Residency · Residency · Neurology

Amyotrophic Lateral Sclerosis: Diagnosis and Multidisciplinary Care

Overview

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting both upper motor neurons (UMN) and lower motor neurons (LMN). It has an incidence of approximately 2 per 100,000 per year and a prevalence of 5-7 per 100,000. The median age of onset is 55-65 years with a slight male predominance. Median survival from symptom onset is 3-5 years, though the range extends from months to decades. Approximately 10% of ALS is familial while 90% is sporadic. There is no cure; management relies on supportive multidisciplinary care with only modest disease-modifying therapy available.

Clinical Presentation

Upper Motor Neuron Signs

Upper motor neuron involvement produces spasticity, hyperreflexia, and clonus. Pathologic reflexes including Babinski and Hoffmann signs are present. Pseudobulbar affect manifests as involuntary laughing or crying disproportionate to the underlying emotion. Speech becomes slow and spastic in quality.

Lower Motor Neuron Signs

Lower motor neuron involvement causes weakness and muscle wasting (atrophy). Fasciculations are often widespread and accompanied by muscle cramps. Reflexes may be reduced or absent in severely denervated regions.

Patterns of Onset

Limb onset accounts for approximately 70% of cases and presents with asymmetric weakness in one limb, such as foot drop, hand weakness, or shoulder weakness, which then progresses to adjacent body segments. Bulbar onset accounts for approximately 25% of cases and presents with dysarthria and/or dysphagia as the initial symptoms; it carries a worse prognosis and is more common in older women. Respiratory onset is rare (approximately 5%) and presents with dyspnea or orthopnea before limb weakness develops, carrying the worst prognosis. Flail arm and flail leg variants show predominantly LMN involvement in a specific distribution and may have slower progression.

What ALS Does NOT Affect (Until Very Late)

Extraocular muscles are spared, so there is no diplopia or ptosis. Sphincter function is preserved, with urinary and bowel control maintained. Sensory function is unaffected, with no numbness or pain from sensory nerve involvement. Cognitive function is preserved in many patients, but up to 50% have some degree of cognitive or behavioral impairment along the ALS-FTD spectrum.

ALS-FTD Spectrum

Approximately 15% of ALS patients meet full criteria for frontotemporal dementia, predominantly the behavioral variant (bvFTD). An additional 35% have subclinical cognitive or behavioral changes. The C9orf72 hexanucleotide repeat expansion is the most common shared genetic cause of both conditions. FTD may precede, coincide with, or follow the onset of motor neuron disease.

<image>Diagram showing the spectrum of motor neuron disease phenotypes from pure UMN (primary lateral sclerosis) through classic ALS to pure LMN (progressive muscular atrophy), with the ALS-FTD overlap</image>

Diagnostic Criteria

Gold Coast Criteria (2019 -- Simplified)

The Gold Coast criteria require progressive motor impairment documented by history or clinical examination, the presence of UMN and LMN signs in at least one body region (or LMN signs in at least two body regions), and investigations that exclude other diagnoses. These criteria were designed to be more sensitive than prior criteria, facilitating earlier diagnosis.

Revised El Escorial Criteria (Historical)

The El Escorial system classified ALS as clinically definite when UMN and LMN signs were present in 3 body regions, and clinically probable when UMN and LMN signs were in 2 regions with UMN signs rostral to LMN signs. The body regions considered are bulbar, cervical, thoracic, and lumbosacral. These criteria were criticized for being too restrictive and delaying diagnosis, and they have been largely superseded by the Gold Coast criteria.

Awaji Criteria

The Awaji criteria incorporated electrodiagnostic findings by treating fasciculation potentials as equivalent to fibrillation potentials for evidence of LMN dysfunction. This modification improved sensitivity, particularly for bulbar-onset ALS.

Electrodiagnostic Findings

EMG

EMG in ALS demonstrates acute denervation with fibrillation potentials and positive sharp waves in multiple myotomes, chronic denervation with reinnervation producing large polyphasic motor unit potentials with reduced recruitment, and widespread fasciculation potentials (though these also occur in benign fasciculation syndrome). The key finding is denervation in at least 2 body regions in the setting of clinical UMN signs. Sensory nerve conduction studies are normal, which distinguishes ALS from neuropathies.

