T A Zesiewicz, R Elble, E D Louis, R A Hauser, K L Sullivan, R B Dewey, W G Ondo, G S Gronseth, W J Weiner, Quality Standards Subcommittee of the American Academy of Neurology
Practice parameter: therapies for essential tremor: report of the Quality Standards Subcommittee of the American Academy of Neurology.
Neurology. 2005 Jun 28;64(12):2008-20. doi: 10.1212/01.WNL.0000163769.28552.CD. Epub 2005 Jun 22.
Abstract/Text
BACKGROUND: Essential tremor (ET) is one of the most common tremor disorders in adults and is characterized by kinetic and postural tremor. To develop this practice parameter, the authors reviewed available evidence regarding initiation of pharmacologic and surgical therapies, duration of their effect, their relative benefits and risks, and the strength of evidence supporting their use.
METHODS: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 1966 and August 2004. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based on the level of evidence.
RESULTS AND CONCLUSIONS: Propranolol and primidone reduce limb tremor (Level A). Alprazolam, atenolol, gabapentin (monotherapy), sotalol, and topiramate are probably effective in reducing limb tremor (Level B). Limited studies suggest that propranolol reduces head tremor (Level B). Clonazepam, clozapine, nadolol, and nimodipine possibly reduce limb tremor (Level C). Botulinum toxin A may reduce hand tremor but is associated with dose-dependent hand weakness (Level C). Botulinum toxin A may reduce head tremor (Level C) and voice tremor (Level C), but breathiness, hoarseness, and swallowing difficulties may occur in the treatment of voice tremor. Chronic deep brain stimulation (DBS) (Level C) and thalamotomy (Level C) are highly efficacious in reducing tremor. Each procedure carries a small risk of major complications. Some adverse events from DBS may resolve with time or with adjustment of stimulator settings. There is insufficient evidence regarding the surgical treatment of head and voice tremor and the use of gamma knife thalamotomy (Level U). Additional prospective, double-blind, placebo-controlled trials are needed to better determine the efficacy and side effects of pharmacologic and surgical treatments of ET.
Joaquim J Ferreira, Tiago A Mestre, Kelly E Lyons, Julián Benito-León, Eng-King Tan, Giovanni Abbruzzese, Mark Hallett, Dietrich Haubenberger, Rodger Elble, Günther Deuschl, MDS Task Force on Tremor and the MDS Evidence Based Medicine Committee
MDS evidence-based review of treatments for essential tremor.
Mov Disord. 2019 Jul;34(7):950-958. doi: 10.1002/mds.27700. Epub 2019 May 2.
Abstract/Text
BACKGROUND: Essential tremor is one of the most prevalent movement disorders. Many treatments for essential tremor have been reported in clinical practice, but it is uncertain which options have the most robust evidence. The International Parkinson and Movement Disorder Society commissioned a task force on tremor to review clinical studies of treatments for essential tremor.
OBJECTIVES: To conduct an evidence-based review of current pharmacological and surgical treatments for essential tremor, using standardized criteria defined a priori by the International Parkinson and Movement Disorder Society.
METHODS: We followed the recommendations of the International Parkinson and Movement Disorder Society Evidence Based Medicine Committee.
RESULTS: Sixty-four studies of pharmacological and surgical interventions were included in the review. Propranolol and primidone were classified as clinically useful, similar to Topiramate, but only for doses higher than 200 mg/day. Alprazolam and botulinum toxin type A were classified as possibly useful. Unilateral Ventralis intermedius thalamic DBS, radiofrequency thalamotomy, and MRI-guided focused ultrasound thalamotomy were considered possibly useful. All the above recommendations were made for limb tremor in essential tremor. There was insufficient evidence for voice and head tremor as well as for the remaining interventions.
