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).

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.

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] approximately 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.

Accuracy of clinical detection of INO in MS: corroboration with quantitative infrared oculography.

The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

Benign paroxysmal positioning vertigo in multiple sclerosis: diagnosis, pathophysiology and therapeutic techniques.

OBJECTIVE: To report on the most common causes of vertigo in patients with multiple sclerosis (MS) and emphasize appropriate diagnostic techniques and treatment interventions. BACKGROUND: True vertigo is estimated to occur in about 20% of MS patients. Lesions within the vestibular nuclei and in the root entry zone of cranial nerve VIII represent the most common locations where demyelinating activity can provoke vertigo in patients with MS. However, other causes of vertigo should be explored in MS patients in order to avoid unnecessary treatment with corticosteroids and vestibular suppressants. Recently, we reviewed our four-year experience with new onset vertigo in our university-based MS population and found that benign paroxysmal positioning vertigo (BPPV) to be the most common cause. All patients diagnosed with BPPV were treated successfully with particle repositioning maneuvers. The remaining patients were treated with conventional therapies appropriate for the specific diagnosis. CONCLUSIONS: Empiric treatments with corticosteroids and/or vestibular suppressants should not be employed until all MS patients undergo a careful bedside examination, which includes diagnostic positional and, if indicated, particle repositioning maneuvers. Here we emphasize the pathophysiology of BPPV and illustrate the proper techniques for the diagnostic and therapeutic maneuvers.

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

OBJECTIVES: Impaired proprioception has been previously reported in patients with Parkinson's 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 Parkinson's 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 tailed t 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.

A randomized, double-blind, placebo-controlled trial of subcutaneously injected apomorphine for parkinsonian off-state events.

OBJECTIVE: To assess the safety and efficacy of subcutaneous apomorphine hydrochloride administration for off-state (poor motor function) periods in patients with Parkinson disease with motor fluctuations under both inpatient titration and outpatient therapeutic conditions. PATIENTS AND METHODS: Twenty-nine patients had advanced Parkinson disease with 2 hours or more off time despite aggressive oral therapy. Patients randomly received titrated doses of subcutaneous apomorphine hydrochloride (2-10 mg, n = 20) or pH-matched vehicle placebo (n = 9) during an inpatient and 1-month outpatient phase. A change in the United Parkinson Disease Rating Scale motor score 20 minutes after inpatient dosing during a practically defined off-state event and the percentage of injections successfully aborting off-state events were the primary inpatient and outpatient efficacy factors. RESULTS: The average (SEM) levodopa equivalent dose of apomorphine hydrochloride was 5.4 +/- 0.5 mg and the mean placebo dose was 1.0 mL. Mean inpatient United Parkinson Disease Rating Scale motor scores were reduced by 23.9 and 0.1 points (62% and 1%) by apomorphine treatment and placebo, respectively (P<.001). The mean percentage of outpatient injections resulting in successful abortion of off-state events was 95% for apomorphine and 23% for placebo (P<.001). Inpatient response was significantly correlated with and predictive of outpatient efficacy (P<.001). The levodopa dose was not predictive of the apomorphine dose requirement. Frequent adverse events included dyskinesia, yawning, and injection site reactions. CONCLUSION: Apomorphine by intermittent subcutaneous injection is effective and safe for outpatient use to reverse off-state events that occur despite optimized oral therapy.

Validation for tremor quantification of an electromagnetic tracking device.

An electromagnetic tracking system was used to record arm motion in subjects with Parkinson's disease (n = 23), essential tremor (n = 28) or without neurological disease (n = 4). Tremor magnitude was calculated by averaging the three-dimensional displacement of individual tremor bursts. Tremor magnitude calculated in this manner was quite closely correlated with a clinician's estimate (r = 0.88 and 0.86 for Parkinsonian and essential tremors, respectively) and was reproducible (r = 0.93 for repeated recordings). The accuracy of the device and algorithm was confirmed by mechanically generating oscillations of known magnitudes and frequencies. This device is adaptable for quantifying different types of tremors and its accuracy is easy to verify. Because position rather than acceleration is tracked, tremor amplitude can be stated in readily comprehensible units.

Vertigo in MS: utility of positional and particle repositioning maneuvers.

