Effect of amantadine in essential tremor: a randomized, placebo-controlled trial.

There is a need for new medication for essential tremor (ET). Preliminary evidence suggests that amantadine may be effective in the treatment of ET. We studied the effects of amantadine in a double-blind, cross-over, placebo-controlled trial in ET patients. Sixteen patients with ET received amantadine 100 mg b.i.d. and placebo for 15 days, with a 1-week wash-out period between treatments. Major evaluation outcomes consisted of a tremor clinical rating scale, accelerometric recordings, and a self-reported disability scale obtained before drug intake and on study days 1 and 15 of each treatment period. A two-way repeated measures analysis of variance (treatment, time) was applied. Any P value < 0.05 was considered significant. On day 15, amantadine did not demonstrate any significant efficacy in reducing tremor with respect to baseline in any tremor measures. An increase in postural tremor as an adverse effect of amantadine was referred by 37.5% of patients. Results from the present trial indicate amantadine at 100 mg b.i.d. is not effective as a treatment for ET.     

Zonisamide for essential tremor: An evaluator‐blinded study

In this evaluator‐blinded open‐treatment trial, subjects with moderate/severe upper limb essential tremor were titrated to 300 mg/day zonisamide, or adjusted to a lesser dose if symptoms warranted, as monotherapy or as adjunct to stable antitremor medication, followed by a 12‐week extension phase. The primary efficacy outcome variables were blinded rater videotaped/drawing tremor score changes at the Treatment and Extension visits compared to Baseline, based on Fahn‐Tolosa‐Marin and Postural Tremor Scales. Subjects also rated Functional Disabilities. Primary outcomes showed reduced tremor scores at the Treatment (P < 0.00001, n = 25) and Extension (n = 16) visits, at mean doses of 252 and 225 mg/day, respectively. Subject ratings indicated 200 mg/day was superior to 100 mg/day, whereas 300 mg/day produced no additional benefit, but instead was associated with more adverse symptoms, most commonly somnolence, poor energy, imbalance, and altered taste. Future double‐blind placebo‐controlled trials are warranted. © 2008 Movement Disorders Society     

A pilot, double-blind, placebo-controlled trial of pregabalin (Lyrica) in the treatment of essential tremor.

We performed a pilot, double-blind, placebo-controlled, randomized trial to evaluate the efficacy and tolerability of pregabalin (PGB, Lyrica), an antiepileptic agent, in treating essential tremor (ET). Twenty two patients with ET were randomly assigned to receive PGB or placebo. PGB was initiated at 50 mg/day and was escalated by 75 mg/day every 4 days to a maximum dose of 600 mg/day. Patients were evaluated by accelerometry and the Fahn-Tolosa-Marin (FTM) rating scale. There was a significant reduction in tremor amplitude in the PGB group compared with the placebo group, as measured by accelerometry, at a mean dose of 286.76+/-100.05 mg/day. Action tremor limb scores on the FTM also improved in the PGB group compared with the placebo group (P-value for multilevel modeling=0.04). PGB was fairly well tolerated, with about one-third of patients dropping out of the study because of adverse events. PGB provided significant improvements in accelerometry and in action tremor limb scores on the FTM. However, larger studies are needed to further evaluate the potential effect of PGB on ET.     

A double-blind placebo-controlled trial of zonisamide (zonegran) in the treatment of essential tremor.

Medical therapy for essential tremor (ET), a common movement disorder, is often inadequate. We performed a double-blind placebo-controlled randomized trial to evaluate the efficacy and tolerability of zonisamide (ZNS), an antiepileptic agent, in treating ET. Twenty patients (mean age, 60 +/- 15 years) with ET were randomized to receive ZNS or placebo. ZNS was initiated at a dosage of 100 mg/day and escalated to 200 mg/day at day 14. Patients were evaluated by accelerometry and the Fahn-Tolosa-Marin (FTM) rating scale at baseline and days 14 and 28, as well as the Clinical Global Impression (CGI-C) scale at day 28. At endpoint, subjects assigned to ZNS were taking a mean dosage of 160 +/- 50 mg/day. There were no significant improvements in the FTM total score or its subsections. Tremor amplitude as assessed by accelerometry significantly improved in the ZNS group compared to the placebo group at endpoint relative to baseline (-0.50 +/- 0.72 vs. 0.30 +/- 0.79 m/s(2); P = 0.03). On the CGI-C, 60% (n = 6) of patients in the ZNS group felt that their tremor was unchanged, while the remaining patients felt that their tremor was "minimally improved." Thirty percent (n = 3) of patients taking ZNS discontinued the study due to side effects (fatigue, headache, paresthesias) while taking 100 mg per day. ZNS did not provide significant improvements in clinical rating scales at study endpoint compared to placebo and was only modestly well tolerated. ZNS was effective in reducing tremor amplitude as measured by accelerometry.     

