: fibrillations, positive sharp waves

— Chronic reinnervation: large-amplitude, long-duration, polyphasic motor units; reduced recruitment

— Fasciculation potentials, especially complex/unstable ones

— Findings must be present in ≥2 muscles in ≥2 body regions (bulbar, cervical, thoracic, lumbosacral) with both acute and chronic denervation

— Progressive motor impairment documented by history/exam

— UMN and LMN dysfunction in ≥1 body region, OR LMN dysfunction in ≥2 regions

— Exclusion of alternative diagnoses via labs and imaging

— Replaces older revised El Escorial criteria; more sensitive, simpler

— Offer in familial ALS, ALS-FTD, or early-onset cases

— Panel includes C9orf72 (hexanucleotide repeat — most common), SOD1, TARDBP, FUS

— SOD1-positive patients are now candidates for tofersen (antisense oligonucleotide)

— Pretest genetic counseling is mandatory

— Lumbar puncture if atypical (inflammatory markers, infection)

— Muscle biopsy only if myopathy suspected

— Neurofilament light chain (NfL) — emerging biomarker, prognostic

Electrodiagnostic studies (EMG/NCS) are the cornerstone confirmatory test.

Nerve conduction studies (NCS)

Needle EMG — the diagnostic workhorse

Gold Coast criteria (2020) — current preferred diagnostic framework:

Genetic testing

Other adjuncts (selective use)

Board pearl: Presence of conduction block on NCS should redirect you to multifocal motor neuropathy — pure LMN, asymmetric, responds to IVIG, and missing this diagnosis is a classic Step 3 trap.

Step 3 management: Confirmatory testing should occur in a specialized neuromuscular center; early referral compresses time to diagnosis (currently ~12 months) and accelerates access to disease-modifying therapy.

Risk Stratification and Management Framework

— Bulbar-onset disease

— Older age at onset (>65)

— Short interval from symptom onset to diagnosis (rapid progression)

— Early respiratory involvement, low baseline FVC

— Significant weight loss / low BMI at diagnosis

— Frontotemporal cognitive/behavioral involvement

— Elevated serum/CSF neurofilament light chain

— Limb-onset, younger age, preserved respiratory function, slow ALSFRS-R decline, normal BMI

— ALSFRS-R (Revised ALS Functional Rating Scale, 48 points): bulbar, fine motor, gross motor, respiratory subscales

— Track every clinic visit; decline >1 point/month = aggressive disease

— Disease-modifying therapy: riluzole, edaravone, tofersen (if SOD1)

— Symptomatic care: sialorrhea, spasticity, cramps, pseudobulbar affect, pain, sleep

— Anticipatory/supportive care: NIV, PEG, communication aids, mobility, hospice planning

— Neurology, pulmonology, PT/OT, speech-language pathology, dietitian, respiratory therapist, social work, palliative care, psychiatry

— Visits every 3 months standard

ALS prognosis varies substantially — risk-stratify at diagnosis to guide intensity and timing of interventions.

Poor prognostic factors

Better prognostic factors

Functional tracking

Management framework — three parallel tracks (start ALL at diagnosis):

Multidisciplinary ALS clinic — independently associated with prolonged survival and improved QOL:

Step 3 management: At diagnosis, the highest-yield interventions are (1) refer to multidisciplinary ALS clinic, (2) start riluzole, (3) establish goals of care and advance directive, (4) baseline PFTs and swallow evaluation, (5) palliative care referral early — not at end of life.

Board pearl: Early palliative care integration in ALS is associated with improved symptom control and quality of life — it is not a substitute for disease-modifying therapy and should be introduced at diagnosis.

Pharmacotherapy — Disease-Modifying and Symptomatic Drugs

— Glutamate release inhibitor

— 50 mg PO BID, on empty stomach

— Extends survival ~3 months and delays tracheostomy

— Monitor LFTs monthly × 3, then periodically; discontinue if ALT >5× ULN

— Available as tablet, oral suspension, oral film (for dysphagia)

— IV (60 mg daily × 14 days, then cyclical) or oral suspension

— Best evidence in early disease with preserved function and FVC ≥80%

— Modest slowing of ALSFRS-R decline

— Monitor for sulfite hypersensitivity

— Intrathecal, monthly

— Only for SOD1-mutation–positive ALS — confirm with genetic testing first

— Reduces neurofilament light chain; functional benefit emerging

— Sialorrhea: glycopyrrolate (preferred, less CNS), atropine drops SL, amitriptyline; refractory → botulinum toxin to parotid/submandibular glands

— Pseudobulbar affect: dextromethorphan-quinidine (first-line, FDA-approved); SSRI/TCA alternatives

— Spasticity: baclofen, tizanidine; intrathecal baclofen for severe

— Cramps: mexiletine (best evidence), gabapentin, quinine generally avoided

— Sleep/anxiety: low-dose benzodiazepines, mirtazapine

— Dyspnea/air hunger (end-stage): low-dose opioids (morphine), lorazepam

— Depression: SSRIs; ~50% of patients

— Pain: musculoskeletal — NSAIDs, PT; neuropathic — gabapentin

Disease-modifying therapy (DMT) — modest survival/functional benefit; start early.

