Essential Tremor: Approaches to Treatment Part 6 of 7

ET: Therapeutic Options No treatment Physical/psychological measures/lifestyle changes Pharmacologic approaches Surgical management The treatment options available for ET may include physical and psychologic measures and lifestyle changes; pharmacologic approaches; and surgical management. In addition, for some patients, no treatment may be required. The selection of treatment options must be based on individual needs, taking into account patient and family history, tremor severity, coexistent disease, current medications, and response to previous therapy. The goal of treatment for ET is to minimize functional disability and facilitate ADLs, improving QOL. www.wemove.org www.wemove.org

Rationale for No Treatment Side effects may be more severe than symptoms or disability from tremor No agents are known to effect the rate of disease progression Disability may be minimal in some patients Therapies for ET do not prevent or slow the rate of disease progression. All treatment measures are considered symptomatic. Clinicians may determine that no treatment is required, particularly when disability is minimal, certain therapies are contraindicated, or treatment side effects become more severe than disability due to tremor. www.wemove.org

Physical and Psychological Measures/Lifestyle Changes Application of weights to affected limbs with decreases in tremor amplitude proportional to the weight applied Biofeedback and relaxation techniques Physical and psychologic measures as well as certain lifestyle changes may be helpful in managing mild tremor. Physical measures may include the application of weights to affected limbs to decrease tremor amplitude. For example, strapping 1- to 2-pound weights to the wrist may promote hand stability. In addition, some patients have experienced limited benefits with biofeedback, relaxation methods, and other behavioral techniques through alleviation of anxiety or stress that may exacerbate tremor. Lifestyle changes may include restricting caffeine intake or other stimulants that may temporarily augment symptoms. In addition, alcohol consumption may lead to transient improvement. In one multicenter study of 678 ET patients, alcohol consumption alleviated tremor in 74% of those who were aware of the effect of alcohol on tremor. The onset of tremor suppression is typically reported at about 10 to 15 minutes, with effects lasting approximately 3 hours. Again, the specific mechanism by which ethanol suppresses ET is unknown; however, PET scanning has demonstrated that alcohol ingestion attenuates the increased bilateral cerebellar blood flow found in ET patients. The potential risk of alcohol dependence and abuse among ET patients who drink alcohol to control symptoms remains controversial. A number of investigations indicated that ET generally does not increase alcohol consumption nor lead to an increased frequency of chronic alcoholism. However, it is possible that consuming alcohol in response to ongoing, stressful situations could lead to alcohol abuse. When alcohol is recommended for symptomatic management of ET, the medical and ethical ramifications must be considered on a case-by-case basis. www.wemove.org

Drug Therapy for Essential Tremor Reasonable option for any patient with disabling tremor Pharmacologic therapy may produce a significant reduction in tremor Pharmacologic therapy is a reasonable option for any ET patient with disabling tremor. Most patients benefit from such therapy, with many experiencing a significant attenuation of tremor. However, only rarely does tremor recede completely. Drug tolerance is reported by some patients receiving long-term therapy, potentially signifying increasing tremor severity with time. The goal of any management program is to minimize the adverse effects of tremor without further compromising function. Initiation of specific pharmacologic therapies is typically based on patient age, coexistent conditions, prior exposure to medications, concurrent drug therapies, contraindications, and the benefits and possible side effects associated with particular agents. www.wemove.org

Pharmacologic Approaches Beta-blockers such as propranolol (Inderal®) Primidone (Mysoline®) Combination Primidone/propranolol therapy Calcium channel blockers Carbonic anhydrase inhibitors Botulinum toxin type A (BOTOX®) Other medications Varying degrees of control in ET have been obtained with the anticonvulsant agent primidone, available as Mysoline® and the beta-blocker propranolol, available as Inderal®. Although neither of these agents will benefit every ET patient, either may be considered an appropriate first-line therapy for the symptomatic management of ET. When appropriate, these agents may be administered in combination, possibly with benzodiazepines, such as lorazepam or clonazepam. Additional therapeutic options that may benefit carefully selected patients include calcium channel blockers, carbonic anhydrase inhibitors, or chemodenervation with localized injections of botulinum toxin type A. www.wemove.org

Beta-blockers Propranolol (Inderal®) is the most studied beta-blocker for ET Response is highly variable and the tremor is rarely totally suppressed Approximately 50% to 70% of patients obtain some symptomatic relief Amplitude may be decreased but frequency typically remains constant Propranolol is the most studied beta-adrenergic receptor antagonist for ET and, historically, was the first medication shown to be efficacious for the condition. This nonselective beta-blocker inhibits sympathetic stimulation by competitively blocking receptors within the vascular and bronchial smooth muscle and the myocardium. Propranolol has no inherent sympathomimetic activity, and only its l-isomer has any substantial beta-adrenergic blocking action. Although its specific mechanism of action in ET is unknown, the agent’s antitremor effect may be mediated via blockage of peripheral beta2 adrenoreceptors. Clinical response to propranolol is highly variable, and complete tremor suppression usually is not achieved. Approximately 50% to 70% of patients obtain some symptomatic relief. Tremor amplitude is usually decreased, although frequency usually remains unaffected. Accordingly, propranolol appears to be most efficacious in managing high-amplitude, low frequency tremor. It also appears to be most effective for tremor of the upper limbs, with some efficacy shown for head, voice, or tongue tremor. By decreasing tremor amplitude, propranolol therapy may lead to some improvement of functional ability. However, some patients will not respond to propranolol. Propranolol is usually well tolerated. Relative contraindications include heart failure, cardiac conduction disorders, asthma or bronchoasthmatic conditions, or diabetes. Adverse effects are usually mild and temporary, typically diminishing with time and rarely requiring cessation of therapy. They may include diminished exercise tolerance, fatigue, bradycardia, peripheral vasoconstriction, bronchospasm, and GI disturbances. With higher doses, side effects may include weakness, depression, insomnia, lassitude, and impotence. Pulse rate declines in most patients, requiring monitoring of blood pressure and pulse rate. Caution should be used when prescribing propranolol for elderly patients, due to lowered heart rate and hypotension, as well as nursing mothers; in addition, such therapy should be avoided in late pregnancy due to risks of IUGR, bradycardia, or neonatal hypoglycemia. Propranolol therapy should not be discontinued abruptly due to possible rebound hypertension. For the treatment of ET, propranolol may be initiated at 40 mg by mouth twice daily. The dosage may be gradually titrated upward as required to 120 to 320 mg/day in once daily or divided doses. Doses of greater than 320mg/day did not result in additional tremor reduction. www.wemove.org

