Amyotrophic Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disorder of the anterior horn cells of the spinal cord and the motor cranial nuclei that leads to progressive muscle weakness and atrophy. Although major recent advances have shed light on its etiology, the key mechanisms in both familial and sporadic ALS remain unknown. No cure is known. This article reviews the major breakthroughs in ALS research, the clinical aspects of the disease, and current therapeutic options. An outline of new and promising technology and its application to the understanding of ALS is presented.

Pathophysiology: ALS primarily involves anterior horn cells in the spinal cord and cranial motor nerves. Patients may have weakness of bulbar muscles or of single or multiple limb muscle groups. Presentation is not always bilateral or symmetrical. A predominantly bulbar form usually leads to more rapid deterioration and death. Limb weakness is predominantly distal. Weakness and atrophy of the intrinsic hand muscles are prominent. Weakness progresses to involve the forearms and shoulder girdle muscles and the lower extremities.

Involvement of both upper and lower motor neurons is characteristic. Patients develop variable hyperreflexia, clonus, spasticity, extensor plantar responses, and limb or tongue fasciculations. Wallerian degeneration of corticospinal and corticobulbar tracts may be demonstrated by MRI (high-intensity T2 lesions in frontal lobes) or in postmortem examination. Extraocular muscles and bladder and anal sphincter muscles typically are spared.

ALS rarely affects cognitive functions. Electromyogram (EMG) shows signs of diffuse denervation with generally preserved nerve conduction velocities. Although an inflammatory process may be present, new evidence points toward multiple mechanisms that promote neuronal cell death in the CNS as the underlying basis for ALS. The recent demonstration of superoxide dismutase 1 (SOD1) mutations in human familial ALS and in murine ALS models supports the view that oxidative stress, mitochondrial dysfunction, and excitotoxicity pathways may be involved in the process of neuronal cell death.

A lack of trophic factor support has been hypothesized, as some authors have reported decreased insulin-like growth factor 1 (IGF-1) in patients with ALS. Aberrant RNA processing in sporadic ALS is thought to lead to abnormal expression of glutamate transporter (EAAT2) variants in the spinal cord. Despite multiple searches for infectious causative agents, no definitive viral or bacterial etiology has been identified.

ALS can be part of a complex with parkinsonism and dementia (ALS/PDC complex). This variant can be seen in patients from southern Guam. An ALS-like motor neuron disease also can be seen as a paraneoplastic syndrome in patients with cancer.

The complexity of ALS pathogenesis is highlighted by the recent discovery that alsin, a molecule putatively involved in cell-signaling, may be affected in a subset of familial ALS cases.

Autoimmunity may play a role in ALS. T cells, activated microglia, and immunoglobulin G (IgG) within the spinal cord lesions may be the primary event that leads to tissue destruction. Supporting this hypothesis, IgG derived from ALS patient sera may affect the conductance of neuronal voltage-activated calcium channels and may induce an excessive release of glutamate from nerve endings. The presence of immune complex formation in spinal cords of patients with ALS also has been demonstrated.

The El Escorial World Federation of Neurology criteria are helpful in diagnosis. Careful clinical history-taking is essential in making the correct diagnosis. For instance, Lyme neuroborreliosis on rare occasions may mimic an ALS-like syndrome.

Intravenous cyclophosphamide treatment has resulted in only temporary and mild amelioration of symptoms.

Patients with ALS may benefit from riluzole, a glutamate antagonist medication that modestly prolongs tracheostomy-free survival. Techniques that aim to elucidate altered pathways of gene expression (ie, gene chip technology) or protein expression (proteomics) may give clues to ALS pathogenesis in animal models. These may also expedite the identification of abnormal pathway-modifying pharmaceutical agents.

Frequency:

• In the US: Taking into account the most comprehensive studies (by Kurtzke), the frequency is approximately 5 cases per 100,000 population.

Mortality/Morbidity:

• ALS leads to death within a decade. In most cases, death occurs within 5 years.

• Some patients with familial, juvenile-onset ALS have been reported to survive for longer periods (2-3 decades).

