Tremor hereditary essential

Tremor--the involuntary oscillation of any body segment--is the movement disorder most frequently encountered by family physicians. The oscillatory movements are produced when alternating or synchronous agonist-antagonist muscles contract in a rhythmic pattern. The amplitude and frequency of the oscillations can vary, as can the factors that precipitate the movements. These parameters are important in classifying a tremor.

Classification and Diagnosis

The first three steps in classifying a tremor are to note its location, determine its relationship to rest and movement and identify provoking or suppressing factors[1-5] (Figure 1). Variables to consider in classification of a tremor are summarized in Table 1, and commonly encountered tremors are listed in Table 2.[5]

Tremor may be unifocal or multifocal. The head, face, jaw, voice, tongue, trunk or extremities may be affected. Tremor may also be generalized.

The oscillatory movements may be present at rest, or they may occur during maintenance of a posture. Tremor may also occur during active movement or during specific goal-directed movement.

A tremor may occur constantly or intermittently. It may be elicited by stressful conditions, fatigue or drug intake, and it may be suppressed by sleep, alcohol or certain medications.

The frequency (rate) of a tremor may be described as slow (3 to 5 Hz), intermediate (5 to 8 Hz) or rapid (9 to 12 Hz). The tremor's regularity also should be noted (Table 3).[3]

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The tremor's amplitude may be described as coarse, medium or fine. A coarse tremor is readily apparent and is characterized by gross displacement of the affected body segment. In contrast, a fine tremor may not be observable without specific maneuvers, such as placing a sheet of paper over an outstretched extremity.

The physician should first determine when the tremor occurs (e.g., at rest or during movement). The character of the tremor may not be immediately obvious. Carefully observing the patient while the history is obtained may be helpful.

Tremor at Rest

If the tremor occurs at rest, it will often worsen when the patient is engaged in mental tasks or moving an unaffected body segment (e.g., clenching a fist or tapping a foot). Since a tremor at rest promptly disappears with muscle contraction (isotonic or isometric), it interferes little with a patient's performance.

Parkinson's disease must be considered whenever a tremor at rest is identified. Parkinsonian tremor has a medium amplitude and a frequency of 4 to 6 Hz. The hands typically are most severely affected, followed by the head and the neck. Involvement of the lower extremities is usually less obvious.

Parkinsonian tremor is generated by alternating contractions of agonist and antagonist muscles, mainly involving the hands in pronation-supination movements and the fingers and the metacarpophalangeal joints in flexion-extension and adduction-abduction movements. These movements are responsible for the classic "pill-rolling" appearance of the hands of patients with parkinsonian tremor.

The diagnosis of Parkinson's disease is straightforward when akinesia, rigidity and loss of postural reflexes are present. However, at the onset of the disease, there may be some uncertainty about the diagnosis. Useful clues include the recent occurrence of clumsiness (hypokinesia), changes in handwriting (micrographia) and frequent falls (loss of postural reflexes).

It may be helpful to closely observe the patient's facial expression, standing posture and synkinetic movements (e.g., arm swinging while walking). The possibility of cogwheel rigidity can be evaluated by having the patient activate the extremity contralateral to the tested one; sometimes this test will enhance subclinical signs. Occasionally, the initial sign of Parkinson's disease is a rather sudden worsening of a longstanding familial essential tremor.

Postural Tremor

The best way to provoke a postural tremor is by isometric contraction of the affected body segments. Having the patient stand unsupported will elicit tremors of the head, neck, trunk and/or lower extremities. Distal fine tremors of the upper extremities can be detected by having the patient stretch out his or her arms with palms down and fingers open.

Postural tremor is the most common category of involuntary oscillatory movements, and it includes both physiologic tremor and pathologic tremor. Physiologic tremor may be further classified as normal and enhanced (sometimes termed "exaggerated"), while pathologic tremor may be subclassified as, among other terms, essential, familial essential and orthostatic.

