Glenn A. Mackin, MD, FAAN, FACP
DESCRIPTION
- Amyotrophic lateral sclerosis (ALS), or “Lou Gehrig's Disease,” is a neurodegenerative disease of unknown cause of corticospinal upper motor neurons (UMNs), brainstem bulbar motor neurons, and spinal cord lower motor neurons (LMNs), causing progressive skeletal muscle weakness.
- Recently recognized, measurable cognitive impairments develop in up to half of ALS patients, from mild to full frontotemporal dementia (FTD).
- ALS starts in a bulbar or limb muscle, spreads to contiguous spinal segments. Progressive loss of strength proceeds at a constant rate in affected persons and varies substantially between individuals. Death usually occurs by progressive ventilatory failure.
EPIDEMIOLOGY
Incidence
- 2 per 100,000/year
- All ages: Highest between 45 and 70 years, mean approximately 60, uncommon under age 40
- Overall male predominance 1.5:1, especially in younger age groups; closer to 1:1 over age 60
- Fairly uniform geographic and ethnic distribution; highest incidence in Caucasians
Prevalence
- 6 per 100,000 (approximately 30,000 in the US)
RISK FACTORS
- Slim body habitus
- History of varsity or professional sports
- Cigarette smoking
- Environmental factors
- ALS–Parkinson–dementia complex of Guam
- Gulf war service
- Exposure to heavy metals, radiation, pesticides, electricity
- Occupations (crafts, trade workers)
- Lymphoma with M protein
- Other neurodegenerative diseases in family
Genetics
- Familial ALS (FALS, 5–10% of all ALS): Younger onset, mean 45. Some subtypes, rapid.
- Multiple mutations; most autosomal dominant.
- 20% of FALS is due to a mutation in copper zinc superoxide dismutase (SOD1) gene.
- 2–5% TARDBP (TDP-43) gene mutations.
Pregnancy Considerations
- Prenatal gene tests (SOD1 in 1–2% of all ALS)
PATHOPHYSIOLOGY
- Loss of motor neurons with intraneuronal ubiquitin-positive inclusions in degenerating UMNs and TDP-43 reactive inclusions in LMNs
- Variable TDP-43 inclusions in frontal neurons
ETIOLOGY
- Unknown
- Suspected interplay between aberrant gene expression, aging, and environmental triggers
- Cause of cell death—upon which dramatically effective pharmacotherapy depends—is unknown
- Proposed mechanisms: Oxidative stress, excitotoxicity, proteosomes, mitochondrial dysfunction, impaired axonal transport, protein aggregation, inflammation, neurotrophic factor deficiency, retroviruses, and accelerated apoptosis
COMMONLY ASSOCIATED CONDITIONS
- FTD
- In ALS, measurable neuropsychological deficits eventually in 50%, dementia in 5–10%
- May follow, overlap, or precede weakness
- Abnormal intraneuronal TDP-43 expression
- Loss of executive function, lack of empathy for caregivers, euphoria, apathy, maladaptive
- Relative preservation of episodic memory, language, and visuospatial capabilities
HISTORY
- Progressive painless weakness and atrophy without numbness in 1 or more limbs
- Progressive dysarthria, dysphagia, or dyspnea
- Muscle fasciculations, cramps (esp. calves)
- Gait unsteadiness and/or hand clumsiness
- Weight loss (usually mild in early onset of disease)
PHYSICAL EXAM
- UMN signs: Hyperreflexia, spasticity, Babinski's sign, emotional lability (pseudobulbar affect)
- LMN signs: Weakness, hyporeflexia, atrophy, diffuse fasciculations, flaccidity, cramps (calves)
- Bulbar (ALS onset 20–30%): Tongue atrophy or fasciculations, dysarthria (flaccid or spastic), jaw jerk/gag (reduced or hyperactive), dysphagia
- Respiratory: Exertional dyspnea, orthopnea
- Chronic ventilatory insufficiency: Heralded by fitful sleep, orthopnea, nightmares, morning headache, drowsiness, change in snoring
- Cognitive: Frontotemporal dysfunction
- El Escorial Criteria [C] (World Federation of Neurology): Progressive weakness or electromyographic (EMG) signs in bulbar, cervical, thoracic, lumbosacral “regions”
- Definite ALS: UMN and LMN signs in 3 regions (bulbar + 2 spinal or 3 spinal)
- Probable ALS: UMN and LMN signs in 2 regions, some UMN rostral to LMN
- Possible ALS: UMN and LMN signs in 1 region
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
- No confirmatory serologic or CSF test for ALS
- EMG and nerve conductions: Mandatory test!