Other Beta-blockers Available and studied for ET... Metoprolol (Lopressor®) Timolol (Timoptic®) Atenolol (Tenormin®) Nadolol (Corgard®) Although no beta-blocking agent is empirically or theoretically superior to propranolol, a number of placebo-controlled, double-blind, crossover studies report that other beta-blockers may be of benefit for carefully selected patients, such as for those who are unable to tolerate propranolol therapy. Alternative beta-blockers for ET may include metoprolol, timolol, atenolol, or nadolol. However, if propranolol proves of no benefit for particular patients, it is unlikely that they will respond to alternative beta-blocking agents. www.wemove.org

Propranolol www.wemove.org Propranolol is currently available in 10, 20, 40, 60, and 80 mg tablets for oral administration. The beta-blocker is also available as Inderal LA® in 60, 80, 120, and 160 mg extended-release capsules. As illustrated here, in a study with 18 ET patients comparing the once daily, long-acting formulation with divided doses of propranolol, the extended-release preparation was preferred by 67% for tremor suppression and 87% for ease of administration. In addition, sustained-release propranolol provided comparable or greater reductions in tremor amplitude in all patients. Propranolol therapy may be administered on an occasional-use or constant-use basis. If administered PRN, 40 mg tablets are typically prescribed, with instructions to take 1/2 to 2 tablets about 30 minutes to 1 hour before important, planned activities, particularly anxiety-provoking events that may result in tremor augmentation. If administered as chronic suppressive therapy, treatment may be initiated at 10 to 60 mg/day in divided doses. For older patients, initial treatment may consist of 10 mg that is gradually titrated upward to an average of 80 to 100 mg/day. If ongoing therapy is required, the prescription may eventually be changed to a once daily, long-acting preparation. Optimal tremor reduction may be achieved at a dose of less than or equal to 120 mg/day. However, as discussed earlier, others may require 240 or 320 mg/day for maximal suppression of tremor. A number of investigations have reported that, in a majority of patients, propranolol retains its antitremor effect after 1 year of chronic therapy; however, to maintain efficacy, dosage increases may be required for some patients. www.wemove.org

Primidone (Mysoline®) Demonstrated efficacy in placebo-controlled trials with reported 66% reduction in tremor severity Initiation of therapy with low dose. Mysoline suspension may be useful (250mg/5ml) Slow upward titration Dosage of 250 mg/day appears to be an effective dose Maximum dosage is 750 mg/day in three divided doses Primidone is a structural analog of phenobarbital that shares sedative and anticonvulsant properties of barbiturate-derived anticonvulsants. The agent is metabolized to phenobarbital, with a plasma half-life of about 10 days, and to phenylmethylmalonamide or PEMA, with a plasma half-life of approximately 30 hours. Both metabolites accumulate with chronic therapy. The major metabolite, PEMA, may potentiate the anticonvulsant effects of phenobarbital. However, the specific mechanism of action of primidone’s antitremor effect is unknown. Because PEMA and phenobarbital appear to have no or little antitremor action, investigators suggest that primidone or an unknown metabolite is the effective component in alleviating tremor. After observing that primidone attenuated ET when administered to a patient for epilepsy, O’Brien and colleagues studied primidone in 28 ET patients, noting a beneficial response in 60%. Its efficacy as a therapy in ET has been further substantiated in numerous open and controlled trials. For example, in several placebo-controlled studies, primidone has been shown to reduce tremor amplitude by approximately 66%. These investigations demonstrated the efficacy of primidone for hand tremor. However, tremors of the head, voice, and other areas appear to be improve with less consistency than in hand tremor. O’Brien MD, Upton AR, Toseland PA. Benign familial tremor treated with primidone. Br Med J (Clin Res Ed). 1981;282:178-180. Clinical responsiveness to primidone appears to be highly variable, from almost complete suppression of upper limb tremors to no effect. The mean efficacy of primidone therapy for ET may be approximately 40% to 50%. Primidone is currently available as scored 50 mg and 250 mg tablets. Therapy is typically prescribed on a constant-use basis. The initial dose of primidone is low—such as 12.5 to 25 mg at bedtime—and slowly titrated upward as needed until optimal tremor reduction is achieved. The maximum dosage is 750 mg/day in three divided doses. However, dosage of less than or equal to 250 mg/day generally appears to be efficacious, with doses over 250 mg conferring little additional benefit. Primidone is also available as a pediatric oral suspension at a concentration of 250 mg/5 mL. www.wemove.org