Riluzole (first-line, FDA-approved 1995)

Edaravone (free radical scavenger)

Tofersen (SOD1 antisense oligonucleotide)

Sodium phenylbutyrate-taurursodiol (Relyvrio) — voluntarily withdrawn from US market 2024 after negative phase 3; do not select on current exams.

Symptomatic pharmacotherapy

Board pearl: Riluzole is the only oral DMT with clear survival benefit; check LFTs before and during therapy. A test stem with riluzole + rising ALT is asking for drug discontinuation.

Step 3 management: For drooling unresponsive to glycopyrrolate, the next step is botulinum toxin injection into salivary glands — not increased anticholinergics, which worsen secretions' viscosity and cause delirium in elderly.

Supportive Procedures — NIV, PEG, and Communication

— Largest survival benefit of any intervention (~7–13 months) and improves QOL

— Indications (any one):

– FVC <50% predicted

– MIP <60 cm H₂O or SNIP <40 cm H₂O

– Symptomatic orthopnea, morning headache, daytime somnolence

– Nocturnal SpO₂ <88% for ≥5 min or elevated PaCO₂

— Start nocturnally, advance to daytime use as tolerated

— Bulbar dysfunction may limit tolerance — try early before bulbar progression

— Add mechanical insufflation-exsufflation (cough assist) when peak cough flow <270 L/min

— Considered when NIV fails or becomes intolerable

— Prolongs life but does not halt disease; eventual "locked-in" state possible

— Requires extensive informed consent and advance care planning — discuss BEFORE crisis

— Many patients in US decline; preferences must be documented

— Indications: dysphagia with weight loss >5–10%, dehydration, prolonged meal times, aspiration risk

— Place when FVC >50% — procedural risk rises sharply below this; use radiologic (RIG) if FVC lower

— Improves nutrition, medication delivery; survival benefit less clear than NIV

— Does not eliminate aspiration risk (oral secretions remain)

— Early speech-language pathology referral; voice banking before dysarthria advances

— Augmentative and alternative communication (AAC) devices, eye-gaze systems

— Power wheelchair with tilt/recline, head support

— Home modifications, ramps, lifts, hospital bed

Three procedural pillars of ALS care — timing matters enormously.

Noninvasive ventilation (NIV / BiPAP)

Tracheostomy with invasive ventilation

Gastrostomy (PEG/PRG/RIG)

Communication and mobility

CCS pearl: In a CCS case with FVC dropping to 55% and 8% weight loss, the correct sequence is: order PEG placement now (while FVC supports safe procedure) and initiate nocturnal NIV — waiting until FVC <50% increases periprocedural mortality.

Board pearl: NIV improves survival even in bulbar-onset ALS, though tolerance is lower — don't withhold a trial based on bulbar symptoms alone.

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher proportion of bulbar-onset disease

— Faster progression, shorter survival

— Higher comorbidity burden complicates NIV/PEG tolerance

— Cognitive screening essential — ALS-FTD more common; affects capacity for advance directives

— Polypharmacy risk: anticholinergics (for sialorrhea) → delirium, falls, urinary retention

– Prefer topical/sublingual atropine or botulinum toxin over systemic glycopyrrolate in frail elderly

— Carefully weigh tracheostomy — outcomes worse, caregiver burden higher

— Riluzole is hepatically metabolized (CYP1A2)

– Baseline LFTs, then monthly × 3, then every 3 months

– Hold if ALT >5× ULN; discontinue if persistent

– Avoid in active hepatitis or Child-Pugh C

— Edaravone — no significant hepatic dose adjustment but caution

— Avoid hepatotoxic adjuncts (acetaminophen high-dose, certain statins) when possible

— Smoking and caffeine induce CYP1A2 → lower riluzole levels; document intake

— Riluzole: no dose adjustment for mild-moderate CKD; data limited in severe CKD/dialysis