CONCLUSION: Propranolol, primidone, and topiramate (>200 mg/day) are the pharmacological interventions in which the data reviewed robustly supported efficacy. Their safety profile and patient preference may guide the prioritization of these interventions in clinical practice. MRI-guided focused ultrasound thalamotomy was, for the first time, assessed and was considered to be possibly useful. There is a need to improve study design in essential tremor and overcome the limitation of small sample sizes, cross-over studies, short-term follow-up studies, and use of nonvalidated clinical scales. © 2019 International Parkinson and Movement Disorder Society.
© 2019 International Parkinson and Movement Disorder Society.
Y Kuroda, R Kakigi, H Shibasaki
Treatment of essential tremor with arotinolol.
Neurology. 1988 Apr;38(4):650-2.
Abstract/Text
We investigated the effect of arotinolol, a new peripherally acting beta-adrenergic blocker, in 15 patients with essential tremor. The patients received 30 mg per day of arotinolol for 8 weeks. Accelerometer readings showed a significant reduction in amplitude of postural tremor after treatment. Action tremor also improved to essentially the same degree as postural tremor. The present findings support the view that the therapeutic effect of beta-blockers in essential tremor is mediated by peripheral beta-adrenergic receptors.
柳澤信夫、田代邦夫、東儀英夫ほか：Arotinololの本態振戦に対する臨床的有用性の検討．多施設二重盲検法による第Ⅲ相群間比較試験．医学のあゆみ 1993; 165: 215-240.
Kwang-Soo Lee, Joong-Seok Kim, Jae-Woo Kim, Won-Yong Lee, Beum-Seok Jeon, Dongjae Kim
A multicenter randomized crossover multiple-dose comparison study of arotinolol and propranolol in essential tremor.
Parkinsonism Relat Disord. 2003 Aug;9(6):341-7.
Abstract/Text
BACKGROUND: A new medication is needed to treat essential tremor. Preliminary evidence suggests that arotinolol may be effective in the treatment of this disorder.
OBJECTIVE: To study the effect of arotinolol and propranolol in a crossover, multiple dose comparative trial of patients with essential tremor.
PATIENTS AND METHODS: One hundred and seventy-five outpatients, with essential tremor were included in the study; 161 patients completed the study. Patients were identically evaluated at eight consecutive visits. The study consisted of two treatments, which were arranged according to a crossover design that evaluated the dose of each (arotinolol 10 mg per day and propranolol 40 mg per day, arotinolol 20 mg per day and propranolol 80 mg per day, arotinolol 30 mg per day and propranolol 160 mg per day). Each course of treatment lasted 6 weeks. Major outcome evaluations consisted of a self-reported disability scale, and motor performance score obtained before drug intake and 14 days after each treatment. The treatment effects were evaluated by analysis of variance using the Hills-Armitage test.
RESULTS: Arotinolol was found to be as effective as propranolol at reducing tremor. Drug effects as evaluated using motor-task performance scores revealed that arotinolol had a more significant effect than propranolol.
CONCLUSIONS: Arotinolol may be more useful than propranolol for the treatment of essential tremor.
Hideto Miwa, Tomomi Kubo, Ai Suzuki, Tomoyoshi Kondo
Effects of zonisamide on c-Fos expression under conditions of tacrine-induced tremulous jaw movements in rats: a potential mechanism underlying its anti-parkinsonian tremor effect.
Parkinsonism Relat Disord. 2009 Jan;15(1):30-5. doi: 10.1016/j.parkreldis.2008.02.008. Epub 2008 Aug 8.
Abstract/Text
OBJECTIVES: To examine the mechanisms underlying the anti-tremor effect of zonisamide in rats under conditions of tacrine-induced tremulous jaw movements (TJMs).
METHODS: Male adult rats received systemic administration of either zonisamide (5 or 50mg/kg) or vehicle at 20min prior to the administration of tacrine hydrochloride (5mg/kg). Animals were sacrificed 2h later, and the brains collected and immunostained for quantitative assessment of c-Fos expression.
RESULTS: There was no effect of zonisamide on tacrine-induced c-Fos expression in the ventrolateral striatum, a primary site of the pharmacological action of tacrine. Zonisamide suppressed the tacrine-induced c-Fos expression in the cortex, the dorsal striatum, and the nucleus accumbens, which are involved in the architecture of the cortico-basal ganglia-thalamocortical circuits.
