Antiepileptic Drugs and the
Treatment of Essential Tremor
Dr. Connor is president of the Neurological Center at Oklahoma, Inc. in Tulsa.
Disclosure: Dr. Connor is on the speaker’s bureau for Ortho-McNeil.
Please direct all correspondence to: Gregory S. Connor, MD, Neurology Center of Oklahoma, 6585 South Yale Blvd, Suite 620, Tulsa, OK 74136; Tel:?918-481-4781; Fax: 918-481-4796; E-mail: GConnor488@aol.com.
• Essential tremor affects 1% to 4% of the population and has a substantial impact on occupational and physical activities.
• In some cases essential tremor may be inherited through autosomal
• Primidone and propranolol are the standard therapies for essential tremor; however, newer antiepileptic drugs may have a role in the treatment of essential tremor.
Essential tremor affects 1% to 4% of the population and can have a substantial impact on physical and social activities. Up to 50% of those affected are functionally disabled and approximately 20% are unable to work. The pathophysiology of essential tremor is distinct from that of Parkinson’s disease and may involve alterations in the activities of the neurotransmitters glutamate and γ-aminobutyric acid. Primidone, an antiepileptic drug (AED), has been the standard treatment for essential tremor. This review will present evidence for the use of newer AEDs, such as gabapentin and topiramate, in the treatment of this disorder.
Essential tremor is an undertreated neurological disorder that can have a substantial impact on a patient’s daily physical and social activities. The pathophysiological causes underlying the involuntary movements associated with this disease are just recently beginning to be explored. By uncovering more information regarding the pathophysiology of essential tremor, physicians may be able to better utilize existing medications, and look forward to the development of new drugs that specifically target the root causes of the disease. The standard drugs that have demonstrated efficacy in the treatment of essential tremor include the β-blocker propranolol and the antiepileptic drug (AED) primidone. However, the newer AEDs, including gabapentin and topiramate, have also demonstrated promise in the treatment of essential tremor.
Tremor is the most common of the various involuntary movement disorders and essential tremor is thought to be the most common tremor disorder. It is not clear precisely how many patients are afflicted with essential tremor, as epidemiological studies of the disorder vary widely in their estimates of prevalence, ranging from <1% to 4% of the population.1 The incidence of essential tremor is thought to increase with age, and may be 10–20 times higher for patients >80 years of age than for those between 20 and 39 years of age.2 A more recent epidemiological study of elderly patients in Spain found that the prevalence of essential tremor increased at ≥65 years of age, peaking at about 7% in the oldest patients (Figure 1).3 The wide range of estimated prevalence is probably due to a lack of consistent definition of the disorder prior to 1998, as well as disparate study methodologies.
The direct and indirect costs of essential tremor are difficult to ascertain, because the disorder is often misdiagnosed as Parkinson’s disease and is not consistently reported among elderly patients and their families (who may misinterpret the symptoms as a natural consequence of aging). A significant proportion of patients with essential tremor are functionally disabled, with ≤20% experiencing impaired job performance and/or early retirement.4
A review of 678 patients by Koller and colleagues5 found that 40% to 50% of patients with essential tremor experienced a distinct functional disability, and 18% experienced disability at work. Essential tremor can exact a psychological price as well as impair physical performance. One study suggested that essential tremor may contribute to the development of social phobia. As many as 33% of essential tremor patients had a lifetime prevalence of primary or secondary social phobia.6
The Movement Disorder Society recently published a consensus statement on the classification of tremor disorders based on clinical criteria, such as tremor frequency, common circumstances for activation, and family/medical history (Table 1).7 Classic essential tremor is typically a persistent symmetric postural or kinetic tremor (4–12 Hz) involving the hands, forearms, and the head, and may be exacerbated by heightened emotional or physical states or by stimulants such as caffeine or methylphenidate.8 The Consensus Statement of the Movement Disorder Society also lists criteria that exclude the diagnosis of essential tremor.7 Some common exclusion criteria would be medication-related tremor, thyroid disease, various dystonias, and degenerative disorders, such as Parkinson’s and Huntington’s.
