The New England Journal of Medicine

Clinical Practice
Volume 345:887-891

September 20, 2001

Number 12
Essential Tremor
Elan D. Louis, M.D.

This Journal feature begins with a case vignette highlighting a common
clinical problem. Evidence supporting various strategies is then presented,
followed by a review of formal guidelines, when they exist. The article ends
with the author's clinical recommendations.
A 66-year-old woman presents with tremor of the hands. She first noticed a
mild tremor six years earlier, but the tremor has been worsening for the
past two years. It occurs when she is using her hands, interfering with some
activities of daily living. For example, she can no longer eat soup without
spilling, put in her contact lenses, or apply lipstick. A writer, she is no
longer able to write in longhand or type her manuscripts and must dictate
them. The tremor causes a great deal of embarrassment in social situations.
How should this patient be evaluated and treated?
The Clinical Problem
The first step in evaluating any patient with tremor is to characterize the
tremor. All humans have physiologic tremor, or rhythmic oscillatory
movements, of their hands that is detectable with the use of
electrophysiological techniques such as quantitative accelerometry.
Stressful circumstances, such as those inducing fear, anger, or fatigue, may
cause transient enhanced physiologic tremor, which may be visible to the
naked eye.
In addition to these normal forms of tremor, there are several pathologic
tremors. They may take several forms: resting tremor, action tremor (also
referred to as akinetic or postural tremor), and intention tremor. Resting
tremor occurs while the limb is relaxed and stationary — for example, in the
hand while a person is standing or walking. Action tremor occurs during
sustained extension of the arm or during voluntary motion such as writing or
pouring. Intention tremor is a coarse terminal tremor that occurs as the
limb approaches a target — for example, during the finger-to-nose maneuver.
It is often accompanied by ataxic gait and other signs of cerebellar disease
(e.g., nystagmus and slurred or scanning speech).
Action tremor is the most prevalent of these types of tremor and, because it
is present when the hands are in active use, is disabling. The most common
action tremor is essential tremor, a tremor of the hands of 4 to 12 Hz. It
may also affect the head, voice, trunk, and legs. Estimates of the
prevalence of essential tremor in the general population range from 0.4 to 6
percent 1 <http://content.nejm.org/cgi/content/short/345/12/#R1>  and are
higher among persons over 65 years of age. Although essential tremor is
often referred to as benign, this description is misleading. Between 15 and
25 percent of patients with essential tremor who are seen in clinical
practice retire prematurely, and 60 percent choose not to apply for a job or
promotion because of the uncontrollable shaking of their hands. 2
<http://content.nejm.org/cgi/content/short/345/12/#R2>
Strategies and Evidence
Diagnosis
In addition to essential tremor, the differential diagnosis of an action
tremor includes enhanced physiologic tremor that is sustained (as a result
of either an identifiable cause, such as medication or hyperthyroidism, or a
cause that is not readily identifiable), Parkinson's disease, adult-onset
idiopathic dystonia, and Wilson's disease ( Table 1
<http://content.nejm.org/cgi/content/short/345/12/#T1> ). With the exception
of essential tremor and enhanced physiologic tremor, these other disorders
are rare (prevalence, <1 percent). The diagnostic approach includes
obtaining a history, physical examination, and laboratory tests.


View this table:
[in this window] <http://content.nejm.org/cgi/content/full/345/12/887/T1>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/12/887/T1>

Table 1. Prevalence, Features, and Differential Diagnosis of Action Tremor.