Primidone (cont.) Primidone as effective or slightly more effective than propranolol (Koller, 1986; Wastelewski et al., 1998) Long duration of benefit from a single dose Occasional acute, transient idiosyncratic toxic response Long-term therapy generally well tolerated Near complete suppression of tremor is more commonly achieved with primidone than with a beta-blocker. In addition, a once-daily dose at bedtime may result in tremor attenuation of long duration. This form of administration may also serve to minimize the drug’s sedative effect and increase compliance. A relatively low number of patients may develop an acute toxic response when primidone therapy is initiated. Associated, usually transient symptoms may include nausea, vomiting, sedation, vertigo, ataxia, and additional flu-like complaints. Adverse effects typically subside with continued therapy, may be minimized with dosage reduction—and may often be prevented if therapy is initiated at low doses. Patient compliance may be increased if clinicians explain to patients the possibility of developing an acute idiosyncratic response, stress that symptoms usually subside, and recommend that the initial dose be taken at bedtime. Administration before retiring in the evening may increase the possibility that patients may sleep through feelings of sedation and other possible adverse effects. Caution should be used when prescribing primidone for debilitated patients and those with impaired hepatic or renal function. In addition, the medication should not be prescribed for patients with porphyria or for women who are pregnant or breast-feeding. Discontinuation of primidone therapy requires gradual tapering of dosage levels. Although propranolol is initially better tolerated than primidone, chronic use of propranolol may continue to be associated with adverse effects. In contrast, side effects of chronic primidone therapy are typically minimal and infrequent www.wemove.org

Primidone (cont.) Experiment with a single evening dose equal to total daily dose CBC before drug initiation Recheck CBC every 6 to 12 months for rare hematologic dyscrasias Some patients become tolerant to the effects, perhaps with disease progression Due to the potential benefits associated with once-daily administration at bedtime, it is appropriate to attempt a single evening dose equal to the total daily dosage for responders who have achieved optimal tremor reduction with divided doses. Before primidone therapy is initiated, a complete blood count should be ordered and subsequently performed every 6 to 12 months to screen for potential blood dyscrasias. Although rare, red cell hypoplasia or aplasia, granulocytopenia, agranulocytosis, and megaloblastic anemia have been reported. Anemia may respond to folic acid therapy without discontinuation of primidone. Some patients may develop tolerance to chronic pharmacologic therapy. For example, tolerance has been observed with chronic primidone therapy in up to 13% of ET patients at 12 months. A number of studies analyzing the long-term effects of therapy have demonstrated that primidone retains its antitremor effect for at least 1 year. www.wemove.org

Response to Primidone Some patients have a shorter clinical response to primidone More frequent dosing may be required (Koller W. Neurology 1986;36:121-124) In an investigation of untreated and propranolol-treated ET patients, administration of primidone at 50 to 1,000 mg/day reduced tremor amplitude, with lower doses as efficacious as higher doses. A single 250 mg dose reduced tremor by 60% in 1 to 7 hours after administration. Because some ET patients have a shorter clinical response to primidone, more frequent dosing may be required. Although serum primidone levels were stable, the metabolite phenobarbital was not detectable. In addition, when phenobarbital was substituted for primidone, tremor attenuation ceased. No correlation existed between serum levels and therapeutic response. Koller WC, Royse VL. Efficacy of primidone in essential tremor. Neurology. 1986;36:121-124. www.wemove.org

Primidone (cont.) Primidone has been shown in several placebo-controlled trials to be... Effective for essential tremor Resulting in a reported 66% reduction of tremor In several placebo-controlled trials, primidone has been shown to be efficacious for ET, resulting in an approximate 66% reduction of tremor amplitude. Based upon documentation of accelerometric testing and clinical rating scales, double-blinded studies have demonstrated that most ET patients achieve tremor attenuation with primidone therapy. However, responsiveness is extremely variable, with some patients having no demonstrable effect and others achieving almost complete tremor suppression. www.wemove.org

Primidone: Adverse Effects Adverse effects with chronic therapy minimal in most patients. Propranolol often less well tolerated Up to 20% or fewer experience an acute toxic reaction Acute reactions are more common with larger initial doses Adverse effects of chronic primidone therapy are typically minimal and infrequent, whereas chronic therapy with propranolol is often not tolerated as well. However, a relatively small percentage of patients may experience an acute toxic response at the initiation of primidone therapy. Acute reactions typically occur with relatively large initial doses. These reactions are also observed with therapy starting as low as 25 mg/day. www.wemove.org

Primidone: Adverse Effects (cont.) Recovery from acute reaction is invariable Ongoing therapy after reaction generally tolerated Patients advised about the risk of acute reactions are more likely to continue therapy Slow upward titration of primidone or use of primidone in suspension may reduce the risk of acute reactions Patients who experience an acute reaction to primidone invariably recover, with adverse effects typically disappearing with continued therapy. Patient compliance is increased for those who are advised in advance about the risk of developing acute reactions. Due to the possibility of initial side effects, clinicians should also counsel patients to take their beginning dose in the evening and to initiate therapy only when family members will be available during the first few days of treatment. The risk of developing an acute response may be reduced if therapy is initiated at low doses and slowly titrated upward, such as in 12.5, 25, or 50 mg increments over 1 to 2 months until optimal clinical response is attained. For example, an appropriate dosing schedule may consist of the following. During week 1, therapy may be initiated at 25 mg/day--or, in some cases, as low as 12.5 mg/day. Patients should be advised about the possibility of initial side effects. With week 2, therapy may be increased to 50 mg/day and, at week 3, dosage may be titrated upward to 75 mg/day. During week 4, therapy may be increased to 100 mg/day; at this time, efficacy should also be assessed. By week 5 or more, therapy may range from 100 up to 350 mg/day in single or divided doses. Some clinicians may continue to slowly titrate the dose upward, prescribing as high as 500 to 750 mg/day. However, again, most ET patients respond to therapy less than or equal to 250 mg/day, with higher doses typically conferring little additional benefit. www.wemove.org

