Richard B. Dewey

Practice Parameter: Therapies for essential tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology

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.

Evidence-based guideline update: Treatment of essential tremor Report of the Quality Standards Subcommittee of the American Academy of Neurology

Background: This evidence-based guideline is an update of the 2005 American Academy of Neurology practice parameter on the treatment of essential tremor (ET). Methods: A literature review using MEDLINE, EMBASE, Science Citation Index, and CINAHL was performed to identify clinical trials in patients with ET published between 2004 and April 2010. Results and Recommendations: Conclusions and recommendations for the use of propranolol, primidone (Level A, established as effective); alprazolam, atenolol, gabapentin (monotherapy), sotalol, topiramate (Level B, probably effective); nadolol, nimodipine, clonazepam, botulinum toxin A, deep brain stimulation, thalamotomy (Level C, possibly effective); and gamma knife thalamotomy (Level U, insufficient evidence) are unchanged from the previous guideline. Changes to conclusions and recommendations from the previous guideline include the following: 1) levetiracetam and 3,4-diaminopyridine probably do not reduce limb tremor in ET and should not be considered (Level B); 2) flunarizine possibly has no effect in treating limb tremor in ET and may not be considered (Level C); and 3) there is insufficient evidence to support or refute the use of pregabalin, zonisamide, or clozapine as treatment for ET (Level U).

Pergolide use in Parkinson disease is associated with cardiac valve regurgitation

Objective: To determine if pergolide injures heart valves, by comparing echocardiographic findings in pergolide-treated patients with those of a historical control group. Methods: Letters were sent to all patients in the authors’ practice believed to be taking pergolide, and those responders who wished to continue it were urged to undergo echocardiography. Echocardiograms were obtained on 46 patients, and scores for valvular regurgitation were compared with those from an age-matched control group derived from the Framingham Study. The composite valve regurgitation score was modeled as a linear function of total milligrams lifetime use of pergolide, controlling for age. Results: Eighty-nine percent of pergolide-treated patients had some degree of valvular insufficiency. For each of the three valves for which there are control data, we found an approximately 2- to 3-fold increased risk of abnormal valves in the pergolide patients (odds ratio [OR] ≈ 3) and an estimated 14-fold increased risk of concerning tricuspid regurgitation (OR = 18.4). The composite valve score (the sum of valve scores for each of the four valves) was a function of lifetime pergolide use. Conclusion: Pergolide may injure cardiac valves, resulting most commonly in tricuspid regurgitation.

Tremor response to polarity, voltage, pulsewidth and frequency of thalamic stimulation

Background: Thalamic deep brain stimulation ameliorates essential and parkinsonian tremors refractory to medications. Stimulus voltage, polarity configuration, frequency, and pulsewidth can each be adjusted in order to optimize tremor control and maximize battery life. The relative impacts of these programmable variables have not previously been quantified. Methods: The thalamus of 11 patients (bilaterally in 2) was studied 4 to 59 months postoperatively. The stimulator was inactivated and medications withheld for 12 hours, and optimal electrode contacts were selected. Stimulation followed at a range of voltages (0, 1, 2, 3, or 4 V), pulsewidths (60, 90, or 120 μs), and frequencies (130, 160, or 185 Hz) for both monopolar and bipolar configurations. Seventy-eight combinations of variables were programmed in random sequence. Postural and action tremors were measured with an electromagnetic tracker, tremor was subjectively graded, and side effects were noted. Results: Voltage was consistently predictive of tremor response. Mean postural tremor amplitude in PD fell from 6.4 cm at 0 V to 2.6, 1.0, 0.3, and 0 cm at 1 through 4 V (bipolar configuration). The voltage response curve for essential tremor was flatter. The monopolar configuration was 10 to 25% more effective than bipolar. The longest pulsewidth tested was up to 30% more effective than the shortest, but frequency changes had little effect on tremor amplitude. Side effects occurred only with monopolar stimulation, and the only setting that was intolerable for the majority was 4 V, 120 μs, and 185 Hz. Conclusion: Bipolar deep brain stimulation at 90 μs, 130 Hz, adjusting the voltage up to 3 V, tends to be effective and well tolerated. Monopolar provides similar benefits for lower voltage, but side effects become common at 3 or 4 V.

Proprioception in Parkinson's disease is acutely depressed by dopaminergic medications

OBJECTIVES Impaired proprioception has been previously reported in patients with Parkinsons disease. It was hypothesised that dopaminergic medications transiently depress proprioception, with amplification of adventitious movements as a result. This study tested for effects on proprioception of dopaminergic drugs, and for associations between such effects and drug induced dyskinesias. METHODS In 17 patients with Parkinsons disease, arm proprioception was tested in the practically defined “off” state, and retested 1 hour after taking levodopa or dopamine agonist. Testing consisted of side to side comparison of elbow angle, matching the contralateral elbow angle, and spatial recall of an unrestrained arm. RESULTS Proprioception deteriorated as hypothesised, reaching significance by one tailedt test for each of the three tasks. The relative deterioration (and the 95% lower confidence bound for estimated deterioration) was 31% (4%) for side to side elbow comparison, was 27% (11%) for accuracy in matching the contralateral elbow angle, and was 11% (0%) for spatial recall. Dyskinetic (n=6) and non-dyskinetic (n=11) patients did not differ significantly in these effects on proprioception. Control subjects (n=6) and untreated parkinsonian subjects (n=5) did not significantly differ from the parkinsonian patients in the off state. CONCLUSIONS Administration of levodopa and dopamine agonists were associated with a modest acute suppression in central responsiveness to joint position. It is speculated that compensatory exaggerated movement could account in part for the phenomenon of drug induced dyskinesias.

