Lateral Sclerosis(Motor Neuron Disease)Amyotrophic

Amyotrophic Lateral Sclerosis(Motor Neuron Disease)

Amyotrophic lateral sclerosis (ALS) is the most common form of progressive motor neuron disease. It is a prime example of a neurodegenerative disease and is arguably the most devastating of the neurodegenerative disorders.

Pathology

The pathologic hallmark of motor neuron degenerative disorders is death of lower motor neurons (consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons

Etiology of Motor Neuron Disorders
Diagnostic Category Investigation
Structural lesions
Parasagittal or foramen magnum tumors
Cervical spondylosis
Spinal cord arteriovenous malformation
MRI scan of head (including foramen magnum and cervical spine)
Infections
Bacterial—tetanus, Lyme
Viral—poliomyelitis, herpes zoster
CSF exam, culture
Lyme titer
Anti-viral antibody
Retroviral—myelopathy HTLV-1 titers
Intoxications, physical agents
Toxins—lead, aluminum, others
Drugs—strychnine, phenytoin
Electric shock, x-irradiation
24-hour urine for heavy metals
Serum lead level
Immunologic mechanisms
Plasma cell dyscrasias
Autoimmune polyradiculopathy
Motor neuropathy with conduction block
Paraneoplastic
Paracarcinomatous
Complete blood count
Sedimentation rate
Total protein
Anti-GM1 antibodies
Anti-Hu antibody
MRI scan, bone marrow biopsy
Metabolic
Hypoglycemia
Hyperparathyroidism
Hyperthyroidism
Deficiency of folate, vitamin B12, vitamin E
Deficiency of copper, zinc
Malabsorption
Mitochondrial dysfunction
Fasting blood sugar
Routine chemistries including calcium
PTH
Thyroid functiona
Vitamin B12, vitamin E, folatea
Serum zinc, coppera
24-h stool fat, carotene, prothrombin time
Fasting lactate, pyruvate, ammonia
Consider mtDNA
Hyperlipidemia Lipid electrophoresis
Hyperglycinuria Urine and serum amino acids
CSF amino acids
Hereditary disorders
Superoxide dismutase
TDP43
FUS/TLS
Androgen receptor defect (Kennedy’s disease)
Hexosaminidase deficiency
Infantile -glucosidase deficiency (Pompe’s)
WBC DNA for mutational analysis
Sporadic Motor Neuron Diseases
Chronic
Upper and lower motor neuron
Predominantly upper motor neuron
Predominantly lower motor neuron
Entity
Amyotrophic lateral sclerosis
Primary lateral sclerosis
Multi focal motor neuropathy with conduction block
Motor neuropathy with paraproteinemia or cancer
Motor predominant peripheral neuropathies
Other
Associated with other neurodegenerative disorders
Secondary motor neuron disorders (see Table 374-1)
Acute
Poliomyelitis
Herpes zoster
Coxsackie virus

Clinical Manifestations

The manifestations of ALS are somewhat variable. With lower motor neuron dysfunction and early denervation, Typically the first evidence of the disease is insidiously developing asymmetric weakness, usually first evident distally in one of the limbs. A detailed history often discloses recent development of cramping with volitional movements, typically in the early hours of the morning (e.g., while stretching in bed). Weakness caused by denervation is associated with progressive wasting and atrophy of muscles and, particularly early in the illness, spontaneous twitching of motor units, or fasciculations.When the initial denervation involves bulbar rather than limb muscles, the problem at onset is difficulty with chewing, swallowing, and movements of the face and tongue. Early involvement of the muscles of respiration may lead to death before the disease is far advanced elsewhere. Dysarthria and exaggeration of the motor expressions of emotion. The latter leads to involuntary excess in weeping or laughing (pseudobulbar affect).
Virtually any muscle group may be the first to show signs of disease, but, as time passes, more and more muscles become involved until ultimately the disorder takes on a symmetric distribution in all regions. Even in the late stages of the illness, sensory, bowel and bladder, and cognitive functions are preserved. In some families, ALS is co-inherited with frontotemporal dementia, characterized by early behavioral abnormalities with prominent behavioral features indicative of frontal lobe dysfunction.
A committee of the World Federation of Neurology has established diagnostic guidelines for ALS. Essential for the diagnosis is simultaneous upper and lower motor neuron involvement with progressive weakness, and the exclusion of all alternative diagnoses

Epidemiology

The illness is relentlessly progressive, leading to death from respiratory paralysis; the median survival is from 3–5 years. There are very rare reports of stabilization or even regression of ALS. In most societies there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per 100,000. While ALS is overwhelmingly a sporadic disorder, some 5–10% of cases are inherited as an autosomal dominant trait.

Familial ALS

Several forms of selective motor neuron disease are inheritable. Apart from its inheritance as an autosomal dominant trait, it is clinically indistinguishable from sporadic ALS.

Differential Diagnosis

Because ALS is currently untreatable, it is imperative that potentially remediable causes of motor neuron dysfunction be excluded (see table above).
Rarely, ALS develops concurrently with features indicative of more widespread neurodegeneration. Thus, one infrequently encounters otherwise typical ALS patients with a parkinsonian movement disorder or dementia.

Differential Diagnosis

Because ALS is currently untreatable, it is imperative that potentially remediable causes of motor neuron dysfunction be excluded (see table above).
Rarely, ALS develops concurrently with features indicative of more widespread neurodegeneration. Thus, one infrequently encounters otherwise typical ALS patients with a parkinsonian movement disorder or dementia.

Treatment: Amyotrophic Lateral Sclerosis

Lateral Sclerosis(Motor Neuron Disease)Amyotrophic

No treatment arrests the underlying pathologic process in ALS. The drug riluzole (100 mg/d) was approved for ALS because it produces a modest lengthening of survival. In one trial, the survival rate at 18 months with riluzole was similar to placebo at 15 months. Riluzole is generally well tolerated; nausea, dizziness, weight loss, and elevated liver enzymes occur occasionally. consequently, multiple therapies are presently in clinical trials for ALS. These include studies of ceftriaxone, which may augment astroglial glutamate transport and thereby be anti-excitotoxic, and pramipexole and tamoxifen, which are neuroprotective. Interventions such as antisense oligonucleotides (ASO) that diminish expression of mutant SOD1 protein prolong survival in transgenic ALS mice and rats and are also now in trial for SOD1-mediated ALS.
In the absence of a primary therapy for ALS, a variety of rehabilitative aids may substantially assist ALS patients. Foot-drop splints facilitate ambulation by obviating the need for excessive hip flexion and by preventing tripping on a floppy foot. Finger extension splints can potentiate grip. Respiratory support may be life-sustaining. For patients electing against long-term ventilation by tracheostomy, positive-pressure ventilation by mouth or nose provides transient (several weeks) relief from hypercarbia and hypoxia. Also extremely beneficial for some patients is a respiratory device (Cough Assist Device) that produces an artificial cough. This is highly effective in clearing
airways and preventing aspiration pneumonia. When bulbar disease prevents normal chewing and swallowing, gastrostomy is uniformly helpful, restoring normal nutrition and hydration. Fortunately, an increasing variety of speech synthesizers are now available to augment speech when there is advanced bulbar palsy. These facilitate oral communication and may be effective for telephone use.