CONCLUSION: The anti-TJM effect of zonisamide may not relate to suppression of neural activity specifically in primary tremor-generating sites, but may be due to a more broad inhibitory effect on tremor-related structures such as the cortex or the striatum. This effect of zonisamide may be a contributing mechanism underlying its therapeutic efficacy on parkinsonian tremor.
Günther Deuschl, Jan Raethjen, Helge Hellriegel, Rodger Elble
Treatment of patients with essential tremor.
Lancet Neurol. 2011 Feb;10(2):148-61. doi: 10.1016/S1474-4422(10)70322-7.
Abstract/Text
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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Fred Rincon, Elan D Louis
Benefits and risks of pharmacological and surgical treatments for essential tremor: disease mechanisms and current management.
Expert Opin Drug Saf. 2005 Sep;4(5):899-913. doi: 10.1517/14740338.4.5.899.
Abstract/Text
Essential tremor (ET) is a neurological disease (and possibly a family of diseases) whose most recognisable feature is an action tremor of the hands and occasionally of the voice and head. Current data support the view that CNS gamma-amino-butyric acid (GABA)-ergic mechanisms may underlie ET and that the tremor may be further modulated by peripheral (muscle) adrenoreceptors. Potential pharmacotherapeutic options, targeted to influence the activity of the neurotransmitter GABA within the CNS and the peripheral adrenergic receptors, are part of the current armamentarium to treat ET. As such, primidone and propranolol remain the mainstays of the therapy for ET. Intramuscular injections of botulinum toxin A may play a role in the treatment of voice and head tremor. Surgical options, which are reserved for patients with severe, medically-refractory tremor, provide adequate tremor control in the majority of patients. As with other progressive neurological disorders of late life, the ability to use neuroprotective medications to intervene in the developing disease to either slow or halt the progression of the pathological process, would involve an understanding of underlying disease mechanisms. The understanding of these mechanisms in ET is limited and further study of these mechanisms is critical for the development of such therapies.
William G Ondo
Essential tremor: treatment options.
Curr Treat Options Neurol. 2006 May;8(3):256-67.
Abstract/Text
The treatment of essential tremor depends on the tremor severity, location, and risk benefit ratios. Mild to moderate tremor usually will respond to oral agents such as noncardiac selective beta-blockers or primidone. Other agents including ethanol, topiramate, benzodiazepines, gabapentin, levetiracetam, and zonisamide may be effective. There are very little data comparing different oral agents, but there is support for polypharmacy in some cases. Botulinum toxin injections are effective in some tremor patterns, especially wrist flexion/extension and head tremor. For severe tremor, surgical lesioning or deep brain stimulation of the thalamus is justified and often dramatically improves function.
Joaquim Jos Ferreira, Cristina Sampaio
Essential tremor.
Clin Evid (Online). 2007 May 1;2007. Epub 2007 May 1.
Abstract/Text
INTRODUCTION: Essential tremor is one of the most common movement disorders throughout the world, with prevalence in the general population of 0.4-3.9%. 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.
W C Koller, B Vetere-Overfield
Acute and chronic effects of propranolol and primidone in essential tremor.
Neurology. 1989 Dec;39(12):1587-8.
Abstract/Text
We studied the acute and chronic effects of propranolol and primidone in essential tremor by administering long-acting propranolol (80 to 160 mg/d) and primidone (50 to 250 mg/d) to 50 patients. We evaluated patients at 1, 3, 6, 9, and 12 months after treatment and assessed tremor by subjective rating by patients, clinical scoring, and thermographic (accelerometer) recordings. Acute adverse reactions occurred in 8% with propranolol and 32% with primidone. Propranolol was without therapeutic effect in 30%, and 32% had no benefit from primidone. Significant chronic side effects occurred in 17% taking propranolol and in 0% with primidone. Tolerance to drug effect occurred with chronic treatment in 12.5% of patients with propranolol and 13.0% with primidone. We conclude that propranolol and primidone are effective long-term treatment for some patients with essential tremor. Acute adverse reactions with primidone and side effects with chronic use of propranolol hamper therapy.