Cognitive functioning in individuals with "benign" essential tremor.

Essential tremor (ET) is the most common type of movement disorder, although its etiology and neurophysiological substrates remain unclear. While thought to be a benign condition, it has yet to be studied from a neuropsychological perspective. We examined the neurocognitive functioning of 13 nondemented subjects with severe ET, including aspects of memory, cognitive flexibility, and attention. Results revealed that 12/13 subjects demonstrated impairment on 1 or more cognitive measures in comparison with published normative data. The pattern of findings was suggestive of relative dysfunction of frontal-mediated processes not unlike that seen in Parkinsons disease. These deficits were found in subjects irrespective of the presence of cognitive complaints, depression, or the existence of other potential neurocognitive risk factors. These findings suggest that mild cognitive deficits are not uncommon in association with severe ET and may be related to subcortical systems.

Questionnaire-based assessment of bladder dysfunction in patients with mild to moderate Parkinson’s disease

OBJECTIVES To assess the lower urinary tract symptoms (LUTS) in men and women with mild to moderate Parkinsons disease (PD) using validated symptom questionnaires. METHODS Eighty men and 39 women with mild to moderate PD (Hoehn and Yahr score less than 3) were mailed LUTS questionnaires to complete and return. Men received the American Urological Association Symptom Index and women received the Urogenital Distress Inventory-6. Patients not responding by mail were called and asked to complete the survey over the telephone. Control populations of both symptomatic and asymptomatic men and women (without PD) were identified for comparison. RESULTS The overall response rate was 78%. Men with early-stage PD had higher American Urological Association Symptom Index scores than age-matched controls (total score of 12.0 versus 7.7, P <0.05) and scores similar to those reported for men with symptomatic benign prostatic hyperplasia (12.5). Specific items noted to be higher among the men with PD included questions regarding frequency and urgency. Women with PD had higher scores on the Urogenital Distress Inventory-6 than non-age-matched controls (total score of 4.8 versus 2.1, P <0.05), but lower scores than an age-matched group of neurologically intact women presenting for urologic evaluation of LUTS (6.9, P <0.05). CONCLUSIONS On the basis of the responses to the validated symptom indexes, the development of LUTS appears to occur at an earlier stage of PD than was once appreciated. Prompt evaluation and treatment of patients with lower urinary tract complaints in the setting of PD may identify bladder dysfunction at an earlier, more treatable stage.

Effect of creatine monohydrate on clinical progression in patients with Parkinson disease: a randomized clinical trial.

IMPORTANCE There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies. OBJECTIVE To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease. DESIGN, SETTING, AND PATIENTS The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013. INTERVENTIONS Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years). MAIN OUTCOMES AND MEASURES The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes. RESULTS The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system. CONCLUSIONS AND RELEVANCE Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00449865.

Risk factors for pathologic gambling and other compulsions among Parkinson’s disease patients taking dopamine agonists

Three hundred patients with Parkinsons disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder.

Modest increase in plasma homocysteine follows levodopa initiation in Parkinson's disease

Levodopa, typically ingested chronically at high daily doses, is predictably methylated by means of a series of reactions using B vitamins, which convert methionine to homocysteine. Elevated total plasma homocysteine (tHcy), a risk factor for dementia, has been found in PD patients using levodopa. We prospectively measured the effects on plasma tHcy and B vitamins of levodopa initiation, and measured the effects of dose changes and of treatment with dopamine agonists and entacapone. We collected paired plasma samples, at baseline and again after several months treatment, from patients initiating levodopa (n = 30), from patients whose levodopa dose was doubled (n = 15), halved or stopped (n = 14), from patients starting or stopping entacapone (n = 15) and from patients initiating or doubling dopamine agonist monotherapy (n = 16). Vitamin B12, folate, and tHcy concentrations were measured. Baseline tHcy concentration of 8.7 (2.8) μmol/L increased to 10.1 (3.1) μmol/L (P = 0.004) an average of 94 (range 36 to 200) days after initiation of 604 (240 to 1050) mg/day of L‐dopa. Average concentration of vitamin B12 fell from 380 to 291 pmol/ L (P = 0.01). Patients who doubled their daily levodopa dose experienced tHcy elevations from 9.5 to 11.1 μmol/L (P = 0.05). Levodopa reduction, agonist treatment, and entacapone treatment did not have significant effects. Levodopa elevates tHcy and lowers vitamin B12 concentration to modest degrees. The clinical implications, if any, have not yet been determined.