Stn

GPi/SNpr

To spinal cord and brainstem

FIGURE 20-8 The basal ganglia in Huntington's disease. HD is characterized by loss of neurons from the striatum. The neurons that project from the striatum to the GPe and form the indirect pathway are affected earlier in the course of the disease than those which project to the GPi. This leads to a loss of inhibition of the GPe. The increased activity in this structure, in turn, inhibits the STN, SNpr, and GPi, resulting in a loss of inhibition to the VA/VL thalamus and increased thalamocortical excitatory drive. Structures in light blue have reduced activity in HD, whereas structures in dark blue have increased activity. (See legend to Figure 20-5 for definitions of anatomical abbreviations.)

responsible for HD and is increased from the normal range (9-34 triplets) to 40—100 triplets in HD patients. Several other neurodegenerative diseases also arise through expansion of a CAG repeat, including hereditary spinocerebellar ataxias and Kennedy's disease, a rare inherited disorder of motor neurons. The mechanism by which the expanded trinucleotide repeat leads to the clinical and pathological features of HD is unknown. The HD mutation lies within a gene designated IT15 that encodes a protein of -348,000 Da. The trinucleotide repeat, which encodes the amino acid glutamine, occurs at the 5' end of IT15 and is followed directly by a second, shorter repeat of (CCG)n that encodes proline. The protein, named huntingtin, does not resemble any other known protein, and the normal function of the protein has not been identified. The HD gene is expressed widely throughout the body, with high levels in brain, pancreas, intestine, muscle, liver, adrenals, and testes. Although the striatum is most severely affected, neurons in all regions of the brain express similar levels of IT15 mRNA.

SYMPTOMATIC TREATMENT OF HUNTINGTON'S DISEASE No current treatment slows the progression of HD, and many medications can impair function because of side effects. Treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious, or psychotic. Depression can be treated effectively with standard antidepressant drugs with the caveat that drugs with substantial anticholinergic profiles can exacerbate chorea. Fluoxetine (see Chapter 17) is effective treatment for both the depression and the irritability manifest in symptomatic HD; carbamaz,epine (see Chapter 19) also is effective for depression. Paranoia, delusional states, and psychosis usually require treatment with antipsychotic drugs, but the doses required often are lower than those usually used in primary psychiatric disorders. These agents also reduce cognitive function and impair mobility and thus should be used in the lowest doses possible and should be discontinued when the psychiatric symptoms resolve. In individuals with predominantly rigid HD, clozapine, quetiapine (see Chapter 18), or carbamazepine may be more effective for treatment of paranoia and psychosis.

The movement disorder of HD per se only rarely justifies pharmacological therapy. For those with large-amplitude chorea causing frequent falls and injury, dopamine-depleting agents such as tetrabenazine and reserpine (see Chapter 32) can be tried, although patients must be monitored for hypotension and depression. Antipsychotic agents also can be used, but these often do not improve overall function because they decrease fine motor coordination and increase rigidity. Many HD patients exhibit worsening of involuntary movements as a result of anxiety or stress. In these situations, judicious use of sedative or anxiolytic benzodiazepines can be very helpful. In juvenile-

onset cases, where rigidity rather than chorea predominates, dopamine agonists variably improve rigidity. These individuals also occasionally develop myoclonus and seizures that can be responsive to clonazepam, valproic acid, and other anticonvulsants.

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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