W G Ondo, J Jankovic, G S Connor, R Pahwa, R Elble, M A Stacy, W C Koller, L Schwarzman, S-C Wu, J F Hulihan, Topiramate Essential Tremor Study Investigators
Topiramate in essential tremor: a double-blind, placebo-controlled trial.
Neurology. 2006 Mar 14;66(5):672-7. doi: 10.1212/01.wnl.0000200779.03748.0f. Epub 2006 Jan 25.
Abstract/Text
BACKGROUND: Essential tremor is most prevalent and most disabling in older patients. Additional therapies are required for patients with an inadequate response or intolerable side effects. In small trials, topiramate appeared to be beneficial in essential tremor.
METHODS: In this multicenter, double-blind, placebo-controlled, parallel-design trial, patients with moderate to severe essential tremor of the upper limbs were randomized to 24 weeks of treatment with placebo or topiramate (target dose, 400 mg/day) as monotherapy or as an adjunct to one antitremor medication. The primary efficacy variable was the final visit tremor score based on the Fahn-Tolosa-Marin Tremor Rating Scale (TRS).
RESULTS: The intent-to-treat population was 208 patients (topiramate, 108; placebo, 100). The final visit score (last observation carried forward) was lower in the topiramate group than with placebo (p < 0.001). Mean percentage improvement in overall TRS scores was 29% with topiramate at a mean final dose of 292 mg/day and 16% with placebo (p < 0.001). Topiramate was associated with greater improvement in function and disability (p = 0.001). A between-group difference (p < 0.001) was observed at the first on-treatment visit at 4 weeks when the target topiramate dose was 100 mg/day (mean achieved dose, 62 +/- 9 mg/day). The most common treatment-limiting adverse events in topiramate-treated patients were paresthesia (5%), nausea (3%), concentration/attention difficulty (3%), and somnolence (3%). Adverse events were treatment limiting in 31.9% of topiramate patients and 9.5% of placebo patients.
CONCLUSIONS: Topiramate was effective in the treatment of moderate to severe essential tremor. Tremor reduction was accompanied by functional improvements, such as in motor tasks, writing, and speaking.
Shuhei Morita, Hideto Miwa, Tomoyoshi Kondo
Effect of zonisamide on essential tremor: a pilot crossover study in comparison with arotinolol.
Parkinsonism Relat Disord. 2005 Mar;11(2):101-3. doi: 10.1016/j.parkreldis.2004.09.004.
Abstract/Text
We performed a pilot, crossover trial of zonisamide (ZNS) on essential tremor patients. Patients were randomly selected to start either ZNS or arotinolol treatment for 2 weeks. After a washout period, the patients were switched to an alternative drug. The assessment of tremor was carried out using the Fahn-Tolosa-Marin's clinical rating scale for tremor at baseline and 2 weeks after administration of each drug. There was a significant improvement after ZNS and arotinolol administration compared with the baseline. There was no significant difference in the antitremor effect between ZNS and arotinolol; however, ZNS was more effective for tremors of cranial nerve areas. Although the number of enrolled patients was limited in the present study, this open-label pilot study suggests that ZNS may have a therapeutic potential for essential tremor. A controlled trial of this drug in the future would be valuable.
I-U Song, J-S Kim, S-B Lee, S-Y Ryu, J-Y An, H-T Kim, Y-I Kim, K-S Lee
Effects of zonisamide on isolated head tremor.
Eur J Neurol. 2008 Nov;15(11):1212-5. doi: 10.1111/j.1468-1331.2008.02296.x. Epub 2008 Aug 27.
