Amyotrophic lateral sclerosis (ALS)

General

Lou Gehrig’s disease

The most common of the motor neuron diseases

A without

Myo muscle

Trophic nourishment

Lateral portion of spinal cord

Sclerosis

Numbers

Prevalence: 4–6/100,000.

Incidence: 0.8–1.2/100,000.

Familial in 8–10% of cases.

Familial cases usually follow autosomal dominant inheritance, but occasionally demonstrate a recessive pattern.

Onset usually after 40 years of age.

Pathophysiology

Usually idiopathic

Advance

Cortical motor cell death due to

Abnormal RNA processing,
SOD1-mediated toxicity,

Superoxide dismutase type 1 (SOD1) is a metalloenzyme that catalyzes the conversion of toxic superoxide radicals to oxygen (O2) and hydrogen peroxide (H2O2)
Damaging accumulation of superoxide could result if SOD1 mutations impaired its antioxidant function.
Protein misfolding — Another hypothesis is that mutant SOD1 induces protein aggregates that are potentially toxic to motor neurons

Excitotoxicity

Excessive activation of glutamate receptors may lead to increased entry of calcium into cells. In turn, intracellular calcium may trigger a cascade of events that causes neuronal cell death via lipid peroxidation, nucleic acid damage, and mitochondrial disruption.

Cytoskeletal derangements
Mitochondrial dysfunction
Viral infections

Poliovirus
Enteroviruses
Exogenous
Inherited endogenous retroviruses

Apoptosis
Growth factor abnormalities,
Inflammatory responses
Others

Cortical motor cells (pyramidal and Betz cells) disappear leading to retrograde axonal loss and gliosis in the corticospinal tract.

(This gliosis results in the bilateral white matter changes sometimes seen in the brain magnetic resonance imaging (MRI) of patients with ALS)

The spinal cord becomes atrophic.

The ventral roots become thin, and there is a loss of large myelinated fibers in motor nerves.

The affected muscles show denervation atrophy with evidence of reinnervation such as fiber type grouping
While sensory involvement is not obvious clinically, the density of myelinated sensory fibers is reduced by approximately 30 percent in peripheral nerves


---
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  layout: dagre
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flowchart TD
    A["Motor neuron (alpha-motoneurons)<br>degeneration and death"] --> B["Replacement by gliosis<br>of lost neurons"]
    B --> C["Spinal cord and brainstem<br>motor nuclei (LMNs)"]
    B --> D["Corticospinal tracts<br>(UMNs)"]
    C & D --> E["Mixed UMN & LMN<br>findings"]
    E --> F["Great variability<br>depending on predominance<br>at any given time"]

Pathology

Loss of Betz cell (Largest pyramidal cell) in motor cortex and brain stem nuclei but this is less striking than anterior horn cell loss.

Bunina bodies

Skein-like inclusions (intracytoplasmic, thread-like structures)

Lewy-like inclusions.

Risk factors

Family history

Cigarette smoking

Clinical features

Progressive muscle wasting

Respiratory difficulty

Weakness

Involvement is of voluntary muscles, sparing the voluntary eye muscles and urinary sphincter.
Classically, presents initially with

Weakness and atrophy of the hands (lower motor neuron)
Spasticity and hyperreflexia of the lower extremities (upper motor neuron).

However, LEs may be hyporeflexic if the lower motor neuron deficits predominate.
Dysarthria and dysphagia are caused by a combination of upper and lower motor neuron pathology.

Fasciculations

Tongue atrophy and fasciculations may also occur.

Although cognitive deficits are generally considered to be absent in ALS, in actuality 1–2% of cases are associated with dementia, and cognitive changes may occasionally predate the usual features of ALS.

Investigations

Not absolutely necessary to make diagnosis in most cases.
Fibrillations and positive sharp waves are found in advanced cases

May be absent early, especially if upper motor neuron pathology predominates

LMN findings in the LE in the absence of lumbar spine disease, or fibrillation potentials in the tongue are suggestive of ALS.

LP (CSF)

Slightly elevated protein.

