Abstract
The safety and efficacy of topiramate (400 mg/d or maximum tolerated dose) as monotherapy or adjunctive treatment of essential tremor were investigated in a placebo-controlled, crossover study (n = 24). Topiramate resulted in significantly greater reductions from baseline based on normalized scores for a clinical rating of tremor location/severity, specific motor tasks/functional disabilities, and tremor-resultant functional disabilities. Most common adverse events were appetite suppression/weight loss and paresthesias.
Traditional treatments for essential tremor (ET) often exhibit limited effectiveness and tolerability. Propranolol and other β-adrenergic blockers and primidone, for example, have demonstrated restricted efficacy and side effects may occur.1 The carbonic anhydrase inhibitors methazolamide and acetazolamide have been used for the treatment of ET, however, their efficacy is modest.2,3⇓ More recently, gabapentin, a drug structurally similar to γ-aminobutyric acid, has been evaluated for the treatment of ET.4 Although only 54 patients have been evaluated in three separate trials, gabapentin was generally well-tolerated and results demonstrated that this drug may be effective in some cases of ET.4
Topiramate is a broad-spectrum anticonvulsant with several pharmacologic actions that include enhancement of γ-aminobutyric acid activity, carbonic anhydrase inhibition, antagonism of α-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid/kainate receptors, and blockade of voltage-dependent calcium and sodium channels.5 Preliminary open-label investigations indicate that topiramate may be clinically useful in the treatment of ET.6,7⇓ Therefore, the current placebo-controlled, crossover study was conducted to evaluate further the efficacy and safety of topiramate in the treatment of ET.
Methods.
Patient characteristics.
Twenty-nine patients were eligible for study and five patients declined participation (figure). Half of the 24 participants were enrolled from the author’s clinical practice, and the remaining patients were recruited by advertisement. Enrollment was from September 1998 through October 1999. All patients gave informed written consent. Diagnosis of ET was based on the Tremor Investigational Group criteria for definite or probable essential tremor.8 Tremor assessment for both diagnosis and treatment was based on a clinical rating scale developed by Fahn et al.9 Inclusion criteria were: age 18 or older; diagnosis of symptomatic ET involving the hands, head, or voice; if female, use of an acceptable form of birth control; if on medication for tremor, use of a stable dose of this medication for at least 4 weeks before study entry and continued use of this dose throughout the study. Exclusion criteria were: epilepsy; a history of nephrolithiasis; current use of carbonic anhydrase inhibitors; known hypersensitivity to topiramate or to carbonic anhydrase inhibitors; if female, pregnancy or lactation; use of an experimental drug or experimental device within 30 days; tremor caused by other neurologic/endocrinologic conditions (including PD).
Figure. Study design. aNo patient withdrew during period 2. bPatient went to another neurologist who discontinued treatment.
Study design.
The study was approved by the institutional review board of St. Francis Hospital, Tulsa, OK. At baseline, complete medical histories were recorded for eligible and consenting patients, and subjects were randomized to either topiramate or placebo in one of two possible orders (topiramate followed by placebo or vice versa). Treatments were separated by a 2-week washout period. Topiramate or matching placebo was administered at 25 mg/d for the first week, followed by weekly increases of 25 to 50 mg/d until a dosage of 200 mg/d was reached. The dosage could then be increased once a week by up to 100 mg/d until a dosage of 400 mg/d or a maximum tolerated dose was reached, and this dose was then continued for 2 weeks.
Tremor was assessed at baseline before each treatment and after 2 weeks on the maximum tolerated dose or 400 mg/d. The same rater performed evaluations throughout the study. Assessment was based on tremor rating scores for tasks based on scales from 0 to 4. Tasks were divided into three parts—tremor location and severity, specific motor tasks/functional disabilities, and tremor-resultant functional disabilities—with a total possible score of 156. Because these parts were not composed of equal numbers of items, the mean of each was used as a normalized subscore value. For the subscale of location/severity, the denominator in the calculation of the mean was the number of items evaluated with a score ≥ 1 at baseline or final visit. The three mean normalized subscores were then summed to yield an overall normalized tremor rating score with a possible range of 1 to 12.