Race: In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.

Sex: The ratio of ALS-affected males to females is 1.5:1.

Age: Onset occurs in the fourth to seventh decades of life. However, exceptions to this do exist.

Treatment
Medical Care:

• Medical care in ALS is primarily palliative.

• Patients should be involved in regular exercise and a physical therapy program.

• Medications such as baclofen and tizanidine may be used to relieve severe spasticity.

• Riluzone is an FDA-approved medication for prolonging tracheostomy-free survival.

Surgical Care:

• Early consideration for elective tracheostomy should be considered in patients with early signs of respiratory difficulty.

• Home health aides can be helpful in managing secretions and feeding.

• Computerized aids for writing and communication also can be helpful.

Consultations:

• Surgeon or gastroenterologist - To perform elective tracheostomy or G-tube placement

• Pulmonologist and respiratory therapist - For ventilator assistance and management of intercurrent infections and tracheostomy

• Physical and respiratory therapists - To enhance muscle function and manage spasticity

• Secretion management - For chest percussion therapy and suctioning

Diet:

• Evaluate swallowing to quantify any dysphagia.

• Modify the patient's diet to prevent aspiration.

• Consider a gastrostomy tube when patient cannot swallow fluids or soft foods.

Activity: No activity restriction is necessary. Patients should maintain a regular exercise regimen if the degree of weakness allows

Medication
Riluzole is the only medication that has shown treatment efficacy for ALS. That it prolongs tracheostomy-free survival compared to placebo has been shown in 2 randomized trials. No statistically significant difference in mortality rates was revealed at the end of these studies, however. In other clinical trials, creatine, human recombinant IGF-1, and ciliary neurotrophic factor (CNTF) also have shown promise, but none are expected to lead to dramatic benefits.
Drug Category: Glutamate pathway antagonist -- Riluzole is thought to counteract the excitatory amino acid (glutaminergic) pathways, but its exact mechanism of action in ALS is unknown.

Drug Name	Riluzole (Rilutek) -- Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 h; steady state reached within 5 d with multiple dose administration; metabolism occurs in liver (P 450-dependent glucuronidation and hydroxylation); 6 major and a few minor metabolites produced.
Adult Dose	50 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, liver disease with elevations in liver function tests
Interactions	Metabolized primarily by liver isoenzyme CYP1A2; other agents also metabolized via this enzymatic pathway (ie, theophylline, caffeine) may affect rate of elimination
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use caution in patients with concomitant liver or renal insufficiency

Drug Category: Antispastic agents -- These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Drug Name	Baclofen (Lioresal) -- Metabolized in liver and excreted primarily in urine; not a DEA-controlled substance.
Adult Dose	5 mg PO tid; not to exceed 80 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol, antipsychotics, MAOIs, narcotics, antipsychotics, tricyclic antidepressants, oral hypoglycemics, or insulin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use with caution in patients with seizure disorder or impaired renal function; serious reactions include somnolence and stupor, cardiovascular collapse, seizures, and respiratory depression; common adverse effects include headaches, dizziness, blurred vision, slurred speech, rash, weight gain, pruritus, constipation, increased perspiration; exercise caution in prescribing to patients already experiencing such symptoms; excessive dosing may lead to weakness

Drug Name	Tizanidine (Zanaflex) -- Centrally acting muscle relaxant metabolized in liver and excreted in urine and feces; used in patients with predominantly UMN involvement; not a DEA-controlled substance.
Adult Dose	4-8 mg PO q8h prn; not to exceed 36 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May interact with alcohol (to increase somnolence, stupor) and oral contraceptives (to decrease its clearance); can increase hypotensive effects when administered concurrently with diuretics
Pregnancy	A - Safe in pregnancy
Precautions	Use with caution in elderly patients and in patients with impaired renal function; serious reactions include hallucinations, severe bradycardia, and liver toxicity; more common adverse effects include dryness of mouth, somnolence and sedation, dizziness, malaise, constipation, increased spasms, and hypotension