NCS

Nerve conduction studies show normal or near-normal sensory nerve conduction, reduced CMAP amplitudes reflecting axonal motor neuron loss, and normal conduction velocities confirming the absence of demyelination.

Differential Diagnosis

Cervical spondylotic myelopathy can produce both UMN signs and LMN signs from root compression; MRI of the spine distinguishes the two. Multifocal motor neuropathy (MMN) causes pure LMN weakness with conduction block on NCS and anti-GM1 antibodies, and is treatable with IVIG. Kennedy disease (SBMA) is X-linked with a CAG repeat expansion in the androgen receptor gene, producing gynecomastia, sensory neuropathy, and slow progression. Inclusion body myositis causes distal weakness (finger flexors, quadriceps) with elevated CK and myopathic EMG. Hirayama disease is a juvenile-onset cervical flexion myelopathy causing non-progressive LMN weakness in the hands. Primary lateral sclerosis shows pure UMN involvement for more than 4 years without LMN signs and has slower progression. Benign fasciculation syndrome produces widespread fasciculations without weakness, atrophy, or EMG denervation.

Genetics of ALS

The C9orf72 hexanucleotide repeat expansion is the most common genetic cause in both familial (approximately 40%) and sporadic (approximately 7%) ALS. It involves a GGGGCC repeat expansion, is associated with ALS-FTD, and causes disease through repeat-associated non-ATG (RAN) translation producing toxic dipeptide repeat proteins. SOD1 mutations account for approximately 20% of familial ALS, represent the first identified ALS gene, and are the target of tofersen. TARDBP encodes TDP-43, whose aggregation is the pathological hallmark of most ALS and FTD. FUS is an RNA-binding protein whose mutations cause aggressive juvenile-onset familial ALS. Genetic counseling should be offered to all ALS patients, especially those with family history or features suggesting genetic forms such as young onset, FTD, or specific phenotypes.

<image>Table of major ALS-associated genes showing gene name, protein, inheritance pattern, frequency, and distinguishing clinical features</image>

Disease-Modifying Therapy

Riluzole

Riluzole is a glutamate release inhibitor and was the first FDA-approved therapy for ALS in 1995. It provides a modest survival benefit of approximately 2-3 months median extension of tracheostomy-free survival. The dose is 50 mg twice daily, available in oral or sublingual (Exservan) formulation. Liver function tests and CBC require monitoring due to hepatotoxicity risk. It should be offered to all ALS patients.

Edaravone (Radicava)

Edaravone is a free radical scavenger FDA-approved in 2017. The original trial showed modest slowing of functional decline in a selected subgroup of patients with early, mild ALS. An oral formulation is available. Its effectiveness remains controversial: a Japanese Phase 3 trial did not meet its primary endpoint, and real-world effectiveness continues to be debated. Clinicians and patients should discuss the uncertain benefit relative to cost and treatment burden.

Tofersen (Qalsody)

Tofersen is an antisense oligonucleotide targeting SOD1 mRNA, receiving FDA accelerated approval in 2023 for SOD1-ALS only (approximately 2% of all ALS). It is administered by intrathecal injection every 4 weeks after loading doses. The VALOR trial did not meet its primary endpoint on the ALSFRS-R but showed significant biomarker improvements including neurofilament light chain reduction, with a clinical benefit signal emerging on longer follow-up. SOD1 genetic testing is now essential for all ALS patients.

Sodium Phenylbutyrate-Taurursodiol (Relyvrio/AMX0035)

This combination targeted mitochondrial and ER stress and received FDA approval in 2022 based on the Phase 2 CENTAUR trial. However, the Phase 3 PHOENIX trial did not confirm efficacy, and the manufacturer voluntarily withdrew the product from the market in 2024. This sequence illustrates the challenge of ALS therapeutics and the importance of confirmatory trials.

Multidisciplinary Clinic Model

Team Members

The multidisciplinary ALS clinic includes a neurologist, pulmonologist, speech-language pathologist, physical therapist, occupational therapist, dietitian, social worker, respiratory therapist, palliative care specialist, and psychologist. Multidisciplinary clinic attendance is associated with an approximately 7-month survival benefit, as demonstrated by Traynor et al.