Although essential tremor can appear at any age, it is thought to be a progressive condition that typically first appears between 40 and 60 years of age. As patients age, tremor frequency decreases while amplitude increases.9 Genetic mapping studies suggest that essential tremor may develop through the autosomal dominant mode of inheritance,10,11 and two studies indicated that inherited essential tremor is associated with specific genes. Gulcher and colleagues12 utilized genetic mapping of 16 Icelandic families, including 75 individuals afflicted with essential tremor, and found a linkage to a gene (termed FET or FET1) located on chromosome 3q.12 Higgins and colleagues13 performed a linkage analysis for 138 members of an American family of Czechoslovakian heritage, 18 of whom were afflicted with essential tremor, and discovered a linkage to a gene (ETM) on chromosome 2p. A subsequent study by the same group linked the ETM gene to essential tremor in three other unrelated families.14 The familial or inherited version of essential tremor may be characterized by early onset of symptoms, which may occur progressively earlier in subsequent generations in some families with distinct genetic mutations (Figure 2).15 New research may uncover what role these candidate genes play in the development and pathophysiology of essential tremor, and may permit the early identification of likely patients.
Essential tremor is not associated with the kind of concrete pathophysiological abnormalities that are the hallmark of Parkinson’s disease. Evidence suggests that an electrochemical “pacemaker” exists in the inferior olive and thalamic nuclei in the normal state.16 The evolution of normal oscillating neuronal activity to a pathophysiologic state such as essential tremor is not clear, but may involve increased electronic coupling of neuronal populations in the inferior olive.16 There is also evidence that afferent neuronal projections to the inferior olive, which utilize the neurotransmitters glutamate and γ-aminobutyric acid (GABA) to modulate synchronous neuronal firing,17 may be involved in essential tremor. The modulatory effects of glutamate and GABA are likely mediated through the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate and GABAA receptor subtypes in the inferior olive.18,19 Essential tremor has been associated with increased concentrations of excitatory neurotransmitters, such as glutamate, in cerebrospinal fluid, and with decreased concentrations of inhibitory transmitters, such as GABA and glycine.20
Essential tremor has been associated with several other neurological and psychiatric disorders, including Parkinson’s disease, neuropathies, migraine, and social phobia, although the association between essential tremor and Parkinson’s disease has been a source of debate. Hubble and colleagues21 reviewed studies spanning almost 30 years reflecting the lack of consensus. The pathophysiologic hallmarks of Parkinson’s disease (eg, neuronal death in the substantia nigra and locus coeruleus) provide clear differentiation with essential tremor, as do the clinical manifestations of each disease.22 However, there continue to be reports suggesting an association between the two conditions. Recently, Yahr and colleagues23 described a multigenerational family where several members were afflicted with essential tremor at an early age, and subsequently developed Parkinson’s in their fifth decade.
Roussy-Levy syndrome, an inherited neuropathy characterized by areflexia, limb weakness, tremor, gait ataxia, and sensory loss, has been described as a hypertrophic variant of Charcot-Marie-Tooth syndrome with essential tremor.24 Biary and colleagues25 noted an association between essential tremor and migraine in a study of 240 patients.Patients with essential tremor were twice as likely to be afflicted with migraines (36% versus 18% control), and patients with migraine were more likely to be afflicted with essential tremor (17% versus 1% control). Not surprisingly, it was shown that the disabilities associated with essential tremor may lead patients to avoid social situations where their tremor may cause embarrassment. In some patients social phobia may develop subsequent to the emergence of essential tremor.6
Treatment of Essential Tremor
The utility of AEDs in the treatment of essential tremor is not new, as primidone has long been considered a primary pharmacologic treatment for essential tremor. However, the development of newer AEDs, or neurostabilizers, has led to more exploration of their utility in the treatment of this disorder.
Primidone is an AED that is metabolized into two major metabolites: phenylethylmalonamide and phenobarbital. Although it was initially suggested that the efficacy of primidone was due to the actions of its barbiturate metabolite, which accentuates inhibitory neurotransmission at the GABAA receptor, subsequent studies suggested that primidone itself, another active metabolite, or some combination thereof, was associated with tremor reduction.26 Eight double-blind, placebo-controlled trials and 13 open-label trials of primidone in essential tremor were recently reviewed.27 Although number of participants in the studies were generally small, most patients experienced tremor reduction with primidone.