Combination Therapy Primidone and propranolol may be used in combination Primidone initiated at 12.5 mg to 25 mg at bedtime Propranolol added, usually at 40 mg tid Long-acting formulation of propranolol may be substituted if once-daily administration is desired Primidone and propranolol are used in combination if they do not sufficiently attenuate tremor with monotherapy. Primidone may be prescribed at 12.5 to 25 mg at bedtime and gradually increased to a range of 125 to 250 mg/day. Propranolol is then added to the regimen at a low initial dose, such as 10 to 60 mg/day in divided doses, and slowly titrated upward over several weeks. Propranolol dosage may be gradually increased to 240 mg—or as high as 320 mg/day if patient response remains inadequate. Alternatively, a long-acting preparation of propranolol may be substituted if once-daily administration is desired. One study has reported that combination therapy with propranolol and primidone was more efficacious in alleviating ET than monotherapy with either drug In addition, when appropriate, primidone and propranolol are administered in combination with benzodiazepines, such as lorazepam or clonazepam. Clonazepam may be initiated at 0.25 mg/day and slowly increased over several weeks to a range of 1.0 to 2.0 mg/day, delivered by mouth in divided doses. Benzodiazepines may be used at small doses on a PRN basis about 30 minutes to 1 hour before an important event. In such cases, propranolol may be administered at 20 to 40 mg; clonazepam or lorazepam may be taken at 0.25 or 0.5 mg. www.wemove.org

Other Pharmacologic Approaches Calcium channel blockers: nimodipine (Nimotop®) and nicardipine (Cardene®) Carbonic anhydrase inhibitors: acetazolamide (Diamox®) and methazolamide (Neptazane®) Benzodiazepines: clonazepam (Klonopin®), diazepam (Valium®) and alprazolam (Xanax®) Primidone and propranolol provide efficacious symptomatic relief for most ET patients. Yet, in some carefully selected patients, other therapeutic agents may be useful in the management of tremor. For example, in small trials, the calcium channel blockers nimodipine and nicardipine have shown some promise in attenuating ET. However, these agents generally appear less effective than propranolol. Larger controlled trials are required to definitively assess their efficacy. In addition, in open trials, the carbonic anhydrase inhibitors acetazolamide and methazolamide have been of benefit to a small number of ET patients with tremor refractory to other agents. However, side effects are common, such as headaches, sedation, confusion, depression, paresthesias, and GI disturbances, potentially necessitating discontinuation of therapy. In addition, in double-blind trials, these agents have had no proven efficacy as compared with placebo. Certain benzodiazepines may sometimes be used as monotherapy for ET. The most commonly prescribed benzodiazepine, diazepam, has not been investigated in controlled studies for the treatment of ET. However, many experts suggest that the agent may have only limited effectiveness. In a small double-blind, placebo-controlled trial, the agent alprazolam significantly improved tremor. The study’s authors suggest that this agent may be of particular benefit for ET patients who require only periodic therapy. In addition, clonazepam has been reported to suppress predominant kinetic tremor; however, it has shown no effect in typical ET. The benefits associated with benzodiazepine therapy in some ET patients may be partially due to the agents’ anxiolytic effects. www.wemove.org

Efficacy of Medications in Essential Tremor Patients* This slide illustrates the efficacy of various pharmacologic agents in ET. The values express the percentage of patients reporting greater than 50% tremor reduction, as indicated in the University of Kansas Database and the National Database. The second column from the right indicates the total percentage of patients reporting such tremor attenuation, and the furthest column on the right reports the total number of patients treated with the medications in question. The majority of patients received treatment with propranolol or primidone. Of the 335 patients who received propranolol, 37% had more than a 50% alleviation of tremor; 42.6% of those who were treated with primidone reported such improvement. In a smaller sample, of 59 ET patients who received clonazepam, 44.1% reported a significant improvement of symptoms. * Values express percentage of patients reporting greater than 50% tremor reduction. † Not applicable as these data were not collected. www.wemove.org

Other Miscellaneous Pharmacologic Agents Theophylline Isoniazid (Nydrazid®): ineffective Clonidine (Catapres®): ineffective Gabapentin (Neurontin®): ineffective Topiramate: under investigation Clozapine (Clozaril®): effective in open-label studies Additional agents that have been investigated in the treatment of ET. Methlyxanthine derivatives have appeared to augment tremor in some ET patients. However, in double-blind crossover trials, administration of theophylline was associated with significant tremor attenuation within 4 weeks of treatment, possibly due to adenosine antagonism and enhancement of GABA sensitivity. In a double-blinded trial with ET patients refractory to treatment with beta-blockers or primidone, high-dose therapy with isoniazid was rarely associated with improvement of tremor. Such therapy must be carefully monitored due to possible toxicity. According to a number of preliminary studies, clonidine appeared to be of some benefit in alleviating ET. However, when evaluated in a double-blinded, placebo-controlled design, clonidine therapy had no significant effect on tremor in ET patients. A number of open-label trials have also reported tremor alleviation with the anticonvulsant gabapentin. However, this has not been corroborated by double-blind controlled studies, in which gabapentin has been no more efficacious than placebo. Clozapine is a dibenzodiazepine-derivative antipsychotic agent primarily used to treat drug-resistant schizophrenia. Several open-label trials have indicated that this agent may be effective in ET. However, there is a persistent, substantial risk of agranulocytosis associated with clozapine therapy. In the US, most cases of clozapine-associated agranulocytosis have occurred within 4 to 16 weeks after initiation of therapy, although a latent period of 1 year or greater has been reported. Performing a baseline white blood cell count is necessary before initiation of clozapine therapy. If the WBC count is less than 3500/mm3, therapy should not be instituted. WBC counts are performed weekly for the duration of therapy and for 4 weeks following discontinuation of therapy. www.wemove.org

