Essential tremor significantly compromises patients' professional and personal lives.
Elvis Presley might have found it exciting to be "all shook up," but for the millions of persons with essential tremor (ET), the story is just the opposite. Eighty-five percent of affected persons report that ET significantly compromises their professional and personal lives.1
Furthermore, a study of persons with hereditary ET found that 60% were unemployed; 25% changed jobs or retired early; 65% did not dine out; 30% avoided parties, participating in sports, or solo shopping; and 20% stopped driving.2
The most common movement disorder in the United States, ET is estimated to affect 0.3% to 5.6% of the general population, or roughly 5 to 10 million persons.3 Men and women appear to be equally affected.4 A 45-year population-based study of persons from Rochester, Minnesota, reported an age-adjusted annual ET incidence of 18.3 and 17.1 per 100,000 for men and women, respectively.5
While it is tempting to think of tremor as a geriatric issue, ET targets 2 age groups: those aged 15 to 20 years and those aged 50 to 70 years.4 It is not unusual, however, for ET to appear in persons aged 35 to 45 years. Rarely, newborns and infants are affected.1
Nobody knows for certain what causes ET.6-9 No evidence suggests that the earlier ET begins, the more severe and disabling it becomes,1 although its characteristics may change over time. Similarly, there is no evidence to indicate that ET has any effect on mortality.1,4
WHAT IS TREMOR?
By definition, tremor is "an involuntary, rhythmic oscillation of a body part within a fixed plane, involving alternating or simultaneous contractions of agonist and antagonist muscles entrained by a signal pattern originating from a central oscillator."10 Everyone has physiologic tremor, which is an asymptomatic, small-amplitude tremor that probably originates from spontaneous oscillatory activity within the olivocerebellar system of the brain.4 Physiologic tremor is influenced by such factors as myocardial contraction and motor neuron firing and can be enhanced under certain circumstances, including exercise, emotional stress, metabolic abnormalities, and exposure to some drugs (eg, sympathomimetic agents, lithium).10
Tremor is generally classified as being either resting or action.4 Resting tremor, which includes that seen in parkinsonism, is present when the body is fully supported in a way that requires no voluntary activation of skeletal muscles-sitting in a chair with hands resting in the lap, for instance. Resting tremor is suppressed by voluntary movement of the affected body part. If you were to evaluate someone with resting tremor, you would notice that his or her hands were shaky at rest but became steady when reaching out to pick up a book or perform some other intentional activity.
Action tremor occurs during voluntary muscle contraction and can be postural, kinetic, or isometric. ET falls into the postural and kinetic categories. Postural tremor occurs when a person voluntarily tries to maintain a position against the pull of gravity, while kinetic tremor occurs during an intended movement such as drawing or pointing. One type of kinetic tremor, intention tremor, worsens as the person is almost done with his activity or task. Another type of action tremor, task-specific tremor, occurs only during specific, skilled activities-writing or playing the piano, for instance. Isometric tremor occurs when a person voluntarily contracts a muscle against a rigid stationary object, as when squeezing a stick.4
CHARACTERISTICS OF ET
The sine qua non of ET is a bilateral postural or kinetic tremor affecting the distal upper extremities. Occasionally, patients have ET affecting the head. Tremor can involve the lips, chin, voice, palate, and tongue-which all affect speech.4 Head tremor can occur alone, but more often follows upper extremity involvement. Alexander Rajput, MD, of the University of Saskatchewan in Canada, in describing a cross section of his patients with ET, notes that about 75% of patients have tremor that originates in an upper extremity; 20% have tremor that starts in an upper extremity and the head, lips, jaw, or vocal cords; and 5% have tremor limited to the head alone.11 There is some thought that hand tremor is more common in men, while women tend to have head involvement, but this is speculative.1 Isolated leg tremor is not a presenting finding of ET and suggests that tremor is related to something else. "We have not found leg tremor to be an initial sign of ET," observes Rajput.11 However, Rajput does point out that he and others have seen that ET can extend to the lower extremities over time.11
The onset of ET is gradual. As the person ages, the frequency of tremor declines but its amplitude increases. This makes it increasingly more difficult for the patient to function normally. Elan Louis, MD, of the Gertrude H. Sergievsky Center of Columbia University in New York City, notes that as function declines, persons with ET tend to become increasingly anxious and depressed.12
Classically, ET occurs alone, unaccompanied by any other neurological disorders. However, you might occasionally encounter a patient who has subtle signs of ataxia or cognitive impairment.13 Some patients with ET also have migraine headache or report being unable to hear or smell as acutely as before the tremor started.14-16
Because no brain lesion is associated with ET, the diagnosis is based on a comprehensive history and physical examination. Sophisticated imaging studies and extensive laboratory testing are generally unnecessary except to rule out other causes for tremor. The most notable include hyperthyroidism and Wilson disease.1,4 The diagnostic criteria for ET, as established by the Movement Disorder Society, are listed in Table 1.1,17
You might consider having the patient complete a tremor questionnaire such as that developed by Abe Lieberman, MD, of the National Parkinson Foundation, Inc. The questionnaire, which can be accessed at www.essentialtremor.org/research/questionnaire/index.php, is informal, not scientifically documented, and is solely intended to help clinicians determine whether the patient has ET. It is not intended to be used in place of a visit to the physician, but patients can be asked to fill out the form either before or during the initial visit.24 This procedure facilitates the evaluation and also helps ensure that no information about the tremor is overlooked.