During the history-taking, the age at onset, type, and rate of progression
of the tremor should be assessed, along with information about family
history ( Table 1 <http://content.nejm.org/cgi/content/short/345/12/#T1> ).
Caffeine, cigarettes, and medications such as lithium, prednisone,
levothyroxine, beta-adrenergic bronchodilators, valproate, and selective
serotonin-reuptake inhibitors commonly result in enhanced physiologic
tremor; a complete inventory of all current medications, as well as caffeine
intake and smoking habits, is important in order to exclude these as the
cause of tremor. Patients with tremor due to other disorders usually have
symptoms of these disorders at presentation; for example, diarrhea or weight
loss in patients with hyperthyroidism, loss of normal facial expression or a
change in normal arm swing in patients with Parkinson's disease, the
sensation that muscles in the hand or neck are being pulled or twisted in
patients with dystonia, and reports of depression, cognitive impairment, or
other involuntary movements in patients with Wilson's disease.
During the physical examination, the clinician should carefully assess the
characteristics of the tremor ( Table 1
<http://content.nejm.org/cgi/content/short/345/12/#T1> ). Although many
patients with Parkinson's disease have a mild postural tremor, 5
<http://content.nejm.org/cgi/content/short/345/12/#R5>  resting tremor is
also present and affects approximately 85 percent of patients in studies of
autopsy-proved Parkinson's disease. 6
<http://content.nejm.org/cgi/content/short/345/12/#R6>  Approximately 20 to
30 percent of patients with dystonia have a postural tremor that
superficially resembles essential tremor ( Table 1
<http://content.nejm.org/cgi/content/short/345/12/#T1> ). If symptoms or
signs of hyperthyroidism are present, then thyroid-function tests should be
performed.
In any patient with action tremor who is younger than 40 years of age, the
possibility of Wilson's disease should be explored with a measurement of
serum ceruloplasmin. The level is low (<20 mg per deciliter) in 95 percent
of patients with this disorder. 7
<http://content.nejm.org/cgi/content/short/345/12/#R7>  If other clinical
features suggestive of Wilson's disease are present, such as dysarthria,
dystonia, and parkinsonism, then a careful slit-lamp examination of the eye
should be performed by an experienced ophthalmologist. Kayser–Fleischer
rings on Descemet's membrane are detectable in 99.3 percent of patients with
Wilson's disease who have neurologic abnormalities. 3
<http://content.nejm.org/cgi/content/short/345/12/#R3>
Quantitative computerized analysis of tremor is available at some tertiary
care centers and may guide the clinician in distinguishing essential tremor
from other types of tremor, but its diagnostic validity, like that of
positron-emission tomography, has not been established. At present, the
diagnosis of essential tremor is based on clinical findings; there are no
validated serologic, radiologic, or pathological markers (videotaped
examples of clinical findings in patients with essential tremor are
available as Supplementary Appendix 1
<http://content.nejm.org/cgi/content/full/345/12/887/DC1> ). There is no
gold standard for diagnosis, but the level of agreement is high between
clinicians using the same clinical criteria ( Table 2
<http://content.nejm.org/cgi/content/short/345/12/#T2> ). 1
<http://content.nejm.org/cgi/content/short/345/12/#R1> , 4
<http://content.nejm.org/cgi/content/short/345/12/#R4>


View this table:
[in this window] <http://content.nejm.org/cgi/content/full/345/12/887/T2>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/12/887/T2>

Table 2. Reliable Clinical Criteria for Essential Tremor.