— Edaravone: caution in severe renal impairment; contains sulfites

— Symptomatic drugs to dose-adjust:

– Gabapentin, baclofen, mexiletine — renally cleared, accumulate in CKD → sedation, encephalopathy

– Reduce dose; consider alternative agents

— Avoid NSAIDs for musculoskeletal pain in CKD

— Riluzole + theophylline, ciprofloxacin, fluvoxamine (CYP1A2 inhibitors) → toxicity

— Riluzole + omeprazole, rifampin (inducers) → reduced efficacy

— Anticholinergics + opioids → constipation, ileus, delirium

Elderly patients (>75) with ALS

Hepatic impairment

Renal impairment

Drug interactions to flag

Step 3 management: In an 80-year-old with ALS, mild CKD, and sialorrhea, the safest first choice is botulinum toxin to salivary glands rather than oral glycopyrrolate, minimizing anticholinergic burden and delirium risk.

Board pearl: A rising ALT on a patient newly started on riluzole = recheck in 2 weeks, hold if >5× ULN, not immediate permanent discontinuation.

Special Populations — Young-Onset, Familial, and Pregnancy Considerations

— Comprises ~5% of cases; more often familial or genetic

— Workup should include:

– Hexosaminidase A (late-onset Tay-Sachs — proximal weakness, cerebellar signs, psychiatric features)

– SMA (survival motor neuron gene) — pure LMN, treatable with nusinersen/risdiplam/onasemnogene

— Kennedy disease (SBMA) — X-linked, men, gynecomastia, perioral fasciculations, androgen insensitivity, CAG repeat in AR gene

– Hereditary spastic paraplegia — pure UMN, slowly progressive

— Refer for genetic counseling; implications for siblings and offspring

— ~10% of cases; autosomal dominant typically

— C9orf72 hexanucleotide repeat — most common, often with FTD

— SOD1 mutations — eligible for tofersen

— TARDBP (TDP-43), FUS — younger onset, aggressive

— Predictive testing in asymptomatic relatives requires formal genetic counseling, psychological support, and informed consent

— Discuss reproductive options: preimplantation genetic diagnosis (PGD), prenatal testing

— Rare given peak age; small case series

— Pregnancy does not accelerate ALS progression in most reports

— Respiratory reserve already compromised — third-trimester diaphragm splinting risky

— Medication concerns:

– Riluzole — pregnancy category C, animal toxicity; avoid if possible; shared decision-making

– Edaravone, tofersen — limited data

– Baclofen — possible neonatal withdrawal

– Benzodiazepines — late pregnancy → neonatal sedation

— Delivery planning: anesthesia (succinylcholine contraindicated — hyperkalemia from denervation); regional anesthesia preferred

— Breastfeeding: limited data; case-by-case

Young-onset ALS (<40 years)

Familial ALS

Pregnancy and ALS

Key distinction: Kennedy disease (SBMA) mimics bulbar ALS in men but features gynecomastia, sensory involvement on NCS, and an absence of UMN signs — and has a much more benign course. Missing this distinction is a classic exam trap.

Board pearl: Succinylcholine is contraindicated in ALS due to upregulated extrajunctional acetylcholine receptors → life-threatening hyperkalemia. Document this in any preoperative note.

Complications and Adverse Outcomes

— Chronic hypoventilation → hypercapnia, morning headaches, cognitive slowing

— Aspiration pneumonia — recurrent; reduces survival sharply

— Acute respiratory failure — often precipitated by infection, sedatives, or PEG-related events

— Pulmonary embolism — immobility-related, underrecognized

— Atelectasis from weak cough; mucus plugging

— Malnutrition and sarcopenia — independently shorten survival

— Dehydration, electrolyte derangement

— Aspiration during eating — even with PEG, oral secretions cause aspiration

— Falls and fractures (femur, hip)

— Frozen shoulder, contractures

— Pressure ulcers in advanced immobility

— Neuropathic and nociceptive pain — present in up to 70% despite ALS being "painless"

— Anarthria — total loss of speech; mitigated by early AAC and voice banking

— Locked-in syndrome after tracheostomy

— Depression (~50%), anxiety, hopelessness

— Caregiver burnout — independently predicts hospitalization

— ALS-FTD (~15%): behavioral disinhibition, executive dysfunction

— Affects decision-making capacity for NIV, PEG, code status decisions — assess early

— Sedentary, paretic limbs → DVT risk elevated

— Prophylaxis controversial; consider in acute hospitalization

— Opioid/benzodiazepine over-sedation → CO₂ retention

— Anticholinergic delirium from sialorrhea regimens

— PEG complications: buried bumper, peritonitis, aspiration during placement when FVC low