Normal physiologic tremor is continuous, but the rate is quite irregular, ranging from 8 to 12 Hz. The tremor has a very low amplitude and usually cannot be detected by the naked eye. Enhanced physiologic tremor has a similar frequency, but the rate is more regular; however, the amplitude is irregular and can be as high as several millimeters.

Enhanced physiologic tremor is elicited by isometric-isotonic efforts and by fatigue. The tremor can be provoked by anxiety (adrenergic effect), hypoglycemia, caffeine, dopaminergic agonists, beta-adrenergic blockers, valproic acid (Depakene), lithium and tricyclic antidepressants[6-8] (Table 4). Thyrotoxicosis and hyperadrenalism also cause a markedly enhanced physiologic tremor.[7,8]

The most prevalent pathologic postural tremor is essential tremor[9-11] (Table 5). Although frequently termed "benign," this tremor can be quite handicapping. Essential tremor can occur at any age, but onset appears to be more common in the second and sixth decades.

About half of patients with essential tremor have a family history of this type of tremor. In such cases, the tremor is termed "familial essential tremor." The prevalence of this tremor is higher in the families of patients who have other movement disorders, such as Parkinson's disease or dystonia. In fact, as many as 50 percent of patients with familial essential tremor have associated dystonia.[11]

Essential tremor typically has a frequency of 6 to 8 Hz; however, the rate can be as slow as 4 Hz (when proximal segments are affected) and as fast as 11 Hz (when distal segments are affected). The amplitude of an essential tremor is inversely related to the frequency. The tremor primarily affects the hands (in flexion-extension), followed by the head (in a vertical or horizontal direction, producing the classic "yes-yes" and "no-no" pattern), the voice (quivering tone and dysphonia), the tongue, the lower extremities and the trunk.

Even when essential tremor is primarily postural, it may be exaggerated during action, particularly with "target" proximity in goal-directed movement. When severe, essential tremor can resemble resting tremor. Essential tremor is a progressive disorder, even though the tremor may not appear to become worse for years.

Orthostatic tremor has a higher frequency (16 Hz) than essential tremor. It is more regular and occurs at the same time in homologous leg muscles. Orthostatic tremor and essential tremor respond to different drug therapies.

Orthostatic tremor affects the lower extremities and the trunk when the patient stands unsupported. The tremor disappears when the patient leans against a wall, sits or walks. Orthostatic tremor is a fine, rippling tremor that is easier to feel than to see. This type of tremor may occasionally cause a patient to fall.[12]

In addition to the tremor that occurs at rest, patients with Parkinson's disease often have a postural tremor. This tremor has a frequency of about 6 Hz.

Kinetic and Intention Tremors

Kinetic (action) and intention (goal-directed) tremors are the most incapacitating types of tremor, and their presence may suggest disorders of the cerebellum and related pathways. These tremors are usually more evident in proximal muscle groups. They tend to be irregular, and they have a frequency of 3 to 5 Hz. The extremities (primarily the upper extremities) are affected when the cerebellar hemispheres are involved. When the head and trunk are affected, the midline vermian aspect of the cerebellum is usually implicated.

Kinetic and intention tremors can be evoked by having the patient perform goal-directed movements, such as finger-to-nose and heel-to-shin testing. As the patient's finger or heel approaches the target, intention tremor will increase.

To look for other signs of cerebellar dysfunction, the patient's gait, coordination, ocular movements, sense of position, tendon reflexes and ability to perform rapidly alternating movements should be carefully examined. The patient's speech may be slurred or scanning (i.e., with scanning speech, each syllable is pronounced as if it were a separate entity, rather than part of a word). Kinetic and intention tremors can develop in patients with heavy-metal poisoning (lead, mercury, bismuth, thallium, etc. , carbon tetrachloride exposure and metal chelator intoxication (Table 6).

Intention tremor is an expression of loss of movement coordination (dymetria) due to dysfunction of cerebellar servomechanisms.[13] In patients with cerebellar pathology, ocular oscillations may also be present. The abnormal eye movements may be in the form of flutter (uninterrupted saccadic oscillations in the horizontal plane), opsoclonus (uninterrupted saccadic oscillations in all directions) or pendular nystagmus (sinusoidal oscillations in one plane, increasing with upgaze; compensatory head oscillations may be present).