Unusual forehead tremor in a patient with essential tremor.

Voice and head (neck) tremor commonly occur in patients with essential tremor (ET), but involvement of cranial musculature is generally limited to these specific cranial structures, and action tremor of the forehead has not been reported. We describe a patient with ET who had forehead tremor. The tremor seemed to be task-specific, and neurophysiological features suggested that the forehead tremor was dystonic. The presence of forehead tremor in a patient with ET probably indicates an additional pathophysiologic process. The explanation for the specificity of involvement of cranial musculature in ET is not known, but this clinical observation might help guide investigators who are interested in the underlying pathophysiology of this condition.     

Randomized trial comparing primidone initiation schedules for treating essential tremor.

Early side effects are common when primidone is used to treat essential tremor, with as many as one-third of patients failing to tolerate the tablets. Lower doses can be prescribed initially using a suspension formulation. We suspected suspension initiation would result in fewer early side effects, allow better acclimatization, and improve compliance. Forty patients with essential tremor were randomized to begin primidone treatment using either 2.5 mg doses in the suspension form or 25 mg doses in the tablet form. Doses gradually increased over 3 weeks to 150 mg/day. This was a double-blind, double-dummy trial. Medication cessation due to side effects was designated the primary end-point. Four patients in the suspension group and two in the tablet group dropped out due to early side effects, resulting in a relative risk of 1.9 (95% confidence interval 0.4 to 9.2). Side effects in the first 48 hours of treatment were equally common, affecting seven subjects in each group. Treatment benefits were the same in both groups. We concluded that use of a very low initial dose and a graduated titration schedule in suspension formulation did not appear to improve primidone tolerability. If anything, compliance tended to be worse when compared with the tablet formulation, though the study was under-powered to reject the null hypothesis of equivalence.     

Effects of levetiracetam on chronic pain in multiple sclerosis: results of a pilot, randomized, placebo-controlled study

Background and purpose:  Central neuropathic pain (CNP) is a prevalent and distressing symptom in patients with multiple sclerosis (MS). The anticonvulsant levetiracetam (LEV) has been shown to be efficacious in some types of CNP, but its efficacy in MS-related CNP has not been confirmed.
Methods:  To investigate the tolerability and potential effects of LEV against CNP in MS subjects, we performed a single-center, prospective, randomized, single-blind, placebo-controlled study in twenty patients with MS and CNP. Outcomes before and during the 3-month study were assessed using validated measures of pain, depression, disability and quality of life.
Results:  The medication was well tolerated and analysis revealed a significant difference between the LEV and placebo arm in all study outcomes related to pain (mean pain intensity score, mean pain difference, percentage of patients with a clinically significant pain reduction). Furthermore, the individual quality of life rating improved in treated patients, showing a significant correlation with pain reduction.
Conclusions:  These findings suggest that further studies with larger samples of patients be carried out in order to confirm the efficacy of LEV in MS-related CNP population.     

Is essential tremor predominantly a kinetic or a postural tremor? A clinical and electrophysiological study

Both postural and kinetic tremors may occur in essential tremor (ET), however the relative contribution of each is not clear. ET has been variably defined with respect to kinetic and postural tremors. To examine the relative severity of postural and kinetic tremors in ET, 50 ET cases from a clinic and 55 from a community underwent a videotaped tremor examination. Kinetic and postural tremors were rated using a validated clinical rating scale (score range, 0-3). Thirty-one cases also underwent accelerometry to precisely quantify tremor amplitude. In clinic cases, the mean postural tremor rating was 1.25 (S.D., 0.89). The mean kinetic tremor rating was 52% higher (1.90; S.D., 0.57; P < 0.001). The community cases had similar characteristics. Sixty percent of the 105 cases had postural tremor ratings scoring 0 or 1 (no tremor or low amplitude, intermittent tremor). In clinic cases, the mean amplitude of postural tremor during tremor analysis was 0.51 mm (S.D., 0.66 mm), and the mean amplitude of kinetic tremor was 2.91 mm (S.D., 2.11 mm; P < 0.01). Similar values were obtained for community cases. These quantitative data suggest that kinetic tremor is more severe than postural tremor in ET. The majority of cases had mild or absent postural tremor. Despite this, ET is defined only as a postural tremor in many studies. Our data argue for a more consistent inclusion of kinetic tremor in diagnostic criteria for ET.     

Report from a U.S. conference on essential tremor.