Abstract/Text
BACKGROUND AND PURPOSE: The medical treatment available for patients with essential tremor (ET) is often inadequate. Furthermore, the efficacy of the medical treatments currently available for patients with ET of cranial nerve areas is less satisfactory than that of the medical treatments available for patients with ET involving the upper extremities. This pilot study was performed to evaluate whether zonisamide (ZNS) is effective in the treatment of patients with isolated head tremor.
METHODS: All subjects with isolated head tremor were randomly treated with either ZNS or propranolol. After a washout period, the subjects were switched to the alternative drug.
RESULTS: ZNS was found to be more effective in the treatment of patients with isolated head tremor than propranolol. No severe adverse effects were reported with either ZNS or propranolol.
CONCLUSION: ZNS may be more useful than propranolol for the treatment of ET patients with head tremor.
Theresa A Zesiewicz, Christopher L Ward, Robert A Hauser, Juan Sanchez-Ramos, Joseph F Staffetti, Kelly L Sullivan
A double-blind placebo-controlled trial of zonisamide (zonegran) in the treatment of essential tremor.
Mov Disord. 2007 Jan 15;22(2):279-82. doi: 10.1002/mds.21282.
Abstract/Text
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.
(c) 2006 Movement Disorder Society.
William G Ondo
Zonisamide for essential tremor.
Clin Neuropharmacol. 2007 Nov-Dec;30(6):345-9. doi: 10.1097/WNF.0b013e318074dd4f.
Abstract/Text
OBJECTIVE: The pharmacological therapy for essential tremor (ET) is inadequate, and many patients resort to surgical procedures. Zonisamide is an antiepileptic with several potential mechanisms of action.
MATERIALS AND METHODS: We evaluated zonisamide for ET in an open-label pilot trial. The primary efficacy point was the change in the Tremor Study Group rating scale (TSGRS) scores.
RESULTS: Twenty-two subjects were enrolled (male, 9; mean age +/- SD, 65.0 +/- 12.6 years; mean duration of ET +/- SD, 25.6 +/- 17.1 years). Six subjects dropped because of either (1) adverse events (AEs) and lack of effect (n = 4) or (2) lack of effect (n = 2). Two were lost to follow-up. Fourteen subjects returned for their complete postmedication evaluation. After 3 months (mean +/- SD, 88 +/- 34 days), the final dose was 200 mg (n = 11), 150 mg (n = 1), 100mg (n = 1), and 12.5 mg (n = 1). The mean Tremor Study Group rating scale scores improved from a mean of 28.9 (SD, +/-9.2) to a mean of 21.1 (SD, +/-6.5) (P = 0.02, unpaired t test). Seven subjects (50%) had at least a 25% improvement. Subjectively, however, only 4 reported marked or moderate improvement, 3 reported mild improvement, and 7 reported no change. Adverse events included decreased concentration/cognition (n = 2), constipation (n = 1), nocturia (n = 1), abdominal pain/diarrhea (n = 1), and sedation (n = 1).
CONCLUSIONS: Zonisamide significantly (albeit modestly) improved the TSGRS scores in this small group of medically refractory subjects who completed the evaluation. However, clinical impressions did not improve, and the study was complicated by a large dropout rate caused by subjective lack of efficacy and by AEs.
Adrian Handforth, Fredricka C Martin, Gail A Kang, Zeba Vanek
Zonisamide for essential tremor: an evaluator-blinded study.
Mov Disord. 2009 Feb 15;24(3):437-40. doi: 10.1002/mds.22418.
Abstract/Text
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.
(c) 2008 Movement Disorders Society.
Douglas Kondziolka, Joseph G Ong, John Y K Lee, Robert Y Moore, John C Flickinger, L Dade Lunsford
Gamma Knife thalamotomy for essential tremor.
J Neurosurg. 2008 Jan;108(1):111-7. doi: 10.3171/JNS/2008/108/01/0111.
Abstract/Text
OBJECTIVES: The purpose of this study was to evaluate the results following Gamma Knife thalamotomy (GKT) for medically refractory essential tremor in a series of patients in whom open surgical techniques were not desirable.