Similar symptoms occur in spinocerebellar degeneration and other conditions in which the dorsal columns and nerves of the spinal cord are involved (e.g., vitamin [B.sub.12] deficiency). In such cases, tremor may be the initial complaint.

Postural tremor often coexists with both kinetic and intention tremors. In such cases, the tremor becomes most evident when the patient holds his or her hands in front of the chest with arms abducted and elbows flexed. The resulting tremor is sometimes termed "wing-beating" tremor.

With midbrain pathology, a peculiar type of large, irregular, predominantly proximal tremor may occur. This rubral tremor is present at rest, and it has a slow frequency, similar to that of the parkinsonian tremor. The rubral tremor becomes more severe during maintenance of a posture and worsens during active movement. The hands are affected in a pronation-supination direction. Signs of midbrain or cerebellar dysfunction are usually present in patients with this tremor. Patients with multiple sclerosis or severe head injuries may also have rubral tremor.

Rarely, postural and kinetic tremors may occur, together or separately, in patients with peripheral neuropathy, especially those who are sensitive to corticosteroids. These tremors can be due to weakness, altered stretch reflexes, altered proprioception[14,15] or adrenergic-receptor dysfunction.

Tremor-like Conditions

A broad spectrum of pathologic conditions may generate mixed-type tremors, tremor-like conditions and conditions that mimic tremor.

Hepatic encephalopathy may cause asterixis, a more proximally pronounced postural tremor-like condition. Asterixis occurs when a sudden loss of muscle tone (an electromyographically silent period) is immediately followed by resumption of contraction, manifested as a rapid, jerky movement, sometimes resulting in overcorrection.[3]

On the basis of its neurophysiologic characteristics, asterixis should more correctly be considered a negative myoclonus (i.e., a brief inhibition of contraction, causing a sudden loss of postural maintenance). If a patient exhibits this disorder, liver function should be evaluated, as well as copper and ceruloplasmin levels, and eye examination should be performed by an ophthalmologist to look for a Kaiser-Fleischer ring to exclude Wilson's disease. Asterixis may also be caused by anticonvulsant intoxication.

Uremia can induce myoclonic twitches or asterixis, but tremor may also be present. hi such cases, the tremor may be of central or peripheral genesis (uremic neuropathy).

Irritation of nerve roots or plexi may generate rhythmic myoclonus. In patients with this condition, the affected body segments have a tremulous appearance.

Cortical disease in itself does not usually cause tremor. In some cases, however, a mixed-type tremor (postural and kinetic) may stem from a multifocal degenerative brain disorder or toxic, metabolic, ischemic or inflammatory encephalopathy. Cortical dysfunction more commonly generates myoclonus (i.e., sudden, brief, rapid, non-rhythmic movements). With cortical dysfunction, the dominant symptom is an altered level of consciousness or a deficit of higher cortical functions.

Tremor in dystonia occurs when antagonist muscles attempt to counteract the spasmodic activity of dystonic muscles; the result may be a jerky correction of the abnormal posture. Dystonic tremor is more commonly seen in the early stages of the disease. Later, the dystonic contractions tend to become tonic, and the tremor disappears. However, when the dystonia affects antagonist muscles, tremor may continue. In such instances, the tremor is present at rest, worsens while the patient maintains a posture, but is not usually significantly affected by movement. With focal action dystonia, the tremor is evoked by a specific movement, such as writing writer's cramp) or speaking (dysphonia).[16]

There is some confusion about how to define the tremors that occur in dystonia. Some authorities consider them to be atypical essential tremor, while others believe that two coexisting conditions (tremor and dystonia) are present. One hypothesis is that these tremors are a mild form of dystonia[16,17]; this theory seems likely, since the tremors respond to anticholinergic drugs, which characteristically improve dystonia, but do not respond to beta blockers, which generally improve familial essential tremor.