— NIV intolerance, skin breakdown, claustrophobia

Respiratory complications — leading cause of death

Nutritional complications

Musculoskeletal/positional

Communication and psychosocial

Cognitive/behavioral

Venous thromboembolism

Iatrogenic complications

Step 3 management: A patient with ALS presenting with new fever, productive cough, and hypoxia → aspiration pneumonia until proven otherwise; cover with ampicillin-sulbactam or ceftriaxone + metronidazole, assess swallow, hold oral intake, escalate respiratory support, and reassess goals of care.

Board pearl: Sudden cognitive change in advanced ALS is more often hypercapnia than dementia — check ABG or end-tidal CO₂ before attributing to FTD.

When to Escalate Care — Hospitalization, ICU, and Consults

— Aspiration pneumonia with hypoxia or sepsis

— Acute hypercapnic respiratory failure (somnolence, confusion, headache, PaCO₂ rising)

— Failed PEG placement or PEG-site complications

— Severe dehydration / malnutrition requiring IV access and feeding initiation

— Falls with fracture or head injury

— Suicidal ideation or acute psychiatric decompensation

— Caregiver collapse — sometimes the genuine reason; arrange respite/SNF rather than ICU

— Goals-of-care discussion BEFORE intubation whenever possible

— Many patients have advance directives declining intubation/tracheostomy — honor them

— If intubated emergently, early extubation onto NIV is preferred when feasible

— Avoid succinylcholine (hyperkalemia); use rocuronium with sugammadex reversal

— Sedation strategy must account for profound CO₂ retention risk with opioids/benzos

— Neurology/neuromuscular — diagnosis and longitudinal care

— Pulmonology — NIV titration, secretion management, tracheostomy planning

— Gastroenterology / interventional radiology — PEG/RIG

— Speech-language pathology — swallow, communication, voice banking

— Nutrition — caloric optimization, enteral feeding regimens

— Physical and occupational therapy — mobility, contracture prevention, equipment

— Palliative care — early, alongside DMT

— Psychiatry — depression, pseudobulbar affect, capacity assessment

— Social work — advance directives, home health, disability, hospice referral

— Genetics — familial cases

— FVC <30%, significant nutritional decline, refusing NIV/PEG, or rapidly progressive disease with prognosis ≤6 months

Outpatient ALS care is the norm; escalation triggers must be recognized early.

Indications for hospitalization

ICU considerations

Consultations to obtain

Hospice criteria (Medicare)

CCS pearl: An ALS patient brought to the ED with somnolence and respiratory acidosis — the first move is NIV with BiPAP, not intubation, after rapid review of advance directives and code status. Skipping the directive review is a CCS deduction.

Step 3 management: Initiate palliative care and hospice referral when NIV/PEG are declined, FVC <30%, or function deteriorates rapidly — these are concurrent with, not replacement for, medical therapy.

Key Differentials — Other Motor Neuron and Motor Unit Diseases

— Pure UMN disease; no LMN signs after 4 years

— Slower progression, much longer survival (decades)

— Spastic paraparesis, spastic dysarthria, pseudobulbar affect

— Some progress to ALS over years

— Pure LMN disease; no UMN signs

— Asymmetric limb weakness, atrophy, fasciculations

— Slightly longer survival than typical ALS

— Many eventually develop UMN signs and reclassify as ALS

— Bulbar-onset ALS variant; rapidly progressive dysarthria/dysphagia

— Often evolves into classical ALS

— Pure LMN, asymmetric, upper limb predominant

— Conduction block on NCS — defining feature

— Anti-GM1 antibodies in ~50%

— Treatable: IVIG — substantial response

— No UMN signs, no bulbar involvement, no sensory loss

— SMN1 gene mutation; younger onset typically

— Pure LMN, symmetric proximal weakness

— Treatable: nusinersen, risdiplam, onasemnogene abeparvovec

— X-linked, men only

— CAG repeat in androgen receptor gene

— Bulbar + limb LMN signs, perioral fasciculations, gynecomastia, androgen insensitivity, mild sensory involvement

— Much slower, more benign than ALS

— Young men, distal upper limb monomelic amyotrophy

— Cervical flexion-induced myelopathy; nonprogressive after years

— MRI in flexion shows anterior dural displacement

— Decades after polio; new weakness in previously affected muscles

— Slow, restricted to old polio distribution

Within the motor neuron/motor unit spectrum, distinguish ALS from these mimics:

Primary lateral sclerosis (PLS)

Progressive muscular atrophy (PMA)

Progressive bulbar palsy

Multifocal motor neuropathy (MMN) — DON'T MISS

Spinal muscular atrophy (SMA)

Kennedy disease (Spinobulbar muscular atrophy, SBMA)

Hirayama disease

Post-polio syndrome

Key distinction: MMN (conduction block, anti-GM1, IVIG-responsive) is the single most important "don't miss" mimic of pure-LMN ALS — always check NCS for conduction block before finalizing ALS diagnosis.

