Neurology & Internal Medicine & Palliative Care
Amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS)—known as Lou Gehrig’s disease in North America (named after the famous baseball player who died of the disease in 1941) or Charcot’s disease in France (Jean-Martin Charcot having provided the first clinical and pathological description in 1869) — is the most common neurodegenerative motor neuron disease in adults, characterized by the progressive and irreversible degeneration of central (cortical—corticospinal tract) and peripheral (anterior horn of the spinal cord and motor nuclei of the brainstem) motor neurons, leading to progressive muscle weakness + fasciculations + muscle atrophy + spasticity + and ultimately to total paralysis, including the respiratory muscles. With a global incidence of 2 to 3 cases per 100,000 people per year, a prevalence of 6 to 8 per 100,000, a median age of onset between 55 and 65 years, and a slight male predominance (M:F = 1.5:1), ALS is a rare but devastating disease with a median survival of 2 to 5 years from the onset of symptoms—with 10 to 15% of patients surviving more than 10 years (including Stephen Hawking—an exceptional survival of over 50 years). The pathophysiology is multifactorial and not fully understood, involving pathological protein aggregation (ubiquitinated TDP-43—present in 97% of ALS + FUS + SOD1 cases), glutamatergic excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, and axonal transport abnormalities. In 5–10% of cases, ALS is familial (fALS) with identified mutations in the SOD1 (20% of fALS) and C9orf72 (expansion of GGGGCC hexanucleotide repeats—the most common mutation — 40% of fALS + 5–10% of sporadic ALS) + TARDBP + FUS. The lack of a curative treatment + the invariably fatal progression + and the extraordinary psychological and physical impact on patients and families make ALS an emblematic disease of palliative medicine—where the central goal is to maintain quality of life + independence + and dignity for as long as possible.
Clinical Manifestations – Signs of Upper and Lower Motor Neuron
- Signs of the peripheral motor neuron progressive muscle weakness + fasciculations (spontaneous visible muscle twitches + pathognomonic of denervation) + muscle cramps + amyotrophy (muscle atrophy) + hypotonia + areflexia or hyporeflexia in the affected areas
- Signs of the central motor neuron (CMN - corticospinal pathway): spasticity (hypertonia + resistance to passive mobilization) + hyperactive osteotendinous reflexes + Babinski sign + Hoffmann sign (hand) + emotional lability (involuntary laughter or crying due to damage to corticobulbar tracts – pseudobulbar affect)
- Bulbar (brainstem) involvement: dysarthria (slurred, nasal, or explosive speech) + dysphagia (difficulty swallowing + risk of aspiration pneumonia) + sialorrhea (excessive saliva production due to inability to swallow saliva) + atrophy and fasciculations of the tongue + vocal cord paralysis → 25–30% of ALS cases begin with bulbar involvement (late-onset bulbar ALS — poorer prognosis)
- Respiratory impairment Diaphragm + intercostal muscles + abdominal muscles → nocturnal hypoventilation (desaturation + apnea) → dyspnea on exertion then at rest + orthopnea + progressively reduced forced vital capacity (FVC) → respiratory failure → main cause of death in ALS
- Preserved functions: cognitive functions (in 85–90% of cases, the patient remains fully conscious and lucid) + eye movements (the oculomotor muscles remain intact until the terminal stages—allowing for communication via eye-tracking) + bladder and bowel control (generally preserved) + sensation (no sensory impairment)
- FTD-SLA (frontotemporal dementia associated) 5–15% of ALS patients develop concomitant frontotemporal dementia (FTD) → behavioral disturbances + apathy + disinhibition + executive cognitive impairments → particularly common in association with the C9orf72 mutation
Revised El Escorial Criteria (Gold Coast 2020)
- Gold Coast Criteria (2020 Simplification): SLA diagnosis with presence of signs of motor neuron dysfunction in at least one region (bulbar + cervical + thoracic + lumbosacral) + progressive evolution over at least 6 months + exclusion of other diagnoses
- Diagnostic Categories (El Escorial Revised): Clinically defined ALS (UMN + LMN in ≥ 3 regions) + Clinically probable ALS (UMN + LMN in ≥ 2 regions) + Possible ALS (UMN + LMN in 1 region) + Laboratory-supported ALS (EMG)
- EMG (electromyogram): Basic exam + signs of acute denervation (fibrillation potentials + positive sharp waves) + chronic denervation (polyphasic motor potentials + long duration + high amplitude) + fasciculations + in several different root territories → confirms diffuse motor neuron disease + EMG cannot detect motor neuron disease (that's the clinical exam)
- Brain and spinal cord MRI Excluding differential diagnoses (tumor + MS + syringomyelia + spinal cord compression + inflammatory myopathy) + FLAIR hyperintensity of corticospinal tracts (sign of LMN involvement) + motor cortex atrophy
- Biological tests : NFS + ionogram + creatinine + blood glucose + CK (elevated in ALS due to denervation) + TSH + vitamin B12 + HIV serology + HTLV-1 serology (infectious para-ALS) + anti-GM1 antibodies (multifocal motor neuropathy - treatable differential diagnosis) + genetic testing (C9orf72 + SOD1 if familial form or young patient)
Pharmacological disease-modifying treatment
- Riluzole (Rilutek®) — the only approved treatment since 1995: Mechanism: Blocks presynaptic glutamate release + blocks voltage-gated sodium channels → reduced glutamatergic excitotoxicity + Dosage: 50 mg x 2/day orally + Efficacy: prolongs median survival by 2 to 3 months (modest but statistically significant) + slightly slows progression + better tolerated in the early phase + Adverse effects: asthenia + nausea + monitoring of transaminases (hepatotoxicity) every 3 weeks for 3 months, then monthly