Rhythmic myoclonus resembles a slow tremor (i.e., a rate of 2 to 3 Hz), but it persists during sleep. It may initially affect one body segment and then spread to other parts of the body. Oscillatory myoclonus is intermittent and can be generalized, while rhythmic myoclonus is more continuous. Synchronous firing of the affected muscle is the usual neurophysiologic finding.[18]

Palatal myoclonus affects the palatal and second branchial pouch musculature at a rate of 2 to 3 Hz. This condition is now considered a tremor. Palatal tremor persists during sleep and is diminished by activation of the affected musculature (e.g., the muscles that control swallowing and talking). Involvement of the perioral muscles may produce the so-called "rabbit syndrome," which is characterized by continuous movements of the perioral and facial muscles. Palatal tremor is generally a consequence of brainstem lesions following trauma or hypoxia.

Finally, hysterical tremor has no specific features, although patients with this condition may appear to be shivering or shaking as if from fear. The "tremor" is irregular, and it diminishes when the patient's attention is diverted. In many cases, hysterical tremor is easily recognized because of the frequently associated psychiatric features.

Treatment

Each type of tremor requires a different therapeutic approach (Table 7). Pharmacotherapy should be used only when a tremor interferes with a patient's ability to function.

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As a first step, the physician should determine features of the tremor and then exclude an external cause, such as a drug or a toxin. If the patient is found to have a condition that produces increased physiologic tremor--for example, stress, thyrotoxicosis, hyperadrenergic state, alcohol or sedative withdrawal--the triggering factor should be removed.

When drug therapy is necessary for patients with essential or enhanced physiologic tremor, the first choice is a beta blocker.[2,3,5,10] The most frequently used drug is propranolol (Inderal). The starting dosage is 80 mg per day, which is administered in divided doses. The dosage may be gradually increased to a maximum of 320 mg per day, which is usually given in divided doses three or four times daily.

Cardiac function should be monitored during beta-blocker therapy Beta blockers that do not cross the blood-brain barrier are effective in treating enhanced physiologic tremor, but not essential tremor.

The short-acting benefit of alcohol consumption should be considered in patients with essential tremor. However, while alcohol may be very helpful in some patients, its use may have adverse consequences (i.e., abuse) in others.

Primidone (Mysoline) is another drug that can be used to treat essential tremor. The drug is started in a dosage of 25 mg per day, which may be increased slowly in increments of 25 mg per day, to a maximum dosage of 750 mg per day. The average required dosage is 250 mg per day.

Clonazepam (Klonopin) is the drug of choice for orthostatic tremor.[3,5] The starting dosage of 0.5 mg per day can be increased gradually in 1-mg increments, to a maximum dosage of 20 mg per day.

Parkinsonian tremor is somewhat responsive to anticholinergic medications such as trihexyphenidyl (Artane). However, other symptoms of Parkinson's disease (e.g., bradykinesia) also should be considered, so that a global effect of therapy is achieved. The usual dosage of trihexyphenidyl ranges from 4 to 10 mg per day. To reduce side effects, the therapy should be started at 2 mg per day, and the dosage should be increased slowly until satisfactory improvement occurs or side effects preclude the use of higher doses.[3,5] The usual maximum dosage is 32 mg per day. Because of significant side effects from anticholinergic medications (particularly in the elderly), they should be used sparingly.

Carbidopa-levodopa (Sinemet) is more effective for treating bradykinesia than tremor in patients with Parkinson's disease.

As a last resort, stereotaxic destruction of thalamic nuclei can be used in patients with severe tremor that does not respond to drug therapy.[20]

Cerebellar and rubral tremors respond poorly to medications. However, a response to 5-hydroxytryptophan has been reported. Alcohol intake should be avoided, because it worsens cerebellar tremor.

