Amyotrophic Lateral Sclerosis Clinical Features And Pathology

ALS is a disorder of the motor neurons of the ventral horn of the spinal cord and the cortical neurons that provide their afferent input, characterized by rapidly progressive weakness, muscle atrophy and fasciculations, spasticity, dysarthria, dysphagia, and respiratory compromise. Sensory function generally is spared, as is cognitive, autonomic, and oculomotor activity. ALS usually is progressive and fatal, with most affected patients dying of respiratory compromise and pneumonia after 2-3 years. The pathology of ALS corresponds closely to the clinical features: prominent loss of the spinal and brainstem motor neurons that project to striated muscles (although the oculomotor neurons are spared), as well as loss of the large pyramidal motor neurons in layer V of motor cortex, which are the origin of the descending corticospinal tracts. In familial cases (FALS, —10% of cases, usually with an autosomal dominant pattern of inheritance), Clarke's column and the dorsal horns sometimes are affected. Mutations in SOD1 account for —20% of cases of FALS; many of the mutations of SOD1 associated with the disease do not reduce the capacity of the enzyme to perform its primary function, the catabolism of superoxide radicals. More than 90% of ALS cases are not associated with abnormalities of SOD1 or any other known gene. The cause of the motor neuron loss in sporadic ALS is unknown.

TREATMENT OF ALS WITH RILUZOLE The only currently approved therapy for ALS is riluzole (2-amino-6-[trifluoromethoxy]benzothiazole; rilutek), an agent with complex actions in the nervous system. Riluzole is absorbed orally and is highly protein bound. It undergoes extensive metabolism in the liver by both CYP-mediated hydroxylation and glucuronidation. Its t1/2 is —12 hours. In vitro, riluzole inhibits glutamate release, blocks postsynaptic NMDA- and kainatetype glutamate receptors, and inhibits voltage-dependent Na+ channels. In clinical trials, riluzole has modest but genuine effects on the survival of patients with ALS. The recommended dose is 50 mg every 12 hours, taken 1 hour before or 2 hours after a meal. Riluzole usually is well tolerated, although nausea or diarrhea may occur. Rarely, riluzole may produce hepatic injury with elevations of serum transaminases; thus, periodic monitoring is recommended. Although the effect of riluzole on ALS is small (mean extension of survival —60 days), it represents a significant therapeutic advance in the treatment of a disease refractory to all previous drugs.

SYMPTOMATIC THERAPY OF ALS: SPASTICITY Spasticity is a clinical feature of ALS that often leads to considerable pain and discomfort and reduces mobility, which already is compromised by weakness. Furthermore, spasticity is the feature of ALS that is most amenable to present forms of treatment. Spasticity is an increase in muscle tone characterized by an initial resistance to passive displacement of a limb at a joint, followed by a sudden relaxation (the so-called clasped-knife phenomenon). Spasticity is the result of the loss of descending inputs to the spinal motor neurons, and the character of the spasticity depends on which nervous system pathways are affected. Whole repertoires of movement can be generated directly at the spinal cord level; it is beyond the scope of this chapter to describe these in detail. In general, pyramidal pathways that use glutamate as a neurotransmitter are impaired, with relative preservation of the other descending pathways, resulting in hyperactive deep-tendon reflexes, impaired fine motor coordination, increased extensor tone in the legs, and increased flexor tone in the arms. The gag reflex often is overactive as well.

The most useful agent for the symptomatic treatment of spasticity in ALS is baclofen (lioresal), a GABAB receptor agonist. Initial doses of 5-10 mg/day are recommended, but the dose can be increased to as much as 200 mg/day if necessary. If weakness occurs, the dose should be lowered. In addition to oral administration, baclofen also can be delivered directly into the space around the spinal cord by use of a surgically implanted pump and an intrathecal catheter. This approach minimizes the adverse effects of the drug, especially sedation, but it carries the risk of potentially life-threatening CNS depression and should be only used by physicians trained in delivering chronic intrathecal therapy. Tizanidine (zanflex), an agonist of a2 adrenergic receptors in the CNS, reduces muscle spasticity and is assumed to act by increasing presynaptic inhibition of motor neurons. Tizanidine is used most widely in the treatment of spasticity in multiple sclerosis or after stroke but may be effective in patients with ALS. Treatment should be initiated at a low dose of 2-4 mg at bedtime and titrated upward gradually. Drowsiness, asthenia, and dizziness may limit the dose that can be administered. Benzodiazepines (see Chapter 16) such as clonazepam (klonipin) are effective antispasmodics but may contribute to respiratory depression in patients with advanced ALS. Dantrolene (dantrium), approved in the U.S. for the treatment of muscle spasm, can exacerbate muscular weakness and thus is not used in ALS (see Chapter 9).

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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