- Looking for evidence of denervation in 3 body regions (bulbar, individual limbs, trunk)
- May show widespread acute and/or chronic LMN axon loss that is not clinically apparent
- Lab tests performed in most patients
- CBC, comprehensive metabolic panel (CMP), CK (normal or mildly elevated)
- ESR, antinuclear antibody (ANA), rheumatoid factor (RF), thyroid stimulating hormone (TSH), parathyroid hormone (PTH), B12
- SIEP/SIFX, UIEP/UIFX (monoclonal)
- Optional tests, based on suspicion and risks
- Gene tests (if possibility of familial ALS is present)
- Lyme titer, rapid plasma reagin (RPR), and/or HIV-1/2 titer
- 24-hour urine heavy metal test (lead, mercury)
- Acetylcholine receptor antibody (bulbar)
- Purely LMN presentations
- GM1 ganglioside antibody (high titers, 40–60% multifocal motor neuropathy, MMN)
- SBMA gene (spinal bulbar muscular atrophy)
- SMN gene (survival of motor neurons 1, 2)
- Hexosaminidase A deficiency (multisystem)
- Purely UMN presentations
- HTLV-1 (tropical spastic paraparesis)
Follow-Up & Special Considerations
- Breaking the news
- Give the diagnosis in person, never by phone (B)
- Discuss implications, respect background (B)
- Give written information, support groups (B)
Imaging
Initial Approach
- Cervical MRI (to exclude cervical stenosis, especially if all UMN and LMN signs occur below neck)
- Brain, thoracic, lumbosacral MRI (as needed)
Diagnostic Procedures/Other
- Muscle biopsy: EMG of chronic myopathy may mimic denervation [e.g., inclusion-body myositis (IBM), dystrophies]; ALS biopsy confirms acute/chronic denervation.
- Lumbar puncture: In atypical cases, CSF may show meningeal lymphoma, carcinomatosis, and Lyme.
DIFFERENTIAL DIAGNOSIS
- ALS phenotype
- Familial ALS (often autosomal dominant)
- ALS with lymphoproliferative disease, monoclonal gammopathy, other malignancies
- ALS-like disease with HIV infection
- ALS–Parkinson–dementia complex (Guam)
- LMN disorders
- Progressive muscular atrophy (PMA): Adult onset; minimal bulbar signs; slower than ALS, similar course, and care. “PMA” LMN onset often develops UMN signs of ALS
- Spinal muscular atrophy: Autosomal recessive (5q11.2–13.3); from birth to young adult. More copies of SMN2 predict longer survival
- Spinal bulbar muscular atrophy (SBMA, “Kennedy's disease”): X-linked, CAG trinucleotide repeat in androgen receptor gene; young adults; slow, proximal > distal LMN signs; chin fasciculation; gynecomastia
- Viral: Poliomyelitis, enteroviruses, West Nile
- UMN disorders
- Primary lateral sclerosis (PLS): Rare, occurring in sporadic middle age/older; purely UMN signs; spastic dysarthria, dysphonia, dysphagia, gait; normal EMG; slower than ALS, but most “PLS” onset will develop LMN signs of ALS
- Hereditary spastic paraplegia (HSP)
- Viral myelopathies: HIV-1 and 2, HTLV-1
- Disorders that may be confused with ALS
- Structural myelopathy (especially at cervical but also at thoracic and lumbosacral levels)
- Lumbosacral or thoracic spinal stenosis
- B12 deficiency (subacute combined degeneration)
- Copper deficiency (gastric bypass, nutritional)
- IBM: Occurring in older males > females; slowly progressive weakness of finger and hip flexors; possible dysphagia
- MMN: Sporadic antibody-mediated multifocal demyelinating motor neuropathy; occurring in middle aged and older patients; male > female; weakness out of proportion to atrophy; nerve conduction study (NCS), motor conduction blocks, high-titer GM1 ganglioside antibody (50%)
- Chronic inflammatory demyelinating polyneuropathy
- Amyotrophies (diabetic, inflammatory, tumor)
- Neuromuscular junction: Myasthenia, Lambert–Eaton myasthenic syndrome (LEMS)
- Heavy metal intoxication
- Hyperthyroidism, hyperparathyroidism
- Benign cramp-fasciculation syndrome
- CNS diseases: Cerebrovascular disease, multiple sclerosis (MS)
- Multisystem CNS: Hexoaminidase A deficient (adult Tay–Sachs), Creutzfeldt–Jakob, progressive supranuclear palsy, corticobasal degeneration, diffuse Lewy body disease, multiple systems atrophy, neurosyphilis
MEDICATION
First Line
- Riluzole: FDA-approved, disease-modifying ALS drug; 3-month survival advantage in placebo trials (2)[A]; mechanism uncertain; expensive
- Dosing: 50 mg PO q12h
- Cautions: Impaired hepatic or renal function
- Side effects: Fatigue, nausea, diarrhea
- Stop statins if possible, deleterious in ALS [C]
Second Line
- All unproven, but commonly used by patients
ADDITIONAL TREATMENT
General Measures
