Drugs potentiating GABAA receptors in the central nervous system (such as phenobarbital, primidone, topiramate, and benzodiazepines) also improve tremor, but phenobarbital is not used clinically because of its sedating effect. Primidone (an antiepileptic drug; see Chapter 24), in gradually increasing doses up to 250 mg three times daily, is also effective in providing symptomatic control in some cases. Patients with tremor are very sensitive to primidone and often cannot tolerate the doses used to treat seizures; they should be started on 50 mg once daily and the daily dose increased by 50 mg every 2 weeks depending on response. In many instances a dose of 125 mg two or three times daily is sufficient.
Topiramate, another antiepileptic drug, may also be helpful in a dose of 400 mg daily, built up gradually. Alprazolam (in doses up to 3 mg daily) or gabapentin (100–2400 mg/d; typically 1200 mg/d) is helpful in some patients. Gabapentin binds to the α2δ subunit of calcium channels. It produces less consistent relief of tremor but is associated with fewer side effects than primidone. Other patients are helped by intramuscular injections of botulinum toxin, but dose-dependent weakness may complicate symptomatic benefit. Thalamic stimulation by an implanted electrode and stimulator is often worthwhile in advanced cases refractory to pharmacotherapy. Magnetic resonance imaging-guided focused ultrasound thalamotomy shows promise. Diazepam, chlordiazepoxide, mephenesin, and antiparkinsonism agents have been advocated in the past but are generally of little benefit. Small quantities of alcohol may suppress essential tremor for a short time but should not be recommended as a treatment strategy because of possible behavioral and other complications of alcohol.
Reports in the early 1980s of a rapidly progressive form of par-kinsonism in young persons opened a new area of research in the etiology and treatment of parkinsonism. The initial report described apparently healthy young people who attempted to support their opioid habit with a meperidine analog synthesized by an amateur chemist. They unwittingly self-administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and subsequently developed a very severe form of parkinsonism. MPTP is a protoxin that is converted by monoamine oxi-dase B to N-methyl-4-phenylpyridinium (MPP+). MPP+ is selec-tively taken up by cells in the substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP+ inhibits mitochondrial complex I, thereby inhibiting oxida-tive phosphorylation. The interaction of MPP+ with complex I probably leads to cell death and thus to striatal dopamine deple-tion and parkinsonism. Recognition of the effects of MPTP suggested that spontane-ously occurring Parkinson’s disease may result from exposure to an environmental toxin that is similarly selective in its target. However, no such toxin has yet been identified. It also suggested a successful means of producing an experimental model of Parkinson’s disease in animals, especially nonhuman primates. This model is useful in the development of new antiparkinson-ism drugs. Pretreatment of exposed animals with a monoamine oxidase B inhibitor such as selegiline prevents the conversion of MPTP to MPP+ and thus protects against the occurrence of par-kinsonism. This observation has provided one reason to believe that selegiline or rasagiline may retard the progression of Parkin-son’s disease in humans.
Intention tremor is present during movement but not at rest; sometimes it occurs as a toxic manifestation of alcohol or drugs such as phenytoin. Withdrawal or reduction in dosage provides dramatic relief. There is no satisfactory pharmacologic treatment for intention tremor due to other neurologic disorders.
Rest tremor is usually due to parkinsonism.