METHODS: Thirty-one patients underwent GKT for disabling essential tremor after medical therapy had failed. Their mean age was 77 years. Most patients were elderly or had concomitant medical illnesses. A single 4-mm isocenter was used to target a maximum dose of 130 or 140 Gy to the nucleus ventralis intermedius. Items from the Fahn-Tolosa-Marin clinical tremor rating scale were used to grade tremor and handwriting before and after radiosurgery.
RESULTS: The median follow-up was 36 months. In the group of 26 evaluable patients, the mean tremor score (+/- standard deviation) was 3.7 +/- 0.1 preoperatively and 1.7 +/- 0.3 after radiosurgery (p < 0.000015). The mean handwriting score was 2.8 +/- 0.2 before GKT and 1.7 +/- 0.2 afterward (p < 0.0002). After radiosurgery, 18 patients (69%) showed improvement in both action tremor and writing scores, 6 (23%) only in action tremor scores, and 3 (12%) in neither tremor nor writing. Permanent mild right hemiparesis and speech impairment developed in 1 patient 6 months after radiosurgery. Another patient had transient mild right hemiparesis and dysphagia.
CONCLUSIONS: Gamma Knife thalamotomy is a safe and effective therapy for medically refractory essential tremor. Its use is especially valuable for patients ineligible for radiofrequency thalamotomy or deep brain stimulation. Patients must be counseled on potential complications, including the low probability of a delayed neurological deficit.
D M Simpson, A Blitzer, A Brashear, C Comella, R Dubinsky, M Hallett, J Jankovic, B Karp, C L Ludlow, J M Miyasaki, M Naumann, Y So, Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology
Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.
Neurology. 2008 May 6;70(19):1699-706. doi: 10.1212/01.wnl.0000311389.26145.95.
Abstract/Text
OBJECTIVE: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders.
METHODS: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and selected movement disorders. Authors reviewed, abstracted, and classified articles based on American Academy of Neurology criteria (Class I-IV).
RESULTS: The highest quality literature available for the respective indications was as follows: blepharospasm (two Class II studies); hemifacial spasm (one Class II and one Class III study); cervical dystonia (seven Class I studies); focal upper extremity dystonia (one Class I and three Class II studies); focal lower extremity dystonia (one Class II study); laryngeal dystonia (one Class I study); motor tics (one Class II study); and upper extremity essential tremor (two Class II studies).
RECOMMENDATIONS: Botulinum neurotoxin should be offered as a treatment option for the treatment of cervical dystonia (Level A), may be offered for blepharospasm, focal upper extremity dystonia, adductor laryngeal dystonia, and upper extremity essential tremor (Level B), and may be considered for hemifacial spasm, focal lower limb dystonia, and motor tics (Level C). While clinicians' practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.
J Jankovic, K Schwartz, W Clemence, A Aswad, J Mordaunt
A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor.
Mov Disord. 1996 May;11(3):250-6. doi: 10.1002/mds.870110306.
Abstract/Text
Twenty-five patients with hand tremor of 2+ (moderate) to 4+ (severe) on the tremor severity rating scale were randomized to receive either 50 U of botulinum toxin (BTX) type A (Allergan, Irvine, CA) or placebo injections into the wrist flexors and extensors of the dominant limb. If patients failed to respond to the initial injection, they were eligible to receive another injection of 100 U 4 weeks later. Rest, postural, and kinetic tremors were evaluated at 2- to 4-week intervals over a 16-week study period using tremor severity rating scales, accelerometry, and assessments of improvement and disability. A significant improvement (p < 0.05) was observed on the tremor severity rating scale 4 weeks after injection in patients treated with BTX as compared with placebo, and this effect was maintained for the duration of the study. Four weeks after injection, 75% of BTX-treated patients vs. 27% of placebo-treated patients (p < 0.05) reported mild to moderate improvement (peak effect rating > or = 2). There were no significant improvements in functional rating scales, although trends were observed for some items. Postural accelerometry measurements showed a > or = 30% reduction in amplitude in nine of 12 BTX-treated subjects and in one of nine placebo-treated subjects (p < 0.05). Although all patients treated with BTX reported some degree of finger weakness, no severe, irreversible, or unexpected adverse events occurred. Chemodenervation with BTX may significantly ameliorate essential hand tremor in patients who fail to improve with conventional pharmacologic therapy.