- Accurate diagnosis is essential to enable the patient and family to come to terms with diagnosis
- Compassion in “breaking the news” is the basis for trust essential to optimal ALS care (2)[B]
- Early diagnosis prevents unnecessary surgery
- Second diagnostic opinions are indispensable for any question and to help some reach “cloture”
- Multidisciplinary ALS care optimizes symptom management and access to adaptive measures
- Intervention by ALS-specialized neurologist, ALS nurse, case manager, therapy services [physical therapy (PT), occupational therapy (OT), speech/swallowing, nutrition], pastoral/spiritual care
- Promptly treat new and changing symptoms
- Broach early and periodically review end-of-life wishes [percutaneous endoscopic gastrostomy (PEG), intubation, long-term ventilation, LTV] advance directives, and power-of-attorney
- Respite care and psychological support for spouse or caregiver; ALS support groups are helpful
- Keep vaccinations current (flu, Pneumovax)
- Respect patient's right to refuse or withdraw any treatment, including mechanical ventilation
Issues for Referral
- Outpatient PT/OT, speech/swallowing, VNA
- Communication specialist (voice synthesizers)
- Wheelchair clinic (power chairs) and orthotists
- PRN: Pulmonary, physiatry, psychiatry, heme
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Dyspnea
- Initiate noninvasive ventilatory support [using bilevel positive airway pressure (biPAP)] >4 hours/night, if symptoms of hypoventilation exist (2)[B]. Indications are dyspnea, daytime sleepiness, morning headaches, awakenings, or if forced vital capacity (FVC) <50%
- Nocturnal biPAP: Prolongs survival if used >4 hours nightly, especially initiated if FVC >50% (2)[B]. Nasal O2 is not germane
- Elevate head of bed or home hospital bed
- Promptly treat emerging respiratory infection
- Ensure palliative/hospice care at end-of-life, whether LTV is declined or withdrawn. Treat dyspnea with opioids alone or with oxygen; anxiety with anxiolytics (2)[B]
- Speech: Communication aids range from low tech (notepads, letter boards) to high tech (voice synthesizers, headset laser pointer)
- Sialorrhea: Glycopyrrolate, benztropine, hyocosine, trihexyphenidyl, atropine, amitriptyline (2)[C]. Also, suction, parotid botulinium injections, scopolamine patches
- Parotid radiation may cause excess dryness
- Thick phlegm: Cough assist devices, suction, acetylcysteine, propranolol, and guaifenesin
- Nasal congestion, postnasal drip: Loratadine
- Dysphagia: Consider placing PEG as soon as symptomatic. Optimal safety and efficacy for PEG placement when FVC >50% (2)[B]
- Spasticity: Lioresal, tizanidine, diazepam
- Cramps: Calcium/magnesium/zinc, quinine sulfate, gabapentin, vitamin E (2)[C]
- Pain control [immobility, degenerative joint disease (DJD)]: NSAID, opioid
- Cognitive (FTD): Family understanding key; consider donepezil, behavioral medications
- Depression and anxiety: Antidepressants, anxiolytics, psychiatry/psychology liaison
- Pseudobulbar affect: Dextromethorphan–quinidine (2)[A]; amitriptyline, fluoxetine
- Insomnia: Consider nocturnal hypoventilation, sleep apnea, depression, anxiety, and/or pain
- Constipation: Stool softener, fiber, laxatives
- Adjunctive treatment
- Durable goods: Ankle foot orthosis (AFO), resting splint, cane, walker, wheelchairs (manual, motorized), head support (head drop), hospital beds
- Home adaptation: Chair lifts, stair glides, shower benches, grab bars, ramps, and vans
- Surgery/other procedures
- Muscle biopsy, PEG tube, tracheostomy
- Botulinium injections (parotid, masseter)
IN-PATIENT CONSIDERATIONS
Admission Criteria
- Avoid hospitalization, as much as possible
- Verify hospital, intubation wish before need
- Pneumonia (biPAP may avoid intubation)
- PEG placement, teaching on care and use
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- ALS clinic: Every 3 months, sooner as needed
- FVC, weight, assess dysphagia—at each visit
- On riluzole, LFTs and CBC every 3–6 months
- Hospice (home, inpatient): Initiate well before end stage for symptom control, end-of-life comfort
DIET
- Food consistency: Monitor swallow function
- Weight stability: Administer supplements, PEG formula
PATIENT EDUCATION
- ALS Association, 1275 K Street NW, Suite 1050 Washington, DC 20005. Website: www.alsa.org
PROGNOSIS
- Average disease duration to death is 3 years; lesser than 10% survive more than 10 years
- Survival after onset: Bulbar 2–3, limb 3–5, years