The most recent of the reviewed studies included a longer-term study of 11 patients who had responded to primidone therapy over a 4-week period.28 Mean tremor magnitude decreased by approximately 40% to 50% and remained reduced at 12 months. Following the discontinuation of primidone therapy, tremor magnitude reverted to pretreatment levels. While mean accelerometry remained reduced through 12 months, other clinical assessments suggested that the clinical effect of primidone might have attenuated over time. It should be noted, however, that accelerometry, an electrophysiologic measure of the amplitude and frequency of tremor, often correlates poorly with clinical response. A subsequent crossover study using primidone and phenobarbital in 15 patients found that treatment with primidone, but not phenobarbital, was associated with a significant reduction in the magnitude of hand tremor. Neither drug was associated with statistically significant improvements in head tremor compared to placebo, although the number of patients may have rendered the assessment not sufficiently sensitive.
Acute reactions to primidone are common—approximately 30% of patients experience a flu-like syndrome or ataxia,21 which usually lasts only several days. Patients should be advised that acute reactions are temporary and they should not discontinue the drug because of them. Once beyond the initial side effects, primidone is very well tolerated long-term, in marked contrast to propranolol, which is typically very well tolerated short-term but has a more cumulative side-effect profile over time.
The case studies are poor in their methods of rating tremor. Unfortunately, even in controlled studies there is no commonly accepted uniform scale that allows comparison of one study to the next.
Newer Antiepileptic Drugs
Gabapentin and topiramate have shown some promising results for the treatment of essential tremor in a variety of case studies, open-label studies, and controlled studies. However, these trials are limited by small sample sizes and lack of uniformity in tremor ratings.
Gabapentin exhibits some structural similarity to GABA, although it is not clear if the clinical actions of the drug are due to GABA-mimetic or antagonistic activity. Proposed biochemical mechanisms of action of gabapentin include increased GABA synthesis,29 inhibition of L-type calcium channels,30,31 and competitive inhibition of branched-chain amino-acid aminotransferase32—an enzyme partially responsible for glutamate synthesis. Several studies have assessed the efficacy of gabapentin in the treatment of essential tremor.
A case series of five patients with essential tremor of the upper limbs utilized gabapentin ≤1,800 mg/day administered in divided doses as monotherapy.33 Each patient exhibited some improvement in essential tremor symptoms, and two patients exhibited elimination of grade 2 tremor at 1,800 mg/day.
Two patients elected to discontinue treatment, one due to hypertension and one due to anxiety. A second case series assessed gabapentin for the open-label treatment of various movement disorders in 23 patients, including five diagnosed with essential tremor.34 Dosing was initiated at 300 mg/day and increased gradually to 600 mg/day in four doses. The five patients with essential tremor all had an excellent response, not further defined by the author, at a mean dose of 1,020 mg/day. Merren35 reported on a series of eight patients with essential/familial tremor who were treated adjunctively with gabapentin. Six patients reported moderate improvement and one reported excellent improvement with gabapentin. The mean daily dose for the patients with essential tremor was approximately 900 mg, often administered BID?or TID. More recently, a case series of patients with varied tremor disorders found that gabapentin appeared to exhibit better efficacy in patients with orthostatic tremor or tremor associated with multiple sclerosis than in patients with essential tremor.36
Pahwa and colleagues37 conducted a double-blind placebo-controlled crossover study of gabapentin administered adjunctively in 14 of 20 patients The remaining six were monotherapy. There was no significant change from baseline for patients treated with gabapentin or placebo on the Fahn-Tolosa-Marin tremor rating scale. Gironell and colleagues38 conducted a double-blind, placebo-controlled crossover study with 16 patients diagnosed with essential tremor. Following washout of previously administered tremor medications, patients received gabapentin 400 mg TID, propranolol 40 mg TID, or placebo for 15 days with a 1-week washout period between treatments. Patients treated with gabapentin or propranolol exhibited significant reductions in mean scores on the Fahn-Tolosa-Marin clinical rating scale and accelerometry measurements. The authors hypothesized that the differences in gabapentin’s efficacy compared to the study by Pahwa and colleagues may have been due to the washout of concurrent tremor medications, suggesting that a better relative picture of a given tremor medication’s efficacy might be achieved by studying it as monotherapy.