Botulinum Toxin Type A (BOTOX®) Hand tremor: Reduced tremor amplitude by 30%. No improvement in functional ratings. Finger weakness usually unacceptable to the patient. Head tremor: BTX-A produced clear improvement in clinical rating scales and subjective patient ratings. Minimal side effects. Botulinum toxin type A was originally introduced in the 1970s for the treatment of strabismus and blepharospasm associated with dystonia or facial nerve disorders. Chemodenervation with botulinum toxin is now being increasingly used as a therapeutic option for selected patients with other disorders characterized by severe muscle hyperactivity, including tremor, spasticity, and cervical dystonia. Seven serologically distinct neuroparalytic toxins, designated as A through G, are produced by Clostridium botulinum bacteria. In the United States and several other countries, it is available as BOTOX®, which is produced by Allergan Inc., Irvine, California. Outside the US, it is also available as DYSPORT®, distributed by Ipsen Pharmaceuticals, United Kingdom. Because these preparations are not equivalent in units, caution must be used when converting units between brands of toxin. One unit of BOTOX® is equivalent to approximately 3 to 4 units of DYSPORT®. Botulinum toxin produces a chemical denervation of treated muscles through presynaptic inhibition of acetylcholine release at the neuromuscular junction. Botulinum toxin type A binds to receptor sites on motor nerve terminals and inhibits neurotransmitter release without impeding acetylcholine synthesis or storage. Although the specific mechanism of action in the attenuation of tremor is unknown, local injections of botulinum toxin are known to affect muscle efferents and afferents and may alter the sensory feedback loop to the CNS. Open-label studies as well as double-blind studies have demonstrated the efficacy of botulinum toxin type A in treating limb, head, vocal, palatal, and other tremors. In one randomized, double-blind, placebo-controlled study of 25 ET patients with hand tremor, subjects were given BOTOX® or placebo injections into wrist flexors and extensors of the dominant limb. Based on accelerometric data and ratings of tremor severity scales, 75% of subjects treated with BOTOX® reported mild to moderate improvement 4 weeks after treatment. Twenty-seven percent of placebo-treated subjects reported mild to moderate improvement. Although no significant improvement was shown based on functional rating scales, postural accelerometry measures showed a 30% or greater reduction in tremor amplitude in 9 of 12 patients treated with botulinum toxin and in 1 of 9 treated with placebo. Although all botulinum-treated patients reported finger weakness, there were no irreversible or severe adverse effects. In addition, in a double-blind study of 43 patients with head tremor, including some with cervical dystonia, 40 of 43 reported subjective improvement of tremor. Although there was no change in the mean dominant frequency, there was a significant decrease in tremor amplitude. Jankovic J, Schwartz K, Clemence W, Aswad A, Mordaunt J. A randomized, double-blind, placebo-controlled study to evaluate botulinum toxin type A in essential hand tremor. Mov Disord. 1996;11:250-256. Wissel J, Masuhr F, Schelosky L, Ebersbach G, Poewe W. Quantitative assessment of botulinum toxin treatment in 43 patients with head tremor. Mov Disord. 1997;12:722-726. www.wemove.org

Summary: Drug Therapy for ET Primidone as initial therapy for patients with disabling tremor Nonselective beta-blocker added to primidone therapy in patients with residual tremor or substituted for primidone in nonresponders Botulinum toxin type A (BOTOX®) injections considered for patients with medication-refractory head tremor BTX-A occasionally considered for patients with severe hand tremor For most patients, the various pharmacologic approaches to treatment are administered in a sequential manner until an acceptable level of symptomatic relief is obtained. Treatment usually begins with primidone or propranolol monotherapy. Dosage should be gradually titrated upward, identifying the most efficacious dose with a minimum of adverse effects. If the medication is of little or no benefit and produces adverse effects, the dosage is gradually tapered down and the drug is discontinued. Another medication or combination of medications is then substituted. When a medication is helpful in attenuating tremor, it should be continued at a regulated dose. If additional symptomatic benefits are desired or tremor control remains inadequate on monotherapy, combination therapy may be initiated. When necessary, combination therapy may include a benzodiazepine, such as lorazepam or clonazepam. Finally, for appropriate candidates in whom pharmacologic therapy is inadequate, localized injections of botulinum toxin may be considered. A sequential approach to the pharmacologic management of ET may be summarized as follows. For patients with disabling tremor, administration of primidone is a suitable first-line therapy, with demonstrated long-term efficacy and tolerability. In those with mild residual tremor, a nonselective beta-blocker, particularly propranolol, may be added to the regimen, as may a benzodiazepine if required. In nonresponders, propranolol may be substituted for primidone. For patients with medication-refractory head tremor, chemodenervation with localized injections of botulinum toxin type A may be an appropriate alternative. Administration of BOTOX® may also occasionally be considered for carefully selected patients with severe hand tremor. www.wemove.org

Surgical Management of ET Procedures with proven efficacy: Stereotactic thalamotomy Chronic thalamic stimulation (DBS) Pahwa R, Koller W. Surgical treatment of essential tremor. In: Bain P, Brin M, Deuschl G, Elble R, Findley L, Jankovic J, Koller W, Pahwah R. Current issues in essential tremor. A continuing medical education monograph. Embryon 1999;27. For ET patients with severe, disabling, medication-refractory ET, a surgical approach is a treatment option of last resort. Surgical management of ET includes ablative therapy through stereotactic thalamotomy or chronic thalamic deep brain stimulation (DBS). Interruption of ventral intermedius thalamic output to the motor cortex has demonstrated efficacy in eliminating several tremor types. In addition, advances in neuroimaging and stereotactic techniques have enabled the performance of such procedures with improved accuracy and lower morbidity. Major contraindications for surgical management of ET include unstable medical illnesses or marked cognitive problems. www.wemove.org