Board pearl: A young man with bulbar weakness, gynecomastia, and perioral fasciculations = Kennedy disease, not ALS. Send androgen receptor CAG repeat testing.

Key Differentials — Non–Motor Neuron Mimics

— UMN legs + LMN arms (Hoffmann, hyperreflexic legs, Babinski, wasted hand intrinsics)

— Often sensory symptoms (numb hands, Lhermitte), gait ataxia, bowel/bladder dysfunction

— No tongue/bulbar involvement

— MRI cervical spine confirms — disc/osteophyte cord compression

— Treat surgically — decompression reverses or halts progression

— Fatigable, fluctuating weakness; ptosis, diplopia, bulbar

— Reflexes preserved, no atrophy, no fasciculations

— AChR (or MuSK) antibodies; decrement on RNS; ice-pack test

— Responds to pyridostigmine, immunotherapy, thymectomy

— Proximal weakness with autonomic features, areflexia that improves with exercise

— VGCC antibodies; small-cell lung cancer association

— EMG: incremental response at high-frequency RNS

— Age >50, slowly progressive

— Asymmetric weakness of finger flexors and quadriceps

— Elevated CK (modest), inflammatory + rimmed vacuoles on biopsy

— Resistant to immunotherapy; mimics ALS but is myopathic on EMG

— Symmetric proximal and distal weakness with sensory loss, areflexia

— NCS: demyelinating features (slowing, prolonged distal latencies)

— Treatable: IVIG, steroids, plasma exchange

— Pain, dermatomal sensory loss, segmental weakness

— Relapsing, sensory + motor + visual; central demyelination on MRI

— Reversible mimics — must screen

— Subacute LMN syndrome; antibody panels (anti-Hu); search for malignancy

Look outside the motor neuron when sensory, autonomic, or fluctuating features appear.

Cervical spondylotic myelopathy (most common ALS mimic on Step 3)

Myasthenia gravis

Lambert-Eaton myasthenic syndrome

Inclusion body myositis (IBM)

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Polyradiculopathy / structural spine disease

Multiple sclerosis

Thyrotoxicosis, vitamin B12 deficiency, copper deficiency, lead toxicity

Paraneoplastic motor neuronopathy

Step 3 management: A 60-year-old with hand wasting, hyperreflexic legs, and vibratory sense loss with neck pain → order MRI cervical spine first; surgical decompression, not ALS workup, is the priority.

Key distinction: Sensory findings, fluctuation, areflexia, or treatment response all push the diagnosis AWAY from ALS toward a treatable mimic — never anchor on ALS until mimics are excluded.

Long-Term Care Plan, Secondary Prevention, and Discharge Planning

— Riluzole 50 mg BID — continue with LFT monitoring

— Edaravone if eligible — continue if tolerating

— Tofersen monthly intrathecal if SOD1+

— Symptom-targeted drugs (glycopyrrolate, baclofen, dextromethorphan-quinidine, etc.) titrated

— Discontinue medications that no longer serve goals (statins, aspirin, bisphosphonates in late disease) — reduce pill burden

— Annual influenza

— Pneumococcal (PCV20 or PCV15 + PPSV23)

— COVID-19 per current schedule

— RSV in age-eligible adults

— Tdap if due

— Target stable weight, high-calorie diet (hypermetabolism)

— Enteral nutrition via PEG when oral intake inadequate

— Thickened liquids/altered textures per SLP

— Vitamin D, calcium for bone health

— NIV nightly, escalating daytime use

— Cough assist (MI-E) for secretion clearance

— Suction equipment at home

— Power wheelchair with tilt/recline

— Hospital bed, Hoyer lift, shower chair

— Home modifications (ramps, grab bars)

— Eye-gaze AAC device

— Advance directive, POLST/MOLST, healthcare proxy — completed and updated

— Code status documented; tracheostomy preferences explicit

— Hospice planning and triggers identified in advance

— Confirm home equipment delivery (NIV, suction, cough assist)

— Home health, PT/OT, SLP visits arranged

— Follow-up with ALS clinic within 2–4 weeks

— Caregiver education on suctioning, NIV, feeding pump, emergencies

— Written action plan for choking, respiratory distress, equipment failure

ALS has no cure; "secondary prevention" means preventing complications and preserving function.