When tremor is a local expression of mild dystonia, the treatment of choice is localized injection of botulinum toxin type A (Botox)., Patients with disabling, medically intractable tremors also benefit from botulinum toxin.[21]

Clonazepam and/or anticholinergic agents are indicated in patients with generalized dystonic tremor. Note that in patients with dystonic tremor, the dosage required to modulate dystonic tremor may have to be higher than that used for parkinsonian tremor.[3,5,18]

Rhythmic and oscillatory myoclonus may respond to clonazepam, 5-hydroxytryptophan, an anticonvulsant or baclofen (Lioresal). Since the response to any of these medications varies, monotherapy should initially be tried, but combination drug therapy may eventually be needed.[18]

REFERENCES

[1.] Brumlik J, Yap C-B, eds. Normal tremor: a comparative study. Springfield, M.: Thomas, 1970. [2.] Koller WC. Diagnosis and treatment of tremors. Neurol Clin 1984;2:499-514. [3.] Jankovic J, Fahn S. Physiologic and pathologic tremors. Diagnosis, mechanism, and treatment. Ann Intern Med 1980;93:460-5. [4.] Hallett M. Differential diagnosis of tremor. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Extrapyramidal disorders. Amsterdam: Elsevier, 1986: 583-95. [5.] Hallett M. Classification and treatment of tremor. JAMA 1991;266:1115-7 [6.] Narabayashi H. Tremor: its generating mechanism and treatment. In: Vinken PJ, Bruyn GW, Klawans HL, eds. Extrapyramidal disorders. Amsterdam: Elsevier, 1986:597-607. [7.] Shahani BT, Young RR. Physiological and pharmacological aids in the differential diagnosis of tremor. J Neurol Neurosurg Psychiatry 1976;39:772-83. [8.] Young RR, Shahani BT. Pharmacology of tremor. Clin Neuropharmacol 1979;4:139-56. [9.] Findley LJ, Koller WC. Essential tremor: a review. Neurology 1987;37:1194-7. [10.] Young RR. Essential tremor. In: Asbury AK, McKhann GM, McDonald WI, eds. Diseases of the nervous system. Vol. 1. 2d ed. Philadelphia: Saunders, 1992:353-67. [11.] Lou JS, Jankovic J. Essential tremor: clinical correlates in 350 patients. Neurology 1991;41(2 Pt 1):234-8. [12.] Britton TC, Thompson PD, van der Kamp W, Rothwell JC, Day BL, Findley LJ, et al. Primary orthostatic tremor: further observations in six cases. J Neurol 1992;239:209-17 [13.] Fahn S. Cerebellar tremor: clinical aspects. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984: 355-64. [14.] Shahani BT. Tremor associated with peripheral neuropathy. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984:389-98. [15.] Smith IS, Furness P, Thomas PK. Tremor in peripheral neuropathy. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984:399-408. [16.] Rosenbaum F, Jankovic J. Focal task-specffic tremor and dystonia: categorization of occupational movement disorders. Neurology 1988;38:522-7. [17.] Yanagisawa N, Goto A, Narabayashi H. Familial dystonia musculorum deformans and tremor. J Neurol Sci 1972;16:125-36. [18.] Fahn S. Atypical tremors, rare tremors and unclassified tremors. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984:431-44. [19.] Findley LJ, Calzetti S, Cleeves L. Primidone in essential tremor. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984:271-82. [20.] Andrew J. Surgical treatment of tremor. In: Findley LJ, Capildeo R, eds. Movement disorders: tremor. New York: Oxford University Press, 1984:339-52. [21.] Jankovic J, Schwartz K. Botulinum toxin treatment of tremors. Neurology 1991;41:1185-8.

PAOLA SANDRONI, M.D. is a neurology resident at the Mayo Clinic in Rochester, Minn. She graduated from the University of Milan, Italy, where she completed the specialty school in clinical neurology. Dr. Sandroni completed fellowships in neurophysiology research at the Mayo Clinic and at the University of California College of Medicine at Irvine.

ROBERT R. YOUNG, M.D. is vice chairman of the Department of Neurology at the University of California College of Medicine at Irvine. He is also director of the neurology section at the Long Beach (Calif.) Veterans Affairs Hospital. Dr. Young graduated from Harvard Medical School, Boston, and completed a residency in neurology at Massachusetts General Hospital, Boston. For 20 years, he served as director of the Movement Disorders Clinic of Harvard Medical School and Massachusetts General Hospital.

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