Treatment
Pharmacotherapy may be used to improve function or reduce the embarrassment
associated with essential tremor. Medications are not indicated for mild
cases that do not cause dysfunction or embarrassment. Surgery is indicated
for severe cases that are refractory to medications. This discussion, with
one exception, 8 <http://content.nejm.org/cgi/content/short/345/12/#R8>
includes results only from double-blind, placebo-controlled trials, but
these have generally been small.
Two issues deserve special emphasis. First, although a reduction in the
amplitude of tremor, measured by clinical rating scales or accelerometric
methods, may be important, the ultimate evidence of efficacy is a reduction
in functional impairment. Second, although in groups of patients these
medications reduce the severity of tremor, on an individual basis, a large
proportion of patients (25 to 55 percent) have no response. A number of
factors may be responsible for this high rate of nonresponse. There is
evidence that essential tremor is not a homogeneous condition, and that
different clinical subtypes (e.g., young-onset essential tremor or essential
tremor with head tremor) may differ in pathogenesis and response to
treatment. 9 <http://content.nejm.org/cgi/content/short/345/12/#R9>  The
value of most current medications was discovered as a result of serendipity
rather than through an understanding of the mechanisms of the disease, which
remains limited.
            First-Line Therapies
Propranolol and primidone are the first-line agents in the treatment of
essential tremor ( Table 3
<http://content.nejm.org/cgi/content/short/345/12/#T3> ). Peripheral
{beta}-adrenergic receptors probably mediate the effects of
{beta}-adrenergic–blocking agents, 11
<http://content.nejm.org/cgi/content/short/345/12/#R11>  although central
mechanisms may be involved as well. Several placebo-controlled studies have
demonstrated that propranolol (at a dose of at least 120 mg per day) results
in a significant reduction in the severity of tremor, 12
<http://content.nejm.org/cgi/content/short/345/12/#R12>  and subjectively,
45 to 75 percent of patients report that propranolol is more effective than
placebo in reducing their tremor. Although propranolol is well tolerated,
relative contraindications include asthma, congestive heart failure,
diabetes mellitus, and atrioventricular block. Propranolol, a nonselective
antagonist, is more effective than antagonists with relatively selective
{beta}1 activity, 11 <http://content.nejm.org/cgi/content/short/345/12/#R11>
and trials of {beta}1-selective agents (such as atenolol and metoprolol)
have had mixed results. 11
<http://content.nejm.org/cgi/content/short/345/12/#R11> , 13
<http://content.nejm.org/cgi/content/short/345/12/#R13>  Long-acting
propranolol is as effective as conventional propranolol, and compliance with
the long-acting formulation is significantly better. 14
<http://content.nejm.org/cgi/content/short/345/12/#R14>


View this table:
[in this window] <http://content.nejm.org/cgi/content/full/345/12/887/T3>
[in a new window]
<http://content.nejm.org/cgi/content-nw/full/345/12/887/T3>

Table 3. Doses and Side Effects of Medications for Tremor.