Thalamotomy for ET For severe unilateral or asymmetric tremor Stereotactic lesioning of the ventralis intermedius (VIM) nucleus Efficacy: approximately 78% to 100% of patients show contralateral improvement and tremor remission Long-term relief with benefits continuing in most patients Surgical procedures have been used to treat ET since the 1950s. Although a number of different areas were initially targeted for tremor control, the ventralis intermedius--or VIM-- nucleus of the thalamus was determined to be the optimal target for surgical ablation. Current theories suggest that efficacy of VIM thalamic lesions for tremor may be explained by connectivity of the basal ganglia-thalamocortical motor loop, a pathway of which is proposed to consist of fibers from the contralateral dentate nucleus of the cerebellum through the posterior ventralis lateralis thalamic nucleus to the motor cortex. Stereotactic thalamotomy is typically reserved for patients with marked functional disability due to severe unilateral or asymmetric tremor that is refractory to the highest tolerated doses of antitremor medications. The first published reports concerning thalamotomy in ET indicated that more than 90% of patients demonstrated contralateral improvement. Although most of these assessments were performed before standardized tremor clinical rating scales were developed, reported studies and current clinical observations indicate the efficacy of unilateral thalamotomy. The percentage of ET patients who experience contralateral improvement, tremor remission, and concomitant functional improvement following thalamotomy reportedly ranges from approximately 78% up to 100%. In addition, long-term follow-up studies report that the benefits of stereotactic thalamotomy continue in most patients. www.wemove.org

Thalamotomy for ET (cont.) Bilateral thalamotomies usually not performed due to high risk of permanent dysarthria ~70% of patients with voice tremor improve with unilateral thalamotomy Incomplete lesioning may lead to reemergent tremor within two months Bilateral thalamotomies usually are avoided due to a high risk of severe, persistent dysarthria. In contrast, persistent morbidity occurs in less than 10% of ET patients who undergo unilateral thalamotomy. In one series of 8 ET patients with a mean follow-up of 17.3 months after VL thalamotomy, subjects were evaluated using a revised tremor rating scale. At follow-up, disability scores were reduced by 82%, with no severe, persistent morbidity or operative mortality. All patients reported complete ablation or significant attenuation of the targeted tremor. Investigators specifically noted that, of those with preoperative voice tremor, tremor was eliminated or improved in 71.4%. Goldman MS, Kelly PJ. Symptomatic and functional outcome of stereotactic ventralis lateralis thalamotomy for intention tremor. J Neurosurg. 1992;77:223-229. Reports indicate that incomplete lesioning may be associated with mild residual tremor or eventual reemergence of tremor. In such cases, repeating the operation may be a valid option. www.wemove.org

Thalamotomies in ET www.wemove.org This table presents a summary of studies mentioned earlier reporting complete, marked, or moderate improvement of tremor following thalamotomy. Included is the total number of ET patients within each study, the number of patients improved, and persistent morbidity. For example, Ohye and colleagues evaluated 15 ET patients who underwent stereotactic thalamotomy, 2 of whom received bilateral procedures. Repeat surgery was required for 1 patient. Improvement was reported in all patients, with minimal postoperative complications including weakness, numbness, and dysarthria. Nagaseki and colleagues, with a mean follow-up of 6.58 years, conducted retrospective analysis of 16 ET patients who had undergone selective VIM thalamotomy. A total of 19 procedures were performed including 1 repeat and 2 bilateral operations. All patients experienced improvement, with 15 sites associated with complete tremor ablation and 3 with mild residual tremor. Persistent morbidity included dysarthria, motor weakness, and paresthesias. Mohadjer et al. reexamined 65 of 104 ET patients for whom they had performed thalamotomies. There was a mean follow-up of 8.6 years. Of the 65 patients, 69% had complete ablation or marked reduction of tremor, and 11% reported moderate improvement. Persistent postoperative complications included gait disturbance and dysarthria. In addition, Jankovic and colleagues conducted retrospective analysis of 6 ET patients who had undergone unilateral thalamotomy. The mean follow-up was 53.4 months. Eighty-three percent had complete ablation or marked to moderate improvement of contralateral tremor. Persistent morbidity included dysarthria and contralateral weakness. 5Cooper IS. Heredofamilial tremor abolished by chemothalamectomy. Arch Neurol. 1962;7:129-131. 6Laitinen L. Stereotaxic treatment of hereditary tremor. Acta Neurol Scand. 1965;41:74-79. 7Blacker HM, Bertrand C, Martinez N, Hardy J, Molina-Negro P. Hypotonia accompanying the neurosurgical relief of essential tremor. J Nerv Ment Dis. 1968;147:49-55. 8Bertrand C, Hardy J, Molina-Negro P, Martinez SN. Tremor of attitude. Confin Neurol. 1969;31:37-41. 9Van Manen J. Stereotaxic operations in cases of hereditary and intention tremor. Acta Neurochir (Wien). 1974;(suppl 21):49-55. 10Ohye C, Hirai T, Miyazaki M, Shibazaki T, Nakajima H. Vim thalamotomy for the treatment of various kinds of tremor. Appl Neurophysiol. 1982;45:275-280. 11Nagaseki Y, Shibazaki T, Hirai T, et al. Long-term follow-up results of selective VIM-thalamotomy. J Neurosurg. 1986;65:296-302. 12Mohadjer M, Goerke H, Milios E, Etou A, Mundinger F. Long-term results of stereotaxy in the treatment of essential tremor. Stereotact Funct Neurosurg. 1990;55:125-129. 13Goldman MS, Kelly PJ. Symptomatic and functional outcome of stereotactic ventralis lateralis thalamotomy for intention tremor. J Neurosurg. 1992;77:223-229. 14Jankovic J, Cardoso F, Grossman RG, Hamilton WJ. Outcome after stereotactic thalamotomy for parkinsonian, essential, and other types of tremor. Neurosurgery. 1995;37:680-687. www.wemove.org

