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KembaraXtra-Medicine – Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative neuromuscular condition of undetermined etiology that affects the corticospinal tracts and anterior horn cells, resulting in dysfunction of both upper motor neurons (UMNs) and lower motor neurons (LMNs). Synonyms include Lou Gehrig disease, ALS, and motor neuron disease. The ICD-10CM code is G12.21 (Amyotrophic lateral sclerosis).
ALS incidence is about two new cases per 100,000 persons per year. Onset is usually between 50 and 70 years, and the male-to-female ratio is 1.8:1. The estimated prevalence is 5.2 per 100,000 population.
Clinical presentation typically includes a combination of LMN signs—weakness, hypotonia, muscle wasting, fasciculations, and hyporeflexia or areflexia—and UMN signs—loss of fine motor dexterity, spasticity, extensor plantar responses, hyperreflexia, and clonus. Extraocular movements, sensation, and bowel and bladder function are typically preserved. Patients may develop dysarthria, dysphagia, pseudobulbar affect, and frontal lobe dysfunction. Respiratory insufficiency progresses to respiratory failure and death, typically late in the disease. Concomitant frontotemporal dementia occurs in about 15%, and executive dysfunction occurs in another 50%. Pseudobulbar affect (inappropriate crying or laughing not triggered by typical emotional cues) is common and treatable.
ALS commonly manifests in one of three onset patterns. Limb onset accounts for 75%–80% of cases and presents with painless muscle weakness, clumsiness (dropping things, stumbling, falling), impaired fine motor skills (e.g., writing), limb stiffness, gait disturbances, and wristdrop or footdrop. Bulbar onset accounts for 20%–25% and presents with dysarthria or voice change, pseudobulbar affect, dysphagia and/or weight loss, drooling, and choking during swallowing. Respiratory onset occurs in <3% and presents with dyspnea on exertion or at rest, orthopnea, daytime sleepiness, difficulty sleeping, other symptoms of respiratory compromise. als makes up about 90% adult-onset motor neuron diseases; disease presentations include progressive muscular atrophy, primary lateral sclerosis, bulbar palsy, pseudobulbar als-parkinsonism-dementia complex.< />pan>
Regarding etiology and classification, 90% of cases are sporadic and 10% are familial. Known genetic mutations include C9orf72 hexanucleotide repeat expansion (responsible for ~40% of familial ALS among those of European origin and nearly 10% of sporadic ALS, and virtually all ALS cases associated with frontotemporal dementia), SOD1 (copper-zinc superoxide dismutase) mutations (~12% of familial cases), TAR DNA-binding protein mutations (~4% of familial cases), and FUS (~4% of familial cases, rarely associated with frontotemporal dementia), among many others. Risk is increased in Whites, non-Hispanics, age >60 years, family history of ALS, and prior exposure to heavy metals, pesticides, or BMAA. A practical classification includes sporadic/acquired ALS variants (classic spinal-onset, Mills hemiplegic variant, pseudoneuritic, flail-arm, monomelic, UMN onset, LMN onset, bulbar onset, dyspnea onset, progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy, Western Pacific ALS) and multiple familial ALS subtypes (ALS1 through ALS25 and additional rare-mutation forms). An FTD-ALS overlap is also recognized (e.g., ALS-FTD associated with C9orf72; and FTD with some ALS features associated with tau and progranulin genes on chromosome 17).
The differential diagnosis includes multifocal motor neuropathy with conduction block; cervical spondylotic myelopathy with polyradiculopathy; spinal stenosis with lumbosacral nerve root compression; chronic inflammatory demyelinating polyneuropathy with CNS lesions; syringomyelia; syringobulbia; foramen magnum tumor; meningeal carcinomatosis; spinal muscular atrophy; polyglucosan body disease; bulbospinal muscular atrophy (Kennedy disease); monomelic amyotrophy; Lyme disease; and ALS-like syndromes reported with lead intoxication, HIV, hyperparathyroidism, hyperthyroidism, lymphoma, and vitamin B12 deficiency.
Diagnosis is based on clinical findings, electromyography results, and exclusion of alternative causes. Workup includes MRI of brain and spine to exclude mimics; electromyography and nerve conduction studies following Revised El Escorial criteria; assessment of respiratory function (forced vital capacity [FVC], negative inspiratory force); assessment of swallowing and nutritional status; and neuropsychologic testing if executive dysfunction or FTD is a concern. The Revised El Escorial criteria require evidence of LMN degeneration (clinical, electrophysiologic, or neuropathologic), evidence of UMN degeneration (clinical), and progressive spread of symptoms/signs within or between regions, together with absence of electrophysiologic/pathologic evidence of another disease explaining UMN/LMN degeneration and absence of neuroimaging evidence of another explanatory disease process. Levels of certainty include Definite ALS (UMN and LMN signs in three regions), Probable ALS (UMN and LMN signs in two regions with UMN signs rostral to LMN signs), Probable ALS—Laboratory Supported (UMN signs in one or more regions with LMN signs by EMG in at least two regions), and Possible ALS (UMN and LMN signs in one region together, or UMN signs in two or more regions, or UMN and LMN signs in two regions without UMN signs rostral to LMN signs).