The primary efficacy variable was the change from baseline in the overall normalized tremor rating score after 2 weeks at the final dose of topiramate or placebo. Secondary variables included the normalized scores for each part of the total tremor rating score, the unadjusted total tremor rating score, and each of the unadjusted scores for the three parts of the tremor rating scale.
Statistical analysis.
The significance of any difference between topiramate and placebo was assessed by analysis of covariance for a two-period, two-treatment, crossover study with the baseline value as covariate based on all patients who completed both treatment periods and on all randomized patients who received study medication (an imputed intent-to-treat analysis in which baseline values were substituted for any missing values). Sample size was based on practical rather than statistical considerations.
Results.
Nine women and 15 men were enrolled in the study (see the figure). Overall, 23 of 24 patients had hand tremor; 2 of 24 had hand, head, and voice tremor; 1 of 24 had head and voice tremor; and 1 of 24 had hand and head tremor. The average age was 63.4 years (range 22 to 75 years). Twelve patients were receiving stable dosages of one or more of the following agents: primidone, a beta-blocker, theophylline, a benzodiazepine, cyclobenzaprine, carbamazepine, amitriptyline, carisoprodol, or gabapentin. Nine patients were receiving one drug and three patients were receiving two or three drugs.
The mean dose of topiramate attained was 333 mg. Topiramate resulted in greater reductions from baseline than placebo in mean normalized tremor rating scores among patients completing the study (table 1; −1.38 with topiramate treatment vs −0.07 with placebo; p = 0.001) and for all patients based on an imputed intent-to-treat analysis (see table 1; −0.88 with topiramate treatment vs −0.15 with placebo; p = 0.015). Reductions in each of the normalized tremor scale subscores also were significantly greater for topiramate than placebo (see table 1). In addition, the reduction in the unadjusted total tremor score was greater for topiramate than for placebo (p = 0.006). Percentage changes in normalized tremor scores ranged from 7.32% to −12.15% for patients on placebo treatment, and from 0% to −60.81% in topiramate-treated patients (table 2). In period 1, total normalized tremor scores improved in 83% of topiramate-treated patients vs 40% of placebo-treated patients; such improvements were seen in 78% vs 33% of patients in period 2. In all analyses, no carryover effects were found between study periods. The most common adverse events with topiramate treatment were appetite suppression/weight loss and paresthesias.
Changes in normalized overall tremor rating scores and subscores
Summary of normalized tremor score by period for subjects completing periods 1 and 2
Discussion.
In this study, comparing topiramate with placebo in the treatment of ET, the primary efficacy analysis as well as an imputed intent-to-treat analysis indicated that topiramate significantly reduced ET. Topiramate was well tolerated; of the nine patients who withdrew from the study, all discontinued during period 1 and only three of nine discontinued because of adverse events (two treated with topiramate and one with placebo).
In a retrospective review of records of 11 patients undergoing open-label topiramate treatment (doses: 75 to 400 mg/d) for 2 to 21 months for ET, subjective ratings or improvement in tremor ranged from 25 to 80%, 7 of 11 subjects reported improvements of 75% or more, and 4 patients discontinued other medications for tremor.6 Side effects included weight loss, paresthesias, and memory problems. In the current study, weight loss and paresthesias were the most frequently reported adverse events in topiramate-treated patients. These are also among the most common adverse events seen in seizure treatment with topiramate.10 Paresthesias with topiramate therapy may be caused by its carbonic anhydrase inhibition.
ET was assessed using the clinical rating scale of Fahn et al.9 That the scale has not been systematically validated, however, represents a potential limitation to this study. In this pilot trial, a single investigator performed tremor assessments as well as evaluated subjective patient assessments of efficacy and tolerability. Further studies should incorporate use of an investigator blinded to medication effects to perform tremor assessments as well as a parallel group, placebo-controlled design.
Acknowledgments
Supported by a research grant from Ortho-McNeil Pharmaceutical.
Footnotes
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G.S.C. is a member of the Ortho-McNeil speaker’s bureau.
- Received November 7, 2000.
- Accepted March 30, 2002.
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