Thalamotomy: Adverse Effects Risk of major operative complications less than 2% Surgical morbidity is rare but can be catastrophic Uncommon but usually transient occurrence of cerebral hemorrhage, seizure, cerebellar signs, hemiparesis, cognitive deficits Dysarthria may be severe in bilateral thalamotomies In summation, persistent postoperative complications are typically minimal and may include dysarthria, motor weakness, paresthesias, dysequilibrium, and gait disturbance. Less commonly, adverse effects may include seizures, involuntary movements, cognitive deficits, or intracranial hemorrhage. www.wemove.org

Thalamic Deep Brain Stimulation (DBS) Approved for use in patients with ET in 1998 No lesioning as in thalamotomy Wire electrode placed in the target area (VIM) During the early to mid 1960s, a number of investigators reported tremor ablation through high frequency, intraoperative stimulation of the VIM thalamic nucleus. Beginning in the late 1980s, several studies reported safety and efficacy of chronic VIM stimulation for the treatment of disabling, medication-refractory ET. Available since 1995 in Canada, Europe, and Australia, deep brain stimulation or DBS was approved by the FDA in 1998 for the treatment of patients with ET and has since gained acceptance as an alternative to surgical ablation of the VIM thalamic nucleus. www.wemove.org

Thalamic DBS (cont.) Connecting wire tunneled under the scalp to subclavicular region Wire connected to surgically placed implantable pulse generator (IPG) Continuous electrical stimulation delivered to the target area Hand-held magnet turns stimulator on or off The FDA has approved the use of Medtronic’s Activa Tremor Control therapy. The DBS lead connects to an implantable pulse generator or IPG, which is implanted subcutaneously in the subclavicular region. The intracranial end of the lead has 4 platinum-iridium stimulating contacts, any one of which may be utilized for monopolar stimulation. In addition, any 2 or more of the contacts may be used for bipolar stimulation. Investigators report that tremor often is markedly reduced immediately following implantation due to associated microscopic lesioning of the VIM thalamic nucleus. Initiation of continuous electrical stimulation to the thalamus typically commences 1 day postoperatively. Patients may turn the IPG off and on by passing a hand-held magnet over the device. IPG batteries typically require surgical replacement every 3 to 5 years. www.wemove.org

Thalamic DBS (cont.) Programming of the pulse generator includes setting… Optimal electrode montage Pulse width Voltage Stimulation frequency Contralateral arm tremor reduced by ~80% An external programming device is used to program adjustable variables, including selection of stimulating contacts, pulse width, amplitude, and frequency. Typical ranges may include a pulse width of about 60 to 120 microseconds, amplitude of 1 to 3 volts, and stimulation frequency of 135 to as high as 185 Hz. In one investigation, Ondo and colleagues evaluated 33 PD and ET patients at 3 months post -unilateral thalamic DBS. The 14 ET patients demonstrated an 83% reduction of contralateral arm tremor, with significant improvement in all measures of tremor, including subjective functional surveys, objective functional performance tests, and disability scores. Adverse effects were generally mild and responded to variable adjustments. Ondo W, Jankovic J, Schwartz K, Almaguer M, Simpson RK. Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology. 1998; 51:1063-1069. www.wemove.org

Pathways Relevant to the Pathophysiology of Tremor This slide illustrates pathways relevant to the pathophysiology of tremor. As shown here, lesions related to tremor emergence are primarily located in the cerebellum, brainstem, and thalamus, with secondary disruption of their pathways. Lesions are most consistently present in dentato-rubro-olivary and cerebello-thalamocortical pathways. The lower arrow points to the thalamic VIM nucleus, indicating the improvement of tremor with chronic stimulation of the VIM. It is important to note, however, that the specific mechanism of action in thalamic DBS remains unknown. Benabid and colleagues have speculated that thalamic stimulation may serve to suppress tremor by providing chronic artificial “neural noise” that essentially interrupts processing of proprioceptive inputs from the spinal cord to the motor cortex. Benabid AL, Pollak P, Hoffmann D, LeBas JF, Ming GD. Chronic high-frequency thalamic stimulation in Parkinson’s disease. In: Koller WC, Paulson G, eds. Therapy of Parkinson’s Disease. New York: Marcel-Dekker; 1995:381-401. Vidailhet M, Jedynak C, Pollak P, Agid Y. Pathology of symptomatic tremors. Mov Disord 1998;13(suppl 3):49-54. www.wemove.org

High Frequency Thalamic Stimulation for ET This table presents a summary of studies on the use of chronic thalamic stimulation in ET. Included is the total number of ET patients within each study, the number of patients improved, and persistent morbidity. For example, Blond and colleagues evaluated 4 ET patients who had undergone unilateral thalamic stimulation. Two patients had major tremor suppression, 1 experienced moderate improvement, and another had mild improvement. In 1991, Benabid et al. originally reported on 6 ET patients who underwent thalamic stimulation of the VIM nucleus, 3 of whom had bilateral stimulation. Complete tremor cessation was achieved with stimulation of 4 sites. Two sites had major improvement, 2 resulted in moderate tremor reduction, and 1 had mild improvement. Postural or resting tremor appeared to be more effectively suppressed than action tremor. In 1993, Benabid and colleagues reported on a total of 13 ET patients, observing major improvement of tremor in 68%. Finally, by 1996, Benabid et al. reported on a total patient population of 20 ET patients. Although satisfactory results continued, augmentation of tremor, particularly action tremor, occurred in 18.5%. Koller and colleagues conducted a multicenter study of unilateral thalamic DBS in patients with ET and PD. At 3-month follow-up, of a total of 29 ET patients, 23 had marked improvement, defined as 50% to 100% tremor reduction. Three patients reported moderate tremor reduction, defined as 25% to 49% improvement. One had mild improvement; and 2 demonstrated no change. As mentioned earlier, in 1998, Ondo and colleagues reported an 83% reduction in contralateral arm tremor in 14 ET patients 3 months after they received unilateral thalamic stimulation. Blond S, Caparros-Lefebvre D, Parker F, et al. Control of tremor and involuntary movement disorders by chronic stereotactic stimulation of the ventral intermediate thalamic nucleus. J Neurosurg. 1992;77:62-68. Benabid AL, Pollak P, Gao D, et al. Chronic electrical stimulation of the ventralis intermedius nucleus of the thalamus as a treatment of movement disorders. J Neurosurg. 1996;84:203-214. Koller W, Pahwa R, Busenbark K, et al. High-frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor. Ann Neurol. 1997;42:292-299. Ondo W, Jankovic J, Schwartz K, Almaguer M, Simpson RK. Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson’s disease tremor. Neurology. 1998;51:1063-1069. www.wemove.org