Seventy researchers met in Washington, DC, on 20-21 October 2005 to identify and discuss the most pressing research issues in essential tremor (ET). The conference attendees concluded that the following six objectives are of immediate and overriding importance: (1) a collaborative network of research centers; (2) an international committee for developing a standard protocol for the diagnosis and quantification of ET; (3) the identification of one or more genes for ET; (4) a centralized repository of DNA and, ideally, immortalized cell lines from well-characterized ET families and healthy controls; (5) a reliable and efficient repository of optimally prepared and categorized brain samples for hypothesis-driven neuropathological examinations in well-characterized ET patients; and (6) animal models of ET for screening promising drugs. The conference attendees hope that this statement from the United States will engender international collaboration in finding a cure for ET.     

Essential tremor centralized brain repository: diagnostic validity and clinical characteristics of a highly selected group of essential tremor cases.

We studied essential tremor (ET) cases enrolled in the Essential Tremor Centralized Brain Repository to (1) assess the validity of their diagnoses and (2) characterize the clinical features in a group of highly selected cases who might reflect a far end of the disease spectrum. Our over-arching goal was to provide a perspective of ET that complements that derived from population-based and clinic-based studies. Based on a history and videotaped examination, 94 of 100 ET cases had their diagnoses confirmed; most of the remainder had Parkinson's disease. When compared with ET cases ascertained through populations and clinics, a large proportion had been prescribed medication for tremor (87.2%), had a family history of tremor (88.3%), had rest tremor (33.0%), or had neck tremor (60.6%). One patient had facial tremor, which has not been reported previously. As has been reported once before, a large proportion wore hearing aids (26.9% of the 67 participants age>or=70). In summary, diagnostic validity was high. In terms of their clinical characteristics, the high proportion of cases with severe tremor and varied disease manifestations (neck tremor, rest tremor) make these cases a valuable resource in pathological studies; the high proportion with familial tremor would provide an enriched sample for genetic studies.     

Electrophysiologic transition from physiologic tremor to essential tremor.

We electrophysiologically examined the transition from physiologic tremor to essential tremor in people at risk for familial essential tremor. Two healthy people from different families with hereditary essential tremor were studied on multiple occasions. A 23-year-old man was studied in 1995, 1997, and 2004, and a 44-year-old woman was studied in 1993, 1995, 1997, and 2003. Hand acceleration and forearm electromyographic readings were measured with and without 300-g loading to determine the characteristic frequency-invariant motor unit entrainment of essential tremor. Clinically and electrophysiologically, the man and woman had normal tremor until the last examination, when both exhibited a fine tremulousness in the outstretched hands and frequency-invariant motor unit entrainment at 7.5 and 6.5 Hz, respectively. At no time did either patient exhibit a prominent 8-12 Hz component of physiologic tremor. Essential tremor in young adults may begin at frequencies less than 8-12 Hz, and this electrophysiologic abnormality is detectable when clinical examinations reveal only questionably abnormal tremor. More young adults at risk for essential tremor must be studied to determine whether initial frequencies less than 8 Hz are the rule or the exception. Nevertheless, the data from our 2 patients demonstrate that a prominent 8-12 Hz component of physiologic tremor does not always precede the development of essential tremor; therefore, the origins of essential tremor and the 8-12 Hz component of physiologic tremor may be different.     

Intention tremor of the head in patients with essential tremor.

Patients with essential tremor (ET) have kinetic arm tremor; this tremor can also have an intentional component. We are unaware of reports of intention tremor of the head in ET. Our aims were to describe, provide electrophysiological data and video documentation of, and estimate the prevalence of intention tremor of the head in our sample. Ten (9.0%; 95% confidence interval = 4.7%-14.3%) of 111 patients had intention tremor of the head; in 7 it involved the neck and in 3 the chin. These patients trended toward having more severe kinetic arm tremor and they had more severe intention tremor of the arms. These observations provide further support for the evolving view that the cerebellum may be involved in ET.     

Interest in participating in clinical research: A study of essential tremor patients.

Enrolling essential tremor (ET) patients in clinical research can be challenging. Investigators can maximize recruitment by targeting patient subgroups with greater interest in participation. Nothing has been published on factors that are associated with higher levels of interest in participation. The objective of this study was to identify factors associated with higher levels of interest in participating in clinical research on ET. A total of 149 ET patients were questioned about level of interest in participating in future research. Two questions were used, although one was of primary interest. Interest was rated from 0 to 10 (maximal). Data were collected on demographic factors, family history, and tremor-related disability. Tremor severity was assessed. The mean level of interest was 8.0 +/- 2.3. Level of interest was not related to age of tremor onset, tremor duration, tremor severity, extent of tremor-related disability, or use of tremor medication. Level of interest was related to family history of tremor (P < 0.05), concern that other family members might develop tremor (P < 0.05), >2 versus 0 live births in women (P < 0.05), the view that the tremor worsens with age (P < 0.05), and presence of head tremor (P = 0.05). A variety of factors were identified that were associated with greater interest in participating in clinical research. These observations should be assessed in additional patient samples. Investigators may use our observations to identify and target patients for clinical trials and other research.