Primidone, an anticonvulsant medication, is metabolized to
phenylethylmalonamide and phenobarbitone. Although the barbiturate
metabolite may contribute to the therapeutic effect, the parent compound is
thought to mediate most of this effect. 15
<http://content.nejm.org/cgi/content/short/345/12/#R15> , 16
<http://content.nejm.org/cgi/content/short/345/12/#R16> , 17
<http://content.nejm.org/cgi/content/short/345/12/#R17>  Primidone is
superior to phenobarbital in reducing the severity of tremor. 18
<http://content.nejm.org/cgi/content/short/345/12/#R18>  Primidone in doses
of up to 750 mg per day was significantly more effective than placebo in
reducing tremor, 15 <http://content.nejm.org/cgi/content/short/345/12/#R15>
, 16 <http://content.nejm.org/cgi/content/short/345/12/#R16> , 17
<http://content.nejm.org/cgi/content/short/345/12/#R17>  but tolerability is
a common problem. Even at a low starting dose (62.5 mg per day), an acute
toxic reaction consisting of nausea, vomiting, or ataxia has been reported
in 23 percent 15 <http://content.nejm.org/cgi/content/short/345/12/#R15>  to
73 percent 16 <http://content.nejm.org/cgi/content/short/345/12/#R16>  of
patients, requiring discontinuation of primidone in approximately 20 percent
of patients in some studies. 15
<http://content.nejm.org/cgi/content/short/345/12/#R15>
A 750-mg daily dose of primidone was compared with a 120-mg daily dose of
propranolol, and although each was significantly better than placebo, 17
<http://content.nejm.org/cgi/content/short/345/12/#R17>  neither was
conclusively shown to be superior to the other in this small study. The mean
reduction in the amplitude of tremor was 76 percent while patients were
taking primidone, as compared with a reduction of 60 percent during
treatment with propranolol, a nonsignificant difference. More patients
indicated a preference for primidone than for propranolol. 17
<http://content.nejm.org/cgi/content/short/345/12/#R17>  In another study,
the amplitude of tremor was reduced by a mean of 60 percent in 9 patients
who were taking primidone (250 mg per day), as compared with a mean
reduction of 35 percent in 22 patients who were taking their maximally
effective dose of propranolol (P value not reported). 19
<http://content.nejm.org/cgi/content/short/345/12/#R19>
Although initial tolerability is a problem with primidone, there is some
evidence that the long-term tolerability of primidone is superior to that of
propranolol. In a study of 25 patients with essential tremor, acute adverse
reactions occurred in 8 percent of the propranolol group and 32 percent of
the primidone group; however, clinically significant long-term (one year)
side effects occurred in none of the patients in the primidone group, as
compared with 17 percent of those in the propranolol group. 20
<http://content.nejm.org/cgi/content/short/345/12/#R20>
            Second-Line Therapies
Gabapentin, an anticonvulsant medication, is structurally similar to the
inhibitory neurotransmitter {gamma}-aminobutyric acid (GABA). There is some
evidence that the GABA-ergic system is disturbed in essential tremor. 21
<http://content.nejm.org/cgi/content/short/345/12/#R21>  There have been
three trials of gabapentin involving a total of 54 patients. In two of the
three studies, gabapentin (1200 to 3600 mg per day) reduced tremor
significantly more than did placebo, and in one of the two, its effect was
similar to that of propranolol. 22
<http://content.nejm.org/cgi/content/short/345/12/#R22>  Gabapentin is well
tolerated.
Benzodiazepines potentiate the effect of GABA by binding to the GABAA
receptor. Alprazolam is the only benzodiazepine shown to be effective in
essential tremor in controlled trials. In one placebo-controlled trial,
alprazolam (0.75 to 2.75 mg per day) resulted in a significant reduction in
tremor, and 75 percent of the patients had at least some improvement;
however, drowsiness or sedation occurred in 50 percent of the patients. 23
<http://content.nejm.org/cgi/content/short/345/12/#R23>  Clonazepam, another
benzodiazepine, did not significantly reduce the severity of tremor in a
placebo-controlled trial. 24
<http://content.nejm.org/cgi/content/short/345/12/#R24>  One concern with
the use of benzodiazepines is the risk of dependence.
Calcium-channel blockers have had variable rates of success. Trials of
flunarizine (10 mg per day), which is not available in the United States,
have reported mixed results. In one placebo-controlled trial, flunarizine
significantly reduced the severity of tremor, with 13 of 15 patients having
an improvement. In a second trial, however, none of the patients had a