- Édaravone (Radicava®) — FDA approved 2017 + Health Canada 2018: Mechanism: free radical scavenger (antioxidant) → reduction of oxidative stress + Dosage: IV 60 mg/day × 10 days/cycle or oral formulation (suspension) + efficacy: slowing of functional decline (ALSFRS-R) in a selected subpopulation (early stage + FVC ≥ 80% 1-second peak flow + probable or confirmed ALS) → modest benefit + very high cost + limited access in Canada
- Tofersen (Qalsody®) — FDA 2023 — SOD1-related ALS: antisense oligonucleotide (ASO) → reduces mutant SOD1 expression + approved for ALS with confirmed SOD1 mutation + administration: intrathecal every 4 weeks + reduction in neurodegeneration biomarkers (serum NfL) + ongoing clinical progression data + first treatment targeting the genetic cause in ALS
- AMX0035 (Relyvrio® — FDA 2022 + withdrawn 2024): sodium phenylbutyrate + tauroursodeoxycholic acid → initially FDA approved + but withdrawn from market May 2024 after confirmatory trial failure → do not prescribe
Symptomatic and multidisciplinary care
| Problem | Support |
|---|---|
| Respiratory failure | Lung function test every 3 months → NIV (non-invasive ventilation—BiPAP mask) if lung function < 50% of predicted value + or nocturnal symptoms + or PaCO₂ > 45 mmHg → improves quality of life + survival + tracheostomy and invasive ventilation (personal decision + lifelong intensive care) |
| Dysphagia and nutrition | Speech therapy + modification of food texture + percutaneous endoscopic gastrostomy (PEG) if FEV1 ≥ 50% (acceptable anesthetic risk) → maintenance of nutrition + quality of life + radiologically guided gastrostomy if FEV1 < 50% |
| Drooling | Scopolamine transdermal patch OR glycopyrrolate OR amitriptyline (anticholinergic) OR botulinum toxin injections into the salivary glands (very effective) |
| Spasticity | Baclofen orally 10–80 mg/day (gradual titration) + tizanidine + dantrolene + physiotherapy + stretching |
| Cramps and twitching | Quinine (use with caution) + magnesium sulfate + mexiletine + gentle exercise + hydration |
| Emotional lability (pseudobulbar affect) | Dextromethorphan + quinidine (Nuedexta®) → FDA approved for pseudobulbar affect + or SSRIs (fluoxetine + sertraline) |
| Communication | Early speech therapy + augmentative communication devices (tablet + eye-tracking — eye control of communication devices if limbs are paralyzed) + voice banking (recording before speech loss) |
| Pain | Appropriate analgesics (paracetamol + NSAIDs + opioids if necessary) + physiotherapy + positioning + morphine at end of life for refractory dyspnea |
ℙ️
NIV (non-invasive ventilation) is the therapeutic intervention with the greatest impact on quality of life and survival in ALS—surpassing riluzole in terms of survival prolongation (an additional 3 to 7 months). It should be offered as soon as the first signs of hypoventilation appear (FVC < 50% FVR3Y + nocturnal desaturations + orthopnea + daytime hypercapnia) and not only in the terminal phase. The discussion regarding tracheotomy and prolonged invasive ventilation should be initiated early in the course of care, before an acute respiratory crisis, to respect the patient’s autonomy in decision-making.
Palliative care and end-of-life support
- Advance care planning Early discussion about patient's wishes regarding ventilation (NIV + tracheostomy + invasive ventilation) + artificial nutrition (gastrostomy) + cardiopulmonary resuscitation + place of death → advance medical directives (AMD) in Quebec → draft at diagnosis while the patient has full decision-making capacity
- SLA Multidisciplinary Team Neurologist + Pulmonologist + Gastroenterologist + Speech Therapist + Physical Therapist + Occupational Therapist + Nutritionist + Social Worker + Psychologist + Liaison Nurse + Palliative Care → ALS Multidisciplinary Clinic Follow-up (available in Quebec university centers)
- Medical Aid in Dying (MAID) in Quebec: ALS is one of the serious and incurable medical conditions that may meet the eligibility criteria for MAID in Quebec (End-of-Life Care Act) → respectful discussion without pressure + the physician does not have to bring up this subject spontaneously but must answer the patient's questions
- Morphine for refractory dyspnea: Low-dose morphine (2.5–5 mg SC or PO every 4 h + titration) is the most effective treatment for relieving end-of-life dyspnea, does not precipitate death at analgesic doses, and allows for a comfortable death.
Neurological consultation recommended
Consult a neurologist urgently if progressive muscle weakness in a limb, fasciculations (visible muscle twitches under the skin), and progressive onset of dysarthria or dysphagia develop in an adult over 40 years of age without an obvious cause. These signs suggest a motor neuron disease requiring urgent neurological assessment (EMG + MRI + biological tests) to confirm or exclude ALS. For rapid referral to neurology and support for families affected by ALS, Clinique Omicron offers consultations at its service points in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
Consult at Clinique Omicron
Clinique Omicron's physicians and nurse practitioners (NPs) recognize the early signs of ALS (fasciculations + progressive weakness + dysarthria), refer to specialized neurology for diagnostic workup (EMG + MRI + genetic testing), support patients and families in symptom management (sialorrhea + spasticity + pain + insomnia), participate in drafting advance medical directives, coordinate with palliative care teams, and support informal caregivers in their crucial role. Consultations are available at several service locations in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The content of this page is provided for informational purposes only and does not replace the advice of a doctor or a neurologist specializing in neuromuscular diseases. ALS is a complex and progressive disease requiring follow-up in a specialized multidisciplinary clinic. NIV should be proposed early, before a respiratory crisis – do not wait for acute respiratory distress to discuss it with the patient.
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