Ongoing medication regimen at every visit, reconcile

Vaccinations (essential — respiratory infections kill)

Nutrition plan

Pulmonary plan

Mobility and equipment

Psychosocial/legal

Discharge from hospital

Step 3 management: Every ALS discharge should include NIV equipment, suction, cough assist, home health, advance directive on file, pneumococcal/influenza vaccination, and follow-up in multidisciplinary clinic within 2–4 weeks.

Board pearl: Vaccination against respiratory pathogens is among the highest-yield "secondary prevention" interventions in ALS — pneumonia is a leading cause of death.

Follow-Up, Monitoring, and Rehabilitation/Counseling

— Multidisciplinary ALS clinic every 3 months (sooner if rapid decline)

— Earlier visits in first 6 months after diagnosis, during respiratory transitions, or after PEG placement

— Home health visits weekly to monthly in advanced disease

— Telemedicine integrated for mobility-limited patients

— Weight and BMI — trend with every visit

— ALSFRS-R — bulbar, fine motor, gross motor, respiratory subscales

— FVC (sitting and supine), MIP, SNIP, peak cough flow

— Overnight oximetry or capnography periodically

— Swallowing function (clinical SLP exam ± video fluoroscopy)

— Skin integrity (pressure areas), contractures, ROM

— Mood, cognition (ALS-specific cognitive/behavioral screen)

— Caregiver burden screen

— PT: range of motion, gentle aerobic activity (do not induce fatigue), gait aids, contracture prevention

— OT: ADL adaptations, splinting, energy conservation

— SLP: swallow strategies, communication training, voice banking before dysarthria

— Respiratory therapy: NIV titration, cough assist training, secretion management

— Aim is maintenance and adaptation, not strengthening (overexertion may worsen weakness)

— Diagnosis disclosure — protected, unhurried, ideally with family present, written summary

— Realistic prognosis with prognostic ranges, not single numbers

— Treatment options including DMT, NIV, PEG, tracheostomy — and the right to decline

— Goals-of-care revisited at every major transition

— Driving cessation when reaction time/grip compromised

— Sexual health, intimacy — often overlooked

— Financial counseling — Social Security disability, Medicare, long-term care insurance

— Genetic counseling for family members

— ALS Association chapters, ALS clinic social workers

— Online communities, equipment loan programs

— Caregiver respite, bereavement services

Recommended cadence

Monitoring parameters at each visit

Rehabilitation

Counseling content

Support resources

Step 3 management: A patient declining 3 ALSFRS-R points/month with FVC dropping 7% per visit needs acceleration of clinic visits to every 4–6 weeks, urgent NIV/PEG decisions, and hospice referral discussion.

Board pearl: Voice banking must occur before dysarthria meaningfully progresses — once speech is unintelligible, the window has closed. Refer to SLP at diagnosis.

Ethical, Legal, and Patient Safety Considerations

— Begin at diagnosis, before cognitive or communication decline

— Document specifically: intubation, tracheostomy, long-term mechanical ventilation, CPR, artificial nutrition/hydration, antibiotics for pneumonia

— Revisit at every major transition (FVC drop, PEG, hospitalization)

— POLST/MOLST form completed and accessible across care settings

— Up to 50% have executive dysfunction; ~15% have frank FTD

— Assess capacity formally when major decisions arise (PEG, tracheostomy, hospice)

— Capacity is decision-specific — a patient may have capacity for one decision but not another

— Identify healthcare proxy/durable power of attorney early, while patient can communicate preferences

— Tracheostomy/long-term ventilation: must disclose possibility of locked-in state, dependence on caregivers, inability to wean; many regret consent given in crisis

— Genetic testing: presymptomatic relatives require pretest counseling, exploration of insurance/employment implications (GINA protects health insurance and employment, not life/disability/long-term care insurance)

— Disease-modifying trials: explain that benefits may be modest; avoid therapeutic misconception

— Patients on long-term NIV or tracheostomy retain the right to withdraw ventilatory support

— Ethically equivalent to withholding; requires palliative sedation planning to prevent air hunger

— Physician-assisted death is legal in some US states under specific eligibility criteria — know your state law; mandatory waiting periods and capacity requirements apply