Ondo and colleagues39 subsequently assessed gabapentin in 25 patients in a double-blind, placebo-controlled crossover study utilizing gabapentin at doses of 1,800 mg/day and 3,600 mg/day. Gabapentin was associated with improvement on some sections of the Unified Tremor Rating Scale (activities of daily living, pouring, observed tremor), but not in accelerometry scores, spirographs, and investigator global impression scores. Higher doses (3,600 mg/day) of gabapentin were not superior to lower doses.
Topiramate is a newer AED that has shown efficacy in the treatment of several neurological and psychiatric disorders, including binge-eating disorder, migraine,40,41 and essential tremor. Several potential mechanisms of action have been associated with topiramate, including state-dependent inhibition of voltage-gated sodium channels, inhibition of high-voltage gated calcium channels, inhibition of glutamate-mediated neurotransmission at AMPA/kainate receptor subtypes, enhancement of GABAA receptor-mediated chloride flux, and inhibition of selected subtypes of carbonic anhydrase.42
The first report regarding the potential efficacy of topiramate in the treatment of essential tremor was a case series of 11 patients, most of whom were treated adjunctively with topiramate.43 The concomitant tremor medications included primidone, clonazepam, lorazepam, clorazepate, and gabapentin. Subjective rating of improvement ranged from 25% to 80%; 7 of 11 patients reported ≥75% improvement in their tremor. Four of the 11 patients were able to discontinue concomitant medications (primidone, clonazepam) while one reduced the primidone dosage by 50%. Subsequently, a randomized, double-blind, placebo-controlled crossover study was performed in 24 patients with essential tremor.44 Treatment with topiramate was initiated at 25 mg/day and increased weekly by 25–50 mg/week up to 200 mg/day. Thereafter, the dose was increased by ≤100 mg/week to the maximum target dose of 400 mg/day or to the maximum tolerated dose. Most patients (20/24) were treated with topiramate as monotherapy. Significant decreases in tremor symptoms were exhibited as assessed by the Tremor Rating Scale, which included assessments of severity, motor function, and functional disability. A second open-label study in a series of nine patients with disabling essential tremor has also been reported. The patients reported a 60% improvement in drawing Archimedes spirals and a 53% improvement in an activities of daily living self-questionnaire.45
Preliminary results from 62 patients that participated in a double-blind, placebo-controlled, crossover trial of topiramate suggest that this medication is effective in the treatment of essential tremor.46 Topiramate was started at 25 mg/day and titrated by 25–50 mg/week until a daily dose of 200 mg/day was achieved. The dose was then increased by 100 mg/week until 400 mg/day or the maximum tolerated dose was reached. Treatment with topiramate was associated with significantly lower total scores on the Fahn-Tolosa-Marin Clinical rating scale, and on scores for each of the subscales (severity, motor tasks, and functional disability). The most common adverse events included paresthesia, difficulty with concentration, and weight loss/reduced appetite. However, as with most AEDs, starting with a low initial dosage and slowly titrating the dosage over time can minimize the side effects of topiramate.
The utility and promise of AEDs in the treatment of essential tremor should be the subject of further investigation. By adapting clinical use to the strengths and weaknesses of each drug, physicians should be able to optimize results. For example, most AEDs should be started at a low dose and titrated to an effective dose gradually, to optimize tolerability. Patients should be counseled as to what side effects they should expect and which side effects they should bring to the attention of their doctor. They should also be informed that some side effects are common during titration and may resolve with time, continued therapy, or an adjustment in dose. As clinical evidence builds regarding the efficacy of AEDs in the treatment of essential tremor and comorbid conditions, the hope is that these additional treatment options will offer physicians and patients additional tools with which to maximize efficacious treatment. PP
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