Thalamic DBS: Side Effects Double-blind study comparing DBS and thalamotomy showed them equally effective but fewer side effects with DBS Bleeding may occur Limb parasthesias most common side effect Hardware failure and infections Potential side effects associated with thalamic stimulation are generally mild and often transient and may include dysarthria, dysequilibrium, limb dystonia, and headache. The most common side effect is mild contralateral limb paresthesia that occurs when the pulse generator is activated. Reports indicate that these side effects are reversible when stimulation is turned off. Complications related to surgery are rare. In some cases, the device has not been implanted due to subdural hematoma during burr hole placement, intracranial hemorrhage, or lack of tremor suppression during surgery. In a few reported cases, asymptomatic intracranial microhematomas were detected on routine postsurgical CT. Rare postsurgical complications have required surgical replacement due to skin erosion from the extension wire, IPG malfunction, and wire breakage. With thalamic DBS, the risk of severe, persistent morbidity, such as permanent neurologic damage, is relatively low. Accordingly, many investigators regard VIM thalamic stimulation as a safe and efficacious procedure that is less invasive than thalamotomy and therefore should be given preference over surgical ablation for ET patients with medically refractive tremor. Following is a short discussion of the relative advantages and disadvantages of thalamic DBS as compared with thalamotomy. www.wemove.org

Thalamic DBS: Advantages Reversibility Adaptability Potential ability to perform bilateral operations for hand tremor with reduced risk of morbidity Late tremor recurrence addressed by adjustments of pulse generator programming parameters Pahwa Rajesh, Koller William C. Surgical treatment of essential tremor. In: Bain Peter, Brin Mitchell, Deuschl Günther, Elble Rodger, Findley Leslie, Jankovic Joseph, Koller William, Pahwah Rajesh. Current issues in essential tremor. Embryon 1999;30. During their investigation of unilateral thalamic DBS in ET and PD patients, Koller and colleagues noted a number of advantages of DBS over surgical ablation. These include reversibility due to minimal lesioning of the VIM and the ability to change impulse variables to minimize side effects and increase efficacy. In addition, appropriate adjustments of stimulus parameters may help to address the late tremor recurrence seen in some patients, such as those reported by Benabid and colleagues. An additional benefit of thalamic stimulation includes the ability to perform bilateral procedures with a reduced risk of permanent morbidity. www.wemove.org

Thalamic DBS: Disadvantages Increased expense Implantation of foreign material Need to replace batteries/hardware Effort and time to optimize stimulation parameters Disadvantages of thalamic DBS may include increased expense due to the system’s cost and the potential risk of inflammatory responses and infection due to implantation of foreign material. Batteries and other hardware will eventually require surgical replacement. IPG batteries typically require replacement every 3 to 5 years. An additional disadvantage is the amount of time and effort required to adjust stimulus variables for optimal benefit with a minimum of side effects. In addition, although rare, it is important to note that a few patients may develop tolerance to chronic VIM stimulation. Effective tremor control may be obtained with regular increases in stimulation frequency. Yet tremor augmentation may occur over days or weeks, requiring repeated adjustments of stimulus parameters. Because tolerance affects patients who initially require high stimulation frequencies for efficacious tremor control, the lead may not be in the optimal location. Shutting off the device during the evenings or ceasing stimulation for short periods may delay tolerance. If tolerance develops, repositioning of the lead or stereotactic thalamotomy is considered. www.wemove.org

Patient Selection for Surgery Possible candidates for stereotactic procedures include ET patients with disabling medication-resistant tremor Contraindicated in those with... Marked cognitive problems Unstable medical diagnosis that may significantly increase surgical risk Appropriate candidates for stereotactic procedures include ET patients with severe, disabling, drug-refractory tremor. Major contraindications for a surgical approach include severe cognitive problems or an unstable medical diagnosis that may significantly increase surgical risk. www.wemove.org

ET Treatment Summary Therapy plan guided by measures of disability, handicap, and quality of life When disability exists, drug treatment should be attempted, unless contraindicated Nonresponders to oral medications may respond to botulinum toxin type A injections Surgical options may be appropriate for severe tremor refractory to conservative management In summation, the symptomatic management of ET should be guided by measures of disability, handicap, and quality of life. When tremor results in functional disability, a pharmacologic approach should be initiated in an attempt to achieve optimal tremor reduction with a minimum of side effects. The initiation of specific pharmacologic therapies is based upon any contraindications, patient age, coexistent conditions, concurrent drug therapies, and other necessary factors. For appropriate candidates with medication-refractory tremor, chemodenervation with localized injections of botulinum toxin type A may be an appropriate alternative. Thalamic DBS or thalamotomy may be considered for disabling tremor refractory to conservative management. www.wemove.org