— Aspiration during meals — SLP-guided diets, supervised feeding

— Falls — home safety assessment, equipment

— Medication errors — caregiver education, pill organizers, simplified regimens

— NIV mask/equipment failures — backup equipment, 24/7 vendor contact

— Sedative-induced respiratory depression — careful opioid/benzodiazepine titration

— Hospitalization frequently disrupts NIV/PEG routines — bring home equipment when possible

— ED clinicians may not know advance directive — bring printed copy

— Handoffs to hospice must include detailed symptom-management plan

— Counsel patients on cessation when motor/cognitive function compromised

— Document discussion; state-specific reporting requirements vary

— Assist with Social Security disability (ALS qualifies for compassionate allowance — expedited, no waiting period for Medicare)

— Workplace accommodation under ADA

Advance care planning — central to ALS ethics

Decision-making capacity

Informed consent edge cases

Withdrawal of life-sustaining treatment

Patient safety risks

Transition-of-care risks

Driving and firearms

Mandatory reporting / disability

Step 3 management: A patient with ALS-FTD whose family wants tracheostomy he previously declined → defer to the previously documented advance directive made with capacity; the family does not override prior autonomous wishes. Involve ethics consultation if conflict persists.

High-Yield Associations and Rapid-Fire Clinical Facts

— C9orf72 hexanucleotide repeat — most common genetic cause; ALS-FTD overlap

— SOD1 — first identified; tofersen target

— TARDBP (TDP-43) — encodes the pathologic protein found in 97% of ALS brains

— FUS — younger onset, aggressive

— TDP-43 cytoplasmic inclusions in motor neurons — hallmark finding

— Bunina bodies, ubiquitinated inclusions

— Loss of Betz cells (motor cortex) and anterior horn cells

— Riluzole: glutamate inhibitor, +3 months survival, LFT monitoring

— Edaravone: free radical scavenger

— Tofersen: antisense oligonucleotide for SOD1

— Dextromethorphan-quinidine for pseudobulbar affect

— Glycopyrrolate for sialorrhea (does not cross BBB)

— Succinylcholine contraindicated (hyperkalemia)

— Worse: bulbar-onset, older age, rapid ALSFRS-R decline, low BMI, early respiratory involvement, FTD

— Better: limb-onset, younger age, normal BMI, slow decline

Genetics

Pathology

Pharmacology pearls

NIV: largest survival benefit; start at FVC <50%, MIP <60, or orthopnea

PEG: best placed while FVC >50%; use RIG when FVC lower

Prognostic signs

Compassionate allowance: ALS qualifies for Medicare without 24-month wait and expedited SSDI

Multidisciplinary clinic: independently prolongs survival

Eye movements and sphincter function are spared in ALS — even in late disease (basis for eye-gaze communication)

Split hand sign: thenar/FDI wasting > hypothenar — highly specific

Frontotemporal dementia overlap: 15% frank FTD, up to 50% subtle executive dysfunction

El Escorial → Gold Coast criteria (2020) — simplified, more sensitive

Hexosaminidase A screen in young patients

ALS-FTD = C9orf72 most common; behavioral variant FTD predominantly

Riluzole CYP1A2 metabolism: smokers/caffeine reduce levels; ciprofloxacin/fluvoxamine increase

Cough peak flow <270 L/min → start cough assist

Mexiletine — best evidence for cramps in ALS

Step 3 management: When a Step 3 vignette mentions "painless asymmetric weakness, atrophy, fasciculations, hyperreflexia, and tongue fasciculations in a 60-year-old" — answer is EMG/NCS and MRI cervical spine for diagnosis, then riluzole + multidisciplinary clinic referral.

Board pearl: Eye movements and sphincters are spared until very late — a vignette with early ophthalmoplegia or incontinence is NOT ALS (think MG or myelopathy).

Board Question Stem Patterns

"62-year-old man with 8 months of progressive right hand weakness, now spreading to right foot. Exam: atrophy and fasciculations of right hand intrinsics, hyperreflexia in right leg, Babinski sign, normal sensation. Next best step?"

→ EMG/NCS + MRI cervical spine; then refer to neuromuscular.

"70-year-old woman with slurred speech, choking on liquids, 6 kg weight loss. Exam: tongue atrophy with fasciculations, brisk jaw jerk. Diagnosis?"

→ Bulbar-onset ALS. Initiate SLP eval, swallow study, PFTs, NIV planning, early PEG.

"ALS patient with FVC 45%, morning headaches, daytime sleepiness. Next step?"

→ Initiate nocturnal NIV (BiPAP).