During the physical examination, you'll want to further exclude other possible causes for tremor. This is also a good time to get additional information about the nature of the patient's tremor.
Asking the patient to perform a few simple maneuvers will quickly reveal the nature of the tremor:
DIFFERENTIATING ET FROM PARKINSONIAN TREMOR
A logical question is whether patients with ET are predisposed to other neurological problems, primarily Parkinson disease (PD). Current data are conflicting-while some studies report that parkinsonism is more common in persons with ET,25 there is no evidence to show that persons with ET consistently have Lewy bodies or lesions in the substantia nigra.11,26 Rajput,11 in reporting on a series of 20 patients with ET, noted Lewy body pathology in only 1 of 6 patients who had clinical evidence suggesting parkinsonism (bradykinesia, rigidity, and resting tremor). Until biologic markers become available, the precise relationship between ET and PD remains speculative, and there is no reason to suspect that PD will develop later in life in a person who presents with ET.
Nonetheless, the ET evaluation cannot be considered complete until PD is ruled out. Persons with ET often have a palpable, cogwheel-like tremor of the arm or hand that is pronounced during voluntary movement of the opposite limb. This so-called Froment sign is distinct from the cogwheel-like rigidity of PD.
Patients with parkinsonism often have a pill-rolling resting tremor of the hand, as well as postural tremor. The presence of rigidity, bradykinesia, and a shuffling gait confirms PD and rules out ET.
As another quick simple test, David M. Swope, MD, of the Movement Disorders Clinic at Loma Linda University Medical Center, Loma Linda, California, suggests asking the patient to extend his arm. ET begins instantly, while a parkinsonian tremor takes several seconds to start.4
Other tests become important only when there are no findings in the history and physical examination to suggest that the patient's symptoms are indeed ET. When there is a question, consider ordering laboratory studies, including a standard electrolyte panel, thyroid function tests, blood urea nitrogen, measurement of creatinine, and liver function tests, and ceruloplasmin levels (to rule out Wilson disease).
Imaging studies, such as MRI, are useful for ruling out an inflammatory process or Wilson disease or if the patient's tremor started suddenly or progressed incrementally. Procedures (electromyography, accelerometry) that measure tremor amplitude are not part of the routine clinical evaluation.1,4
The extent of the patient's functional or psychosocial impairment determines the approach to treatment. Many patients with mild or intermittent disability respond well to medications. When medication is ineffective and tremor is hindering the patient's ability to eat, write, speak, remain employed, or otherwise enjoy a satisfactory quality of life, surgery becomes an option. Patients with tremor of the head or voice have the option of botulinum toxin type A (Botox [BTX-A]) therapy.4
David Swope, MD, finds that education, lifestyle/behavioral modification, and support are worthwhile for all patients with ET.4 Indeed, such measures may be the primary treatment for persons with very mild ET who do not want to take medications.
Patients can learn to avoid situations that trigger or worsen tremor.
These and other simple lifestyle modifications can help persons manage more effectively. Persons with intermittent tremor that occurs primarily in social settings might benefit from a light cocktail as their primary protection against ET, although alcohol is not a first-line therapeutic mainstay-especially for persons with daytime or frequent tremor.
Medications can blunt tremor amplitude and improve the patient's functional ability but tend not to affect tremor frequency.4,27 They also do not cure ET.4,11,27 A frank discussion before starting treatment can help ensure that the patient's expectations about medications are realistic.