M F Brin, K E Lyons, J Doucette, C H Adler, J N Caviness, C L Comella, R M Dubinsky, J H Friedman, B V Manyam, J Y Matsumoto, S L Pullman, A H Rajput, K D Sethi, C Tanner, W C Koller
A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.
Neurology. 2001 Jun 12;56(11):1523-8.
Abstract/Text
OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand.
BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor.
METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer.
RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness.
CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.
日本脳神経外科学会 新医療機器使用要件等基準策定事業（MRガイド下集束超音波治療器）委員会：令和元年度 新医療機器使用要件等基準策定事業（MRガイド下集束超音波治療器）事業報告書．2020年3月 [Internet]. Available from: http://jns.umin.ac.jp/jns_wp/wp-content/uploads/2020/06/20200331【最終】令和元年度新医療機器使用要件等基準報告書Exablate-4000.pdf
W Jeffrey Elias, Nir Lipsman, William G Ondo, Pejman Ghanouni, Young G Kim, Wonhee Lee, Michael Schwartz, Kullervo Hynynen, Andres M Lozano, Binit B Shah, Diane Huss, Robert F Dallapiazza, Ryder Gwinn, Jennifer Witt, Susie Ro, Howard M Eisenberg, Paul S Fishman, Dheeraj Gandhi, Casey H Halpern, Rosalind Chuang, Kim Butts Pauly, Travis S Tierney, Michael T Hayes, G Rees Cosgrove, Toshio Yamaguchi, Keiichi Abe, Takaomi Taira, Jin W Chang
A Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor.
N Engl J Med. 2016 Aug 25;375(8):730-9. doi: 10.1056/NEJMoa1600159.
Abstract/Text
BACKGROUND: Uncontrolled pilot studies have suggested the efficacy of focused ultrasound thalamotomy with magnetic resonance imaging (MRI) guidance for the treatment of essential tremor.
METHODS: We enrolled patients with moderate-to-severe essential tremor that had not responded to at least two trials of medical therapy and randomly assigned them in a 3:1 ratio to undergo unilateral focused ultrasound thalamotomy or a sham procedure. The Clinical Rating Scale for Tremor and the Quality of Life in Essential Tremor Questionnaire were administered at baseline and at 1, 3, 6, and 12 months. Tremor assessments were videotaped and rated by an independent group of neurologists who were unaware of the treatment assignments. The primary outcome was the between-group difference in the change from baseline to 3 months in hand tremor, rated on a 32-point scale (with higher scores indicating more severe tremor). After 3 months, patients in the sham-procedure group could cross over to active treatment (the open-label extension cohort).
RESULTS: Seventy-six patients were included in the analysis. Hand-tremor scores improved more after focused ultrasound thalamotomy (from 18.1 points at baseline to 9.6 at 3 months) than after the sham procedure (from 16.0 to 15.8 points); the between-group difference in the mean change was 8.3 points (95% confidence interval [CI], 5.9 to 10.7; P<0.001). The improvement in the thalamotomy group was maintained at 12 months (change from baseline, 7.2 points; 95% CI, 6.1 to 8.3). Secondary outcome measures assessing disability and quality of life also improved with active treatment (the blinded thalamotomy cohort)as compared with the sham procedure (P<0.001 for both comparisons). Adverse events in the thalamotomy group included gait disturbance in 36% of patients and paresthesias or numbness in 38%; these adverse events persisted at 12 months in 9% and 14% of patients, respectively.
CONCLUSIONS: MRI-guided focused ultrasound thalamotomy reduced hand tremor in patients with essential tremor. Side effects included sensory and gait disturbances. (Funded by InSightec and others; ClinicalTrials.gov number, NCT01827904.).
