Essential tremor

Abstract

Introduction

Essential tremor is one of the most common movement disorders throughout the world, with prevalence in the general population of 0.4% to 3.9%. Although most people with essential tremor are only mildly affected, those who seek medical care are disabled to some extent, and most are socially handicapped by the tremor.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of drug treatments in people with essential tremor of the hand? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2006 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 41 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: adding mirtazepine to other antitremor drugs; benzodiazepines; beta-blockers other than propranolol; botulinum A toxin-haemagglutinin complex; calcium channel blockers; carbonic anhydrase inhibitors; clonidine; flunarizine; gabapentin; isoniazid; Phenobarbital; primidone; propranolol; and topiramate.

Key Points

Essential tremor refers to a persistent bilateral oscillation of both hands and forearms, or an isolated tremor of the head, without abnormal posturing, and when there is no evidence that the tremor arises from another identifiable cause.

• Essential tremor is one of the most common movement disorders throughout the world, with a prevalence of 0.4% to 3.9% in the general population.

• Although most people with essential tremor are only mildly affected, those who seek medical care are disabled to some extent, and most are socially handicapped by the tremor.

Overall, we found few RCTs assessing the long-term effects of drug treatments for essential tremor of the hand.

Propranolol seems to effectively improve clinical scores, tremor amplitude, and self-evaluation of severity compared with placebo in people with hand tremor.

• We didn't find sufficient evidence to judge the efficacy of other beta-blockers such as atenolol, metoprolol, nadolol, pindolol, and sotalol in treating essential tremor of the hand.

Barbiturates such a phenobarbital (phenobarbitone) and primidone may improve hand tremor in the short term, but are associated with depression, and with cognitive and behavioural adverse effects.

Benzodiazepines may improve hand tremor and function in the short term, but we were unable to draw reliable conclusions because of the weakness of the studies.

• Benzodiazepines are also associated with adverse effects such as dependency, sedation, and cognitive and behavioural effects.

We don't know whether carbonic anhydrase inhibitors, dihydropyridene calcium channel blockers, flunarizine, clonidine, isoniazid, or gabapentin are useful in treating essential tremor of the hand, because the studies have all been too small to detect clinically important differences in symptoms.

Botulinum A toxin-haemagglutinin complex and topiramate both appear to improve clinical rating scales for hand tremor in the short term, but are associated with frequent adverse effects.

• Botulinum A toxin-haemagglutinin complex is associated with hand weakness which is dose dependent and transient.

• The most common adverse effects of topiramate are appetite suppression, weight loss, and paraesthesia.

Adding mirtazapine to antitremor drugs such as propranolol does not seem to improve outcomes further in people with essential tremor of the hand, and leads to more frequent adverse effects, such as drowsiness, confusion, dry mouth, and weight gain.

About this condition

Definition

Tremor is a rhythmic, mechanical oscillation of at least one body region. The term essential tremor is used when there is either a persistent bilateral tremor of hands and forearms, or an isolated tremor of the head, without abnormal posturing, and when there is no evidence that the tremor arises from another identifiable cause. The diagnosis is not made if there are: abnormal neurological signs; known causes of enhanced physiological tremor; a history or signs of psychogenic tremor; sudden change in severity; primary orthostatic tremor; isolated voice tremor; isolated position-specific or task-specific tremors; and isolated tongue, chin, or leg tremor.

Incidence/ Prevalence

Essential tremor is one of the most common movement disorders throughout the world, with a prevalence of 0.4% to 3.9% in the general population.

Aetiology/ Risk factors

Essential tremor is sometimes inherited with an autosomal dominant pattern. About 40% of people with essential tremor have no family history of the condition. Alcohol ingestion provides symptomatic benefit in 50% to 70% of people.

Prognosis

Essential tremor is a persistent and progressive condition. It usually begins during early adulthood and the severity of the tremor slowly increases. Only a small proportion of people with essential tremor seek medical advice, but the proportion in different surveys varies from 0.5% to 11%. Most people with essential tremor are only mildly affected. However, most of the people who seek medical care are disabled to some extent, and most are socially handicapped by the tremor. A quarter of people receiving medical care for the tremor change jobs or retire because of essential tremor-induced disability.

Aims of intervention

To reduce tremor; to minimise disability and social embarrassment; to improve quality of life, with minimal adverse effects from treatment.