Treatment

Goal minimizing disability

Risk of aspiration may be reduced with

Tracheostomy
Gastrostomy tube to allow continued feeding
Vocal cord injection with Teflon

Noninvasive ventilation

Improves quality of life
BiPAP spasticity that occurs when upper motor neuron deficits predominate may be treated (usually with short-lived response) with

Baclofen: also may relieve the commonly occurring cramps
Diazepam

Riluzole (Rilutek®)

Inhibits presynaptic release of glutamate, may prolong survival
Doses of 50–200mg/d increases tracheostomy-free survival at 9 & 12 months, but the improvement is more modest or may be non-existent by ≈ 18 months

Edaravone

Initially developed for stroke treatment

Prognosis

Most patients die within 5 years of onset (median survival: 3–4 yrs). Those with prominent oropharyngeal symptoms may have a shorter life-span usually due to complications of aspiration

Differential diagnosis

Cervical spondylotic myelopathy

Feature	ALS (Amyotrophic Lateral Sclerosis)	CSM (Cervical Spondylotic Myelopathy)
Cause	Progressive neurodegenerative disease of upper and lower motor neurons	Chronic, non-traumatic, progressive cervical cord compression due to degenerative spine disease
Clinical Course	Fatal, progressive; most die within 2 years of diagnosis	Progressive; treatable; requires surgery in moderate-severe cases
Motor Symptoms	Weakness, atrophy, fasciculations, spasticity, upper & lower motor neuron signs	Weakness, clumsiness, atrophy, hyperreflexia, spasticity; upper motor neuron signs predominate (anterior horn involvement possible)
Bulbar/Cranial Nerve & Cognitive Involvement	Bulbar signs common: dysarthria, dysphagia, tongue atrophy/fasciculations; up to 50% may exhibit cognitive (especially executive) dysfunction or frontotemporal dementia	No bulbar or cognitive involvement
Sensory Symptoms	Absent	Sensory changes common (paresthesia, numbness) Pure motor forms ("cervical spondylotic amyotrophy") exist and mimic ALS
Diagnostic “Red Flags”	Bulbar/cognitive/behavioral symptoms Rapidly progressive weakness Split-hand atrophy Tongue fasciculations Absence of marked sensory or sphincter signs	Sensory level on exam Typical radiological finding Sphincter dysfunction Absence of bulbar/cognitive features Improvement or stabilization with surgery
Sphincter Dysfunction	Rare in ALS; points against diagnosis if present	Early or significant sphincter dysfunction points toward CSM
EMG/Neurophysiology	Shows widespread denervation (fibrillations, sharp waves), both upper and lower motor neuron features, including unaffected limbs; lower motor neuron degeneration in areas without clinical deficit	Abnormalities confined to compressed spinal segments; EMG and nerve conduction can help exclude ALS and peripheral neuropathies. Special EMG differences: e.g., ulnar/median CMAP ratios, repetitive stimulation more abnormal in ALS; "split hand" and MUNIX tests helpful
Imaging	MRI is normal or shows only muscle atrophy; does not show cord compression	MRI: confirms cord compression (criteria needed for diagnosis); important as imaging alone may not rule out ALS—must correlate with symptoms
Prognosis	Invariably progressive; no disease-modifying cure available	Potential for stabilization or improvement post-surgery; surgical treatment indicated as disease progresses
Treatment	Supportive, multidisciplinary; manage symptoms, maintain nutrition and respiration; surgery not beneficial (may even cause diagnostic delay or iatrogenic intervention)	Physical therapy, immobilization, anti-inflammatories, removal of high-impact activities, followed by surgery (anterior or posterior approach, depending on case) for moderate-severe or progressive disease
Misdiagnosis/Overlap Issues	Very high risk of being misdiagnosed as CSM (CSM is the most common neurologist-made misdiagnosis in ALS); up to 14% undergoes unnecessary surgery; imaging and clinical "red flags" are critical for correct differentiation	CSM can have pure motor forms that closely resemble ALS ("CSA"); when ALS and CSM co-exist, surgical outcomes are poor, and improvement is rare; careful clinical and neurophysiological assessment required