The primary drugs used to manage ET are Ã-blockers, anticonvulsants, and benzodiazepines. For most patients, treatment begins with either propranolol or primidone.28 When deciding which of these medications to prescribe, the patient's age should be taken into consideration.1,4
Younger persons tend to tolerate Ã-blockers better than the elderly, so typically start out with propranolol. Ã2-Agonists are more effective than Ã1-agonists, although both have been shown to be better than placebo in clinical trials.
A Ã1-agonist is a viable option for patients with conditions that preclude the use of propranolol.1 Propranolol, at a dosage ranging from 60 to 240 mg/d, can reduce tremor by 50% to 60% in 75% of patients treated.1
Older patients are good candidates for primidone, which has a mildly sedating effect that can be annoying or even detrimental for younger persons, especially those who attend school or work. Primidone is also an effective option for patients in whom propranolol is contraindicated.1,4
The general approach is to start at a low dosage and increase as needed. If you find that the patient responds well to a given dosage of medication and maintains that response, consider changing to a long-acting formulation. If there is no improvement at maximum dosage, gradually discontinue the medication and try a different drug. To test the patient's response to treatment, ask him to perform some of the manual tasks performed during the initial evaluation-writing, drawing a circle, or lifting a glass of water to his lips.
If the patient notices some improvement but needs more control, he might respond well to combination therapy with a Ã-blocker and an anticonvulsant (continue the first medication as you add the second). Increase the dosage of combination therapy as needed to control tremor satisfactorily. If the patient is not responding as you hoped, gradually discontinue the treatment and try a different medication.
Robert A. Hauser, MD, professor in the departments of neurology, pharmacology, and experimental therapeutics at the University of South Florida in Tampa, observes that some patients respond well to mirtazapine as a second-line agent.1 Other choices are a benzodiazepine if the tremor is more of a nuisance than a disability or clozapine if the tremor is disabling.1,4 The American Academy of Neurology Quality Standards Subcommittee has released their recommendations concerning treatment approaches to ET.29 Their suggestions, based on a review of the literature, are summarized in Table 3.29
Injections of BTX-A are useful for persons with voice or head tremors, which tend to respond poorly to medications. BTX-A is not generally used to treat hand or upper extremity trauma because the toxin can cause weakness, compromising function.1,4
A single treatment involves multiple point injections of BTX-A at a dose ranging from 1.25 U for voice tremor to 400 U for head tremor. Injections are repeated every 3 to 4 months. Serious adverse reactions to BTX-A are rare. The agent is contraindicated for patients with myasthenia gravis, postpolio syndrome, or motor neuron disease; those who are pregnant; and those being treated with aminoglycoside antibiotics.1,4
When patients have disabling ET that is not controlled by medications, surgery becomes a consideration and is usually definitive. The primary procedures used to control ET are stereotactic thalamotomy and deep brain stimulation (DBS) of the thalamus. Hauser notes that both procedures offer high rates of tremor reduction in the contralateral arm.1
Stereotactic thalamotomy. In this procedure neurons in the ventralis intermedius are ablated with thermocoagulation, creating a lesion that disrupts tremor. Thalamotomy is usually performed unilaterally, on the side of the brain contralateral to the most severely affected limb.
Bilateral thalamotomy is performed under local anesthesia and takes about 2 to 3 hours. Evidence indicates that the procedure is effective. Jankovic and colleagues30 examined the results of thalamotomy in 60 patients with various forms of tremor. Over the course of follow-up, which extended to 13 years, the investigators noted significant to complete reduction in tremor in 86% of patients with parkinsonism, 50% of patients with post-traumatic tremor, 67% of patients with cerebellar tremor, and 83% of patients with ET.
Thalamotomy is not without risks; it can cause permanent, severe dysarthria.1 Cerebral hemorrhage, motor weakness, and memory loss are other possible complications but occur in fewer than 2% of cases.1
Thalamic DBS. Thalamic DBS may work by providing chronic artificial "noise" that disrupts tremor activity within the motor circuit pathway. The ventralis intermedius remains relatively intact, and impulse variables can be changed to reduce adverse effects and increase efficacy. Evidence indicates that thalamic DBS is very effective: Ondo and colleagues31 reported an average 83% reduction in contralateral arm tremor in 14 patients with ET. Other studies report similar efficacy rates.32,33
Thalamic DBS is preferred to thalamotomy because it does not involve ablation, and stimulation can be adjusted according to the severity of tremor. Another advantage is that DBS can be done bilaterally, without exposing the patient to risk of severe adverse effects. Disadvantages include expense and the need to implant hardware in the brain-hardware that requires periodic maintenance and replacement of batteries.
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