Outcomes

Tremor severity measured by clinical rating scales or patient self-evaluation. Clinical rating scales are often composite scores that grade tremor amplitude in each body segment in specific postures or tasks. Few scales have been formally validated. In the more recent trials, the Fahn–Tolosa–Marin clinical evaluation scale, which addresses the impairment and the disability domains of tremor, has become the preferred scale. Accelerometer recordings are reported in many trials but they are proxy outcomes that have been included in this review only when clinical outcomes were not available.

Methods

Clinical Evidence search and appraisal December 2006. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2006, Embase 1980 to December 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 4, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded. We excluded single-dose studies and RCTs lasting under 1 week. We included small RCTs because of the paucity of evidence in this population. Most of the RCTs we identified used a crossover design. This design is useful in situations like tremor, believed to be relative constant along months despite the existence of fluctuations, because it allows an intrasubject comparison, which increases the power of the analysis. However this analysis can be confounded by factors such as carryover of the effect seen before the crossover to the post-crossover period or because the effect is dependent on the moment of administration, meaning that effects of an intervention may differ in the period before and after crossover. Since most of the studies do not assess results before crossover and do not explicitly address these confounders or the impact of withdrawals from the trial, it is very difficult to interpret the data provided completely. We also use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Essential tremor.

Important outcomes	Tremor severity
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of drug treatments in people with essential tremor of the hand?
11 (less than 189)	Tremor severity	Propranolol versus placebo	4	–2	0	–1	0	Very low	Quality points deducted for sparse data and no intention-to-treat analysis. Directness point deducted for exclusion of many comorbidities
1 (151)	Tremor severity	Propranolol versus clonidine	4	–1	0	–1	0	Low	Quality points deducted for no intention-to-treat analysis. Directness point deducted for restricted patient group
2 (158)	Tremor severity	Botulinum versus placebo	4	–1	–1	–1	0	Very low	Quality points deducted for sparse data. Consistency points deducted as not all outcomes were significantly different. Directness points deducted as participants in one RCT were unresponsive to medical therapy, but this was not defined
3 (45)	Tremor severity	Phenobarbital versus placebo	4	–3	–1	0	0	Very low	Quality points deducted for sparse data, no intention-to-treat analysis, and high withdrawals. Consistency points deducted for contradictory results
3 (60)	Tremor severity	Primidone versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and no intention-to-treat analysis
1 (87)	Tremor severity	Different doses of primidone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
3 (263)	Tremor severity	Topiramate versus placebo	4	–1	–1	0	0	Low	Quality points deducted for sparse data. Consistency point deducted for contradictory results
2 (46)	Tremor severity	Alprazolam versus placebo	4	–1	–1	–1	0	Very low	Quality points deducted for sparse data. Consistency point deducted for contradictory results. Directness points deducted for indirect comparison
1 (6)	Tremor severity	Clonazepam versus placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and poor follow-up
6 (107)	Tremor severity	Other beta-blockers (atenolol, metoprolol, nadolol, pindolol, and sotalol) versus placebo	4	–3	–1	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and poor methodology. Consistency point deducted for contradictory results
4 (247)	Tremor severity	Other beta-blockers versus propranolol	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and poor crossover methodology. Consistency point deducted for contradictory results
2 (29)	Tremor severity	Calcium channel blockers versus placebo	4	–2	0	–1	0	Very low	Quality point deducted for sparse data and possible publication bias. Directness point deducted for indirect comparison
2 (40)	Tremor severity	Carbonic anhydrase inhibitors versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, poor follow-up, and no intention-to-treat analysis
1 (10)	Tremor severity	Clonidine versus placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete presentation of data
1 (17)	Tremor severity	Flunarizine versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and short follow-up
3 (61)	Tremor severity	Gabapentin versus placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and short follow-up. Consistency point deducted for contradictory results
1 (15)	Tremor severity	Isoniazid versus placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (17)	Tremor severity	Mirtazapine versus placebo	4	–3	0	0	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and short follow-up

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Accelerometer recording

Recording of the movements from a body segment to allow measurement of frequency, amplitude, or intensity of a tremor. Intensity of tremor is a measure of the overall magnitude of movement; it often refers to the product of the amplitude of tremor multiplied by its frequency.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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