Respiratory Management

FVC should be monitored at every visit in both sitting and supine positions. Non-invasive ventilation (NIV/BiPAP) should be initiated when FVC falls below 50% predicted, when orthopnea or nocturnal hypoventilation develops (morning headaches, daytime somnolence), or when sniff nasal inspiratory pressure is below 40 cmH2O. NIV improves survival by approximately 7-13 months and improves quality of life, as shown by Bourke et al. Discussion of long-term invasive ventilation (tracheostomy) versus a palliative approach should occur early; only 5-10% of ALS patients in Western countries opt for tracheostomy ventilation. Cough assist devices (mechanical insufflation-exsufflation) help with secretion management.

Nutritional Management

Dysphagia should be assessed at every visit with modified diet texture introduced as needed. Weight loss is an independent negative prognostic factor. PEG tube placement should be considered when swallowing becomes unsafe or weight loss exceeds 10%, ideally while FVC remains above 50% because anesthetic risk increases with lower FVC. Radiologically inserted gastrostomy (RIG) or per-oral image-guided gastrostomy (PIG) are alternatives for patients with low FVC.

Symptom Management

Sialorrhea is managed with glycopyrrolate, atropine sublingual drops, or botulinum toxin injections to salivary glands. Pseudobulbar affect is treated with dextromethorphan/quinidine (Nuedexta). Spasticity is addressed with baclofen, tizanidine, and stretching. Cramps may respond to mexiletine or quinine (with limited evidence). Depression and anxiety are treated with SSRIs and counseling. Pain, which is common from musculoskeletal causes, cramps, and spasticity, is managed with NSAIDs, gabapentin, and opioids in advanced disease. Communication aids including augmentative and alternative communication (AAC) devices and eye-tracking technology maintain the patient's ability to communicate.

Palliative Care Integration

Early palliative care involvement improves quality of life and facilitates end-of-life planning. Advance directives and goals-of-care discussions should be initiated at the time of diagnosis. Hospice referral should occur when appropriate, though the median hospice stay in ALS is unfortunately short. End-of-life management includes opioids and benzodiazepines for dyspnea and distress; withdrawal of NIV is a common mode of death.

<image>Timeline of ALS disease progression showing typical milestones from diagnosis through respiratory support, PEG placement, communication device use, and end-of-life care planning</image>

Clinical Pearls

ALS is a clinical diagnosis supported by electrodiagnostics with no single confirmatory test; the key is demonstrating combined UMN and LMN involvement with progressive spread and exclusion of mimics. Anti-GM1 antibodies should always be checked and NCS performed looking for conduction block to exclude MMN, a treatable mimic of ALS. SOD1 genetic testing should now be performed in all ALS patients because of the availability of tofersen. The split hand sign (preferential thenar greater than hypothenar wasting) is characteristic of ALS and helps distinguish it from cervical radiculopathy or carpal tunnel syndrome. Fasciculations without weakness, atrophy, or denervation on EMG are likely benign fasciculation syndrome, not ALS. Weight loss is an independent prognostic factor, and aggressive nutritional support with early PEG placement improves outcomes. NIV is the single most impactful intervention for survival and quality of life in ALS and should be initiated proactively based on FVC and symptoms, not as a last resort. The ALS Functional Rating Scale-Revised (ALSFRS-R) is the standard clinical trial outcome measure, scored from 48 (normal) to 0 (worst).

References

• Shefner JM, Al-Chalabi A, Baker MR, et al. A proposal for new diagnostic criteria for ALS. Clin Neurophysiol. 2020;131(8):1975-1978. (Gold Coast Criteria)
• Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110.
• Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 2006;5(2):140-147.
• Traynor BJ, Alexander M, Corr B, et al. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996-2000. J Neurol Neurosurg Psychiatry. 2003;74(9):1258-1261.
• Feldman EL, Goutman SA, Petri S, et al. Amyotrophic lateral sclerosis. Lancet. 2022;400(10360):1363-1380.

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