Laboratory tests that may be considered include vitamin B12, thyroid function, parathyroid hormone, and HIV, plus serum protein electrophoresis with immunofixation. In pure LMN syndromes, consider DNA studies for spinal muscular atrophy, bulbospinal atrophy (Kennedy disease), and hexosaminidase levels (late-onset Tay-Sachs). A 24-hour urine heavy metal screen may be done if indicated. In familial ALS, genetic studies should be performed with appropriate genetic counseling. Imaging is guided by clinical scenario; MRI brain and spinal cord help exclude structural mimics, and a modified barium swallow evaluates aspiration risk.
Treatment includes symptomatic management plus disease-modifying therapy that slows progression in some patients. Symptomatic treatment options span multiple domains: fatigue (pyridostigmine bromide, antidepressants, methylphenidate, amantadine, modafinil; energy conservation, work modification, sleep study with BiPAP if abnormal), spasticity (baclofen, tizanidine, dantrolene sodium, diazepam; physical therapy, range-of-motion exercises, botulinum toxin), jaw clenching (benzodiazepines, botulinum toxin into masseters), cramps (quinine sulfate, baclofen, vitamin E, clonazepam; massage, physical therapy), fasciculations (carbamazepine and reassurance), sialorrhea (hyoscyamine sulfate, diphenhydramine, scopolamine patch, glycopyrrolate, atropine, TCAs; suction machine, botulinum toxin into salivary glands, parotid radiation therapy, steam inhalation, nebulization, dark grape juice), pseudobulbar laughing/crying (TCAs, SSRIs, L-dopa/carbidopa, lithium, mirtazapine, venlafaxine, quinidine/dextromethorphan), thick phlegm (guaifenesin, nebulized N-acetylcysteine, nebulized saline, propranolol; insufflation-exsufflation, high-flow chest wall oscillation therapy, cool mist humidifier, rehydration, pineapple/papaya juice, reduced dairy/caffeine/alcohol), aspiration (cisapride and modified food consistency; in severe cases tracheostomy or modified laryngectomy with tracheal diversion), joint pains (anti-inflammatory drugs, analgesics, range-of-motion and heat), depression (TCAs; SSRIs/venlafaxine/mirtazapine/bupropion; counseling, support groups, psychiatry), insomnia (zolpidem tartrate, lorazepam, opioids, TCAs; pressure air pad/gel mattress; noninvasive ventilation where appropriate), laryngospasm (sublingual lorazepam), respiratory failure (bronchodilators, morphine sulfate; hospital bed, nocturnal noninvasive ventilator, IPPB), and constipation (increase oral fluids, Metamucil, Dulcolax suppositories, lactulose/other laxatives, exercise, “power pudding” of prune juice/prunes/applesauce/bran).
Nonpharmacologic therapy is central. Noninvasive ventilation can improve quality of life and may increase tracheostomy-free survival in patients with respiratory difficulty (orthopnea or FVC ≤50% predicted). Percutaneous endoscopic gastrostomy (PEG) can improve nutrition, stabilize weight, and ease medication administration; some studies suggest it may prolong life by 1–4 months, especially when placed before FVC falls to ≤50% predicted. Supportive services include nutrition support, speech therapy, physical and occupational therapy, suction devices for sialorrhea, cough assist devices for ineffective cough and airway clearance, and computerized assistive communication devices. Early advance-care planning discussions should address living will, resuscitation orders, preferences regarding PEG and tracheostomy, and long-term care options, and patients should be encouraged to connect with local support groups.
Disease-modifying medications do not cure ALS but can slow progression in selected patients. Riluzole (glutamate antagonist) was the first FDA-approved medication shown to extend tracheostomy-free survival; typical dosing is 50 mg every 12 hours, taken at least 1 hour before or 2 hours after meals, and it prolongs survival by about 2–3 months; ALT monitoring is recommended monthly for the first 3 months, then every 3 months until completion of the first year, and periodically thereafter. Edaravone (FDA approved 2017) slowed physical decline by 33% versus placebo in a 6-month phase III trial; it is given IV with an initial cycle of daily infusions for 14 days followed by 14 days off, then subsequent cycles of 10 infusions over 14 days followed by 14 days off; cost and insurance coverage can be limiting. Relyvrio (sodium phenylbutyrate/taurursodiol) is an FDA-approved oral fixed-dose combination (approved 2022) for adults with ALS that helps slow progression; its exact mechanism is unknown, but it targets endoplasmic reticulum and mitochondria-dependent neuronal degeneration pathways, and is thought to reduce neuronal death and dysfunction.
Chronic management includes targeted symptom control such as treating sialorrhea with glycopyrrolate or amitriptyline (and considering propranolol or metoprolol if secretions are thick), using botulinum toxin if refractory; treating spasticity with baclofen, tizanidine, or clonazepam; and treating pseudobulbar affect with amitriptyline, sertraline, or dextromethorphan/quinine.
Disposition reflects the progressive nature of ALS: there is currently no cure, mean symptom duration is 3-5 years, and about 20% of patients survive more than 5 years. Referral to a neurologist experienced in neuromuscular disease is recommended to confirm diagnosis, and multidisciplinary ALS clinics may improve survival. Gastroenterology referral for PEG placement is recommended while FVC remains >50% to reduce procedural morbidity, and pulmonology referral is appropriate for noninvasive ventilation such as BiPAP.
Pearls include the importance of patient-physician communication at diagnosis and throughout care, and the value of a multidisciplinary supportive approach to improve daily functioning and independence. Related content includes patient information resources on ALS.
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