decrease in the severity of tremor. 25
<http://content.nejm.org/cgi/content/short/345/12/#R25>  Differences in the
severity of tremor and the use of concurrent medications may have accounted
for some of this variation. In one placebo-controlled trial, nimodipine (30
mg per day) significantly reduced the severity of tremor, with 8 of 15
patients having an improvement. 26
<http://content.nejm.org/cgi/content/short/345/12/#R26>  Some
calcium-channel blockers, such as nifedipine, 27
<http://content.nejm.org/cgi/content/short/345/12/#R27>  may worsen tremor.
Theophylline may enhance the sensitivity to GABA. Theophylline (150 mg per
day) was compared with propranolol (80 mg per day) and placebo. 10
<http://content.nejm.org/cgi/content/short/345/12/#R10>  Theophylline
reduced tremor significantly more than did placebo, and its effect was
similar to that of propranolol. However, the investigators acknowledged that
although the trial was designed as a double-blind study, the side effects
experienced by the patients meant that in practice the treatments could be
distinguished.
            Other Therapies
Intramuscular injections of botulinum toxin A into the intrinsic muscles of
the dominant hand may reduce tremor by weakening the muscles or by blocking
gamma motor efferents and muscle spindle afferents. 28
<http://content.nejm.org/cgi/content/short/345/12/#R28>  Although there was
a significant reduction in the amplitude of tremor among patients receiving
one to two such injections, no significant improvement in function was
observed.
Action tremor may be mediated by neuronal loops that pass from the
cerebellum to the cortex by way of the ventral intermediate nucleus of the
thalamus. Two surgical approaches to tremor reduction involve continuous
deep-brain stimulation through an electrode implanted in the ventral
intermediate nucleus of the thalamus and surgical lesioning of this nucleus
(thalamotomy) contralateral to the more disabled arm. The two methods were
compared in a prospective, randomized, single-blind study. 8
<http://content.nejm.org/cgi/content/short/345/12/#R8>  Both procedures were
equally effective in reducing tremor. Thalamic stimulation resulted in
greater improvement in self-reported measures of function and fewer adverse
events, including cognitive deterioration, dysarthria, and gait or balance
disturbances. 8 <http://content.nejm.org/cgi/content/short/345/12/#R8>
Thalamic stimulation is the surgery of choice, because there are fewer
adverse events and the clinician can adjust the stimulator settings during
follow-up care.
Areas of Uncertainty
The response to medications is variable, and factors that predict a positive
response have not been identified. It is often necessary to try several
agents sequentially. Some clinical trials have suggested that the efficacy
of medications is lower in patients with tremor of the head than in those
with tremor of the hands, although most have not enrolled adequate numbers
of patients with head tremor, so have had limited power to detect changes in
this subgroup.
Guidelines
There are no guidelines from the American Academy of Neurology or the
Movement Disorder Society on the diagnostic workup or treatment of essential
tremor.
Conclusions and Recommendations
Action tremor is commonly seen in clinical practice, and essential tremor is
the most frequent cause. There is no diagnostic laboratory test for
essential tremor; the diagnosis is based on the history and physical
examination. In persons younger than 40 years of age, the possibility of
Wilson's disease should be excluded. Treatment of essential tremor should be
reserved for patients who have functional impairment or embarrassment, as is
the case for the patient described in the vignette. Both primidone and
propranolol are effective. There is some evidence that primidone may be more
effective and better tolerated than propranolol, although this needs to be
studied further. Therefore, I consider primidone to be a reasonable first
choice, and if it cannot be tolerated, then propranolol is my second choice.
Gabapentin and benzodiazepines are alternatives, although the latter may
result in sedation at the doses required to treat tremor. There are too few
data to support the use of nimodipine and theophylline. If the patient has
no response to medications and is sufficiently disabled, then unilateral
implantation of a deep-brain thalamic stimulator contralateral to the more
disabled arm is another option in centers where this is available.
Supported by a grant from the National Institutes of Health (R01 NS39422)
and by a Paul Beeson Physician Faculty Scholars in Aging Research Award.