"FVC 55%, 9% weight loss, prolonged meals. Next step?"

→ Place PEG now, while FVC supports safe placement.

"55-year-old man with asymmetric LMN-only arm weakness, no UMN signs. NCS shows conduction block. Best management?"

→ IVIG for multifocal motor neuropathy — not ALS.

"Hand wasting, hyperreflexic legs, neck pain, vibratory loss in feet. Next step?"

→ MRI cervical spine; surgical decompression if compressive lesion.

"45-year-old man with bulbar weakness, gynecomastia, perioral fasciculations, mild sensory loss on NCS."

→ Androgen receptor CAG repeat testing.

"ALS patient laughs uncontrollably at funeral. Treatment?"

→ Dextromethorphan-quinidine.

→ Botulinum toxin injection to salivary glands.

"Patient on riluzole 2 months, ALT 6× ULN. Next step?"

→ Hold riluzole, recheck; discontinue if persistent.

"ALS patient needs emergency surgery. Anesthetic to avoid?"

→ Succinylcholine (hyperkalemia risk).

"ALS patient previously documented refusal of intubation; family demands it during respiratory failure."

→ Honor advance directive; offer NIV, palliative measures.

"30-year-old with ALS and brother with FTD." → C9orf72 testing + genetic counseling.

"ALS patient asks about Medicare wait." → Compassionate allowance; no 24-month wait.

Stem 1 — Classic presentation

Stem 2 — Bulbar-onset

Stem 3 — Respiratory failure trigger

Stem 4 — PEG timing

Stem 5 — Mimic — MMN

Stem 6 — Mimic — cervical myelopathy

Stem 7 — Mimic — Kennedy disease

Stem 8 — Pseudobulbar affect

Stem 9 — Sialorrhea unresponsive to glycopyrrolate

Stem 10 — Riluzole monitoring

Stem 11 — Surgery in ALS

Stem 12 — Advance directive conflict

Stem 13 — Familial ALS

Stem 14 — Disability benefits

CCS pearl: On a CCS case, the order set "EMG, NCS, MRI C-spine, CBC, CMP, TSH, B12, CK, neurology consult, multidisciplinary referral, riluzole, NIV when FVC<50%, PEG planning, advance directive discussion, palliative care" hits the high-yield management spine for ALS.

One-Line Recap

High-yield bullet recaps:

— UMN + LMN signs in same region without sensory loss; Gold Coast criteria; EMG confirms acute denervation + chronic reinnervation in ≥2 regions

— MRI C-spine to exclude myelopathy; NCS to exclude MMN (conduction block, anti-GM1, IVIG-treatable)

— Split hand sign, tongue fasciculations, brisk reflexes in wasted limb

— Noninvasive ventilation — start at FVC <50%, MIP <60, orthopnea, or nocturnal hypoventilation (largest survival benefit, +7–13 months)

— Multidisciplinary ALS clinic — independently prolongs life

— Riluzole 50 mg BID with LFT monitoring (+3 months)

— Adequate nutrition / PEG placed while FVC >50%

— Edaravone in early disease, tofersen if SOD1+

— Sialorrhea → glycopyrrolate → botulinum toxin

— Pseudobulbar affect → dextromethorphan-quinidine

— Spasticity → baclofen; cramps → mexiletine

— Dyspnea → low-dose opioids; depression → SSRIs

— Succinylcholine contraindicated (hyperkalemia)

— Advance directive at diagnosis, specifying tracheostomy/intubation preferences

— Capacity may be limited by ALS-FTD (15% frank, up to 50% subtle)

— ALS qualifies for Medicare compassionate allowance — no 24-month wait

— Cervical spondylotic myelopathy, MMN, MG, Kennedy disease, IBM, CIDP, B12/copper deficiency

ALS is a progressive, painless, purely motor neurodegenerative disease defined by coexisting upper and lower motor neuron signs in the same body region, diagnosed clinically with EMG support after excluding treatable mimics, and managed with riluzole, early noninvasive ventilation, timely PEG, and multidisciplinary supportive care framed by ongoing advance care planning.

Diagnostic essence

Survival-extending interventions (in order of impact)

Symptom management essentials

Safety and ethics

Don't-miss mimics

Board pearl: If the vignette features painless asymmetric weakness + mixed UMN/LMN + tongue fasciculations + normal sensation + spared eye movements, the answer is ALS — confirm with EMG, exclude mimics with MRI C-spine and NCS, start riluzole, refer to multidisciplinary clinic, and initiate advance care planning today.