Elsevier

The Lancet Neurology

Volume 10, Issue 2, February 2011, Pages 148-161
The Lancet Neurology

Review
Treatment of patients with essential tremor

https://doi.org/10.1016/S1474-4422(10)70322-7Get rights and content

Summary

Essential tremor is a common movement disorder. Tremor severity and handicap vary widely, but most patients with essential tremor do not receive a diagnosis and hence are never treated. Furthermore, many patients abandon treatment because of side-effects or poor efficacy. A newly developed algorithm, based on the logarithmic relation between tremor amplitude and clinical tremor ratings, can be used to compare the magnitude of effect of available treatments. Drugs with established efficacy (propranolol and primidone) produce a mean tremor reduction of about 50%. Deep brain stimulation (DBS) in the thalamic nucleus ventrointermedius or neighbouring subthalamic structures reduces tremor by about 90%. However, no controlled trials of DBS have been done, and the best target is still uncertain. Better drugs are needed, and controlled trials are required to determine the safety and efficacy of DBS in the nucleus ventrointermedius and neighbouring subthalamic structures.

Introduction

Essential tremor (ET) is one of the most common neurological diseases; its prevalence (0·9%)1 is comparable to that of epilepsy (0·7%).2 Although the prevalence of ET for all ages is about 0·9% and 4·6% for people aged 65 years or older,1 only 27% of a population-based cohort of patients with ET in Germany had ever seen a doctor for tremor treatment.3 Less than 1% of patients had sought care in an epidemiological study in Sweden in the 1950s,4 and only 4% were treated in a recent door-to-door survey in Turkey.5 However, two community-based studies reported at least mild functional impairment due to tremor in 73%6 and 60% of patients.3 Reasons for patients not seeking medical care are unknown and might depend on tremor severity, coping skills, and disease recognition. Similar findings have been reported for elderly adults with severe hearing loss; only 15% sought help with hearing aids.7 These data suggest that effective therapies would be requested by many patients.

The notion of ET has changed from that of a non-specific action tremor that could be associated with other neurological disorders8 to a more narrowly defined disorder that produces action tremor in the hands, and commonly in the head and voice, with little or no tremor in the lower limbs and torso.9 Impaired balance (tandem walking) and upper-extremity rest or intention tremor can be seen in advanced patients.9, 10

This evidence-based review of therapies for patients with ET begins by summarising diagnosis and differential diagnosis, non-motor features, and measurement of tremor and its effect on quality of life. We also introduce a new and simple method for estimating the magnitude of tremor reduction from changes in clinical rating, with which we assess the strength of evidence in conjunction with the magnitude of effect for pharmacological and surgical treatments.

Section snippets

The diagnosis of essential tremor

Diagnosis of ET is still based solely on clinical examination and neurological history, as a specific biological marker or diagnostic test is not available. Differences exist in published clinical criteria for ET. The Movement Disorder Society (MDS) consensus diagnostic criteria for ET (panel 1) were developed by an ad-hoc committee of the MDS.11 They considered isolated head tremor in the absence of dystonic posturing as a variant of ET. By contrast, the Tremor Investigation Group (TRIG)

Rating scales and motion transducers to measure tremor

A major clinical and research problem is the heterogeneity in the quantification of tremor. Until 1993, there were no validated rating scales for assessment of ET.39, 43 The widely used FTM rating scale was published in 1993,33 but was not validated for ET until 2007.44, 45 Before 1993, many ad-hoc scales were used, and results were frequently reported incompletely, making comparisons among trials difficult or impossible. Fortunately, accelerometry became popular in 1971, when clinical trials

Background

Neurotransmitter deficits in patients with ET have not been identified, the manner by which reported microscopic pathology might lead to tremor is still unknown, the source and mechanism of pathological oscillations are not known, and the genetic defects that cause ET have not been identified, except for a risk factor—LINGO1.9, 10 All drugs for treatment of ET have been discovered by chance and were originally developed for other diseases; drug discovery will remain largely trial-and-error

Stereotactic surgery

Stereotactic surgery is an option for patients with disabling hand tremor that is not suppressed adequately by drug treatment. Previous reviews have suggested that DBS of the nucleus ventrointermedius of the thalamus and Vim thalamotomy were highly efficacious treatments for upper limb tremor in patients with ET but gave these procedures only a level C recommendation, as results from double-blind placebo-controlled trials of these procedures were not available.48 There are still no class I or

Gamma knife thalamotomy

The gamma knife delivers external radiation to the Vim nucleus, guided solely by neuroimaging and a stereotactic frame. Intraoperative electrophysiological monitoring is not possible, and the ultimate effects of radiation usually are not apparent until 6–12 months after the procedure.133, 134, 135, 136, 137, 138 Currently, most lesions are made with a single isocentre by use of the 4 mm secondary collimator of the gamma knife and a radiosurgical dose of 130–141 Gy.133, 134, 135, 136 Most

Treatment of head and voice tremor

Head and voice tremor are common in patients with ET, but hand tremor is usually the predominant symptom.10 Whether isolated and predominant (with minimal hand tremor) head and voice tremors are variants of ET, forms of dystonia, or separate entities is unclear. Patients with isolated head tremor might eventually manifest dystonia after years of observation.139 Suppression of head tremor with a sensory trick is characteristic of dystonic tremor, not ET, so the presence of a sensory trick is

Minimum clinically significant effect of treatment

Minimum clinically significant effect is defined as the smallest change that represents a clinically meaningful improvement. Usually a seven-point global clinical improvement item is used as the anchor to assess changes on a more detailed severity scale. For interventions to treat ET, only a few such studies are available. In one study of DBS,116 the mean FTM hand-tremor score fell from 3·18 to 0·64 and the handwriting score fell from 2·76 to 0·89, and these scores corresponded to a mean 0–10

Conclusions

We have identified several challenges in the clinical research of patients with ET. One major problem is that other tremor disorders are commonly mistaken for ET,14, 15 and this can be a substantial barrier to therapeutic and genetic research. Therefore the MDS consensus and the TRIG criteria for ET need to be reconciled. The quality of many pharmacotherapy trials is poor by current standards, and long-term pharmacotherapy studies are almost completely absent. Propranolol and primidone have

Search strategy and selection criteria

We searched Medline, Embase, the Cochrane Library, and references from relevant articles for reports published in English, between January, 1970, and August, 2010, using the search terms “essential tremor” or “familial tremor” alone and with the terms “treatment”, “surgery”, “thalamotomy”, “deep brain stimulation”, “gamma knife”, and “botulinum”. We focused our review on drugs that were studied in at least one double-blind placebo-controlled trial. Surgery trials were all uncontrolled but

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