Source Information
From the Gertrude H. Sergievsky Center and the Department of Neurology,
Columbia University, New York.
Address reprint requests to Dr. Louis at Unit 198, Neurological Institute,
710 W. 168th St., New York, NY 10032, or at [log in to unmask]
<mailto:[log in to unmask]> .
References
1.      Louis ED, Ford B, Frucht S, Barnes LF, X-Tang M, Ottman R. Risk of tremor
and impairment from tremor in relatives of patients with essential tremor: a
community-based family study. Ann Neurol 2001;49:761-769. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=11409428&link_type=MED>
2.      Bain PG, Findley LJ, Thompson PD, et al. A study of hereditary essential
tremor. Brain 1994;117:805-824. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=brain&resid=11
7/4/805>
3.      Walshe JM, Yealland M. Wilson's disease: the problem of delayed
diagnosis. J Neurol Neurosurg Psychiatry 1992;55:692-696. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=55/
8/692>
4.      Louis ED, Wendt KJ, Pullman SL, Ford B. Is essential tremor symmetric?
Observational data from a community-based study of essential tremor. Arch
Neurol 1998;55:1553-1559. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=9865800&link_type=MED>
5.      Koller WC, Vetere-Overfield B, Barter R. Tremors in early Parkinson's
disease. Clin Neuropharmacol 1989;12:293-297. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2804993&link_type=MED>
6.      Louis ED, Klatka LA, Liu Y, Fahn S. Comparison of extrapyramidal features
in 31 pathologically confirmed cases of diffuse Lewy body disease and 34
pathologically confirmed cases of Parkinson's disease. Neurology
1997;48:376-380. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=48/2/376>
7.      Scheinberg IH, Sternlieb I. Wilson's disease. Philadelphia: W.B.
Saunders, 1984.
8.      Schuurman PR, Bosch DA, Bossuyt PMM, et al. A comparison of continuous
thalamic stimulation and thalamotomy for suppression of severe tremor. N
Engl J Med 2000;342:461-468. [Abstract/Full Text]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=342
/7/461>
9.      Louis ED, Ford B, Barnes LF. Clinical subtypes of essential tremor. Arch
Neurol 2000;57:1194-1198. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10927801&link_type=MED>
10.     Mally J, Stone TW. Efficacy of an adenosine antagonist, theophylline, in
essential tremor: comparison with placebo and propranolol. J Neurol Sci
1995;132:129-132. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8543937&link_type=MED>
11.     Jefferson D, Jenner P, Marsden CD. {beta}-Adrenoreceptor antagonists in
essential tremor. J Neurol Neurosurg Psychiatry 1979;42:904-909. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=42/
10/904>
12.     Tolosa ES, Loewenson RB. Essential tremor: treatment with propranolol.
Neurology 1975;25:1041-1044. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=25/11/1041>
13.     Dietrichson P, Espen E. Effects of timolol and atenolol on benign
essential tremor: placebo-controlled studies based on quantitative tremor
recording. J Neurol Neurosurg Psychiatry 1981;44:677-683. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=44/
8/677>
14.     Cleeves L, Findley LJ. Propranolol and propranolol-LA in essential
tremor: a double blind comparative study. J Neurol Neurosurg Psychiatry
1988;51:379-384. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=51/
3/379>
15.     Findley LJ, Cleeves L, Calzetti S. Primidone in essential tremor of the
hands and head: a double blind controlled clinical study. J Neurol Neurosurg
Psychiatry 1985;48:911-915. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=48/
9/911>
16.     Sasso E, Perucca E, Fava R, Calzetti S. Primidone in the long-term
treatment of essential tremor: a prospective study with computerized
quantitative analysis. Clin Neuropharmacol 1990;13:67-76. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=2306749&link_type=MED>
17.     Gorman WP, Cooper R, Pocock P, Campbell MJ. A comparison of primidone,
propranolol, and placebo in essential tremor, using quantitative analysis. J
Neurol Neurosurg Psychiatry 1986;49:64-68. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnnp&resid=49/
1/64>
18.     Sasso E, Perucca E, Calzetti S. Double-blind comparison of primidone and
phenobarbital in essential tremor. Neurology 1988;38:808-810. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=38/5/808>
19.     Koller WC, Royse VL. Efficacy of primidone in essential tremor.
Neurology 1986;36:121-124. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=36/1/121>
20.     Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol
and primidone in essential tremor. Neurology 1989;39:1587-1588. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=39/12/1587>
21.     Louis ED. A new twist for stopping the shakes? Revisiting GABAergic
therapy for essential tremor. Arch Neurol 1999;56:807-808. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10404981&link_type=MED>
22.     Ondo W, Hunter C, Vuong KD, Schwartz K, Jankovic J. Gabapentin for
essential tremor: a multiple-dose, double-blind, placebo-controlled trial.
Mov Disord 2000;15:678-682. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=10928578&link_type=MED>
23.     Huber SJ, Paulson GW. Efficacy of alprazolam for essential tremor.
Neurology 1988;38:241-243. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=38/2/241>
24.     Thompson C, Lang A, Parkes JD, Marsden CD. A double-blind trial of
clonazepam in benign essential tremor. Clin Neuropharmacol 1984;7:83-88.
[Medline]
<http://content.nejm.org/cgi/external_ref?access_num=6367975&link_type=MED>
25.     Curran T, Lang AE. Flunarizine in essential tremor. Clin Neuropharmacol
1993;16:460-463. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8221708&link_type=MED>
26.     Biary N, Bahou Y, Sofi MA, Thomas W, al Deeb SM. The effect of
nimodipine on essential tremor. Neurology 1995;45:1523-1525. [Abstract]
<http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=neurology&resi
d=45/8/1523>
27.     Topaktas S, Onur R, Dalkara T. Calcium channel blockers and essential
tremor. Eur Neurol 1987;27:114-119.
28.     Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J. A randomized,
double-blind, placebo-controlled study to evaluate botulinum toxin type A in
essential hand tremor. Mov Disord 1996;11:250-256. [Medline]
<http://content.nejm.org/cgi/external_ref?access_num=8723140&link_type=MED>


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.