A 4-year experience with new-onset vertigo in a university-based MS population was retrospectively reviewed. Of 1,153 patients with MS, 25 could be clinically evaluated during the vertiginous episode. Of these, 13 (52%) were diagnosed with benign paroxysmal positioning vertigo and eight (32%) had acute MS exacerbations with corresponding lesions within the brainstem. All patients diagnosed with benign paroxysmal positioning vertigo were treated successfully with particle repositioning maneuvers.

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 Parkinson's 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.

Neuropsychological outcome following unilateral stereotactic pallidotomy in intractable Parkinson's disease.

Neuropsychological functioning was examined at baseline and 2- to 3-month follow-up in 40 subjects with advanced Parkinson's disease (PD) who underwent unilateral posteroventral pallidotomy. Most subjects demonstrated improved verbal learning, visual memory, confrontation naming, and figural fluency at follow-up. Right pallidotomy was associated with decreased cognitive flexibility and increased verbal fluency, whereas Left pallidotomy uniquely resulted in a decline in verbal fluency. Significant motor improvement was demonstrated in both groups. Pallidotomy appears to be an effective treatment for advanced PD, providing a significant improvement in motor functioning, while resulting in few deleterious neurocognitive changes in most cases.

Clinical outcome of unilateral stereotactic pallidotomy without microelectrode recording for intractable Parkinson's disease.

OBJECTIVE: To study the effects of unilateral stereotactic pallidotomy performed without microelectrode recording for advanced Parkinson's disease. METHODS: Stereotactic coordinates were calculated by comparing preoperative inversion recovery MRI sequences with intraoperative CT scans. Conventional stereotactic stimulation techniques were employed to confirm correct probe placement. Patients were assessed using a modified CAPIT protocol with the off-state UPDRS motor score as the primary efficacy measure. RESULTS: A statistically significant decline in off-state UPDRS motor scores occurred at 2months (21% improvement in 32 patients) and also at 1year postoperatively (30% improvement in 12 patients). Levodopa-induced dyskinesias on the side contralateral to surgery were reduced 97% in the cohort with 1year of follow-up. No deleterious effects of surgery on global neuropsychological functioning were seen. A major surgical complication (mild but persistent hemiparesis) occurred in one patient. CONCLUSIONS: We believe that stereotactic pallidotomy can be performed safely and effectively without microelectrode recording when coordinates are calculated using CT with comparison to preoperative MRI sequences.

Long-term follow-up of levodopa responsiveness in generalized dystonia.

OBJECTIVES: To assign an accurate diagnosis to patients with dystonia based on the presence of sustained levodopa responsiveness and to determine whether motor fluctuations occur in patients with dystonia who are withheld from levodopa. PATIENTS AND METHODS: Patients with generalized dystonia who responded to treatment in the 1970s with levodopa/carbidopa were surveyed by phone and then examined during a 3-day levodopa holiday. Functional imaging with fluorodopa positron emission tomography was performed on a subset of patients. RESULTS: In the phone interview, 4 of 7 patients with a diagnosis of dopa-responsive dystonia reported the wearing-off effect a short while (within 4-8 hours) after missing a dose of levodopa. Five patients with dopa-responsive dystonia were examined repetitively during levodopa withdrawal, and 3 developed recurrent symptoms of dystonia as the drug was withheld. In each case, worsening of dystonia did not occur until 29 hours or more after levodopa withdrawal, providing evidence for a response profile similar to the long duration response described in Parkinson disease. No significant changes were seen in the dystonia scores of the 3 patients with idiopathic torsion dystonia who were withheld from levodopa. CONCLUSIONS: We suggest that the subjective feeling of wearing off experienced by our patients with dopa-responsive dystonia may have been for one of the nonmotor effects of levodopa, such as mood elevation. Our data provide objective evidence for the often-repeated assertion that motor fluctuations (analogous to those in levodopa-treated patients with Parkinson disease) do not occur in patients with dopa-responsive dystonia.

A double-blind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson's disease.

Nine patients with advanced levodopa-responsive Parkinson's disease were enrolled in a double-blind, placebo-controlled crossover trial of intranasal apomorphine as rescue therapy for parkinsonian off-states. Patients were assigned in random order to each of four possible combinations of apomorphine, trimethobenzamide antiemetic, and their matched placebos and received detailed in-office motor scoring during each of the four study periods. Patients also completed diaries describing the effectiveness of the nasal spray for reversing off-states. A statistically significant reduction in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score was seen following active apomorphine during in-office evaluation visits but not following placebo nasal spray. Patient diaries revealed that active apomorphine had a latency to onset of 11 minutes and a duration of 50 minutes. Significant nausea from apomorphine spray was seen in only one patient whereas nasal irritation was disabling in three and mild in two. We conclude that intranasal apomorphine is an effective rescue agent for parkinsonian off-states although nasal irritation is a limiting factor.

Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization.

OBJECTIVE: The optimal choice of imaging and localization for stereotactic surgery for movement disorders remains uncertain, with controversy surrounding the use of microelectrode recording and the role of distortion of magnetic resonance imaging (MRI) scans in reducing the accuracy of lesion placement. We review our experience with 67 pallidotomies and 35 thalamotomies performed without microelectrode recording, using instead individual variations in anatomic landmarks. METHODS: Computed tomography is used as the primary modality, with comparison with carefully angled MRI scans and the use of neural structures, such as the mamillary bodies and the vascular anatomy. Pallidal target sites are chosen immediately lateral and superior to the optic tract on a line bisecting the axis of the peduncle, with macrostimulation guiding the final adjustment of target position. Forty-seven patients undergoing unilateral pallidotomies were studied in the "off" state and the "on" state using a modified Unified Rating Scale for Parkinson's disease (URSP) score and a dyskinesia scale, preoperatively and postoperatively at 2 weeks, 2 months, 6 months, and 12 months. In the 31 patients undergoing thalamotomy, tremor was rated preoperatively and postoperatively as near-complete resolution, partial resolution, and failure. RESULTS: The "off" state Unified Rating Scale for Parkinson's disease motor score declined from 42.0 to 32.2 at 2 weeks after surgery (P < 0.0001, n = 42). The Unified Rating Scale for Parkinson's disease motor score was 34.2 at 2 months (P < 0.0001, n = 35), 29.4 at 6 months (P < 0.0001, n = 27), and 24.9 at 12 months (P = 0.005, n = 12), representing an overall improvement in "off" state motor function of approximately 25 to 40%. The "on" state dyskinesia score fell from 5.5 to 2.0 at 2 weeks (P < 0.0001) and persisted in the later visits. The dyskinesia score for the contralateral side fell from 2.5 preoperatively to 0.26 at 2 weeks, 0.28 at 2 months, 0.22 at 6 months, and 0.0 at 12 months. Of the patients undergoing thalamotomies, 65% experienced near-complete or complete tremor resolution, 23% experienced partial tremor relief, and 13% were considered treatment failures. CONCLUSION: Stereotactic procedures for movement disorders requiring high precision can be safely and successfully performed without the use of microelectrode recording techniques. Meticulous alignment of MRI and computed tomographic scans based on visualized anatomy allows precise lesion placement and avoids the distortion inherent in MRI scans.

Choreoathetosis as a side effect of gabapentin therapy in severely neurologically impaired patients.

OBJECTIVE: To evaluate the relationship of gabapentin therapy with choreoathetotic movements in mentally retarded patients treated with intractable epilepsy. DESIGN: Case reports of 2 institutionalized patients who developed choreoathetosis temporally related to adjunctive therapy with gabapentin at dosages of 1200 to 1800 mg/d. RESULTS: Both patients experienced resolution of abnormal movements on discontinuation of the therapy. One patient developed recurrent choreiform movements after drug rechallenge. CONCLUSION: We suggest that, in patients with mental retardation and epilepsy, involuntary movements may either occur as reversible side effects of gabapentin therapy or result from a previously undescribed adverse drug interaction with other antiepileptic agents.

Intranasal apomorphine rescue therapy for parkinsonian "off" periods.

Eleven patients with levodopa-related motor fluctuations were scored before and after intranasal apomorphine monotherapy, and the motor responses were compared with those with levodopa/carbidopa in this openlabel study. Oral trimethobenzamide was used to prevent apomorphine-induced nausea. Three measures of motor performance were employed: (a) the Unified Parkinson's Disease Rating Scale (UPDRS) motor battery; (b) a timed hand-tapping test; and (c) the Webster's step-seconds test. The magnitude of the motor-score improvement after apomorphine administration was very similar to that after the usual doses of levodopa/carbidopa in the 10 patients completing the study; this was true for all three outcome measures. A major advantage of apomorphine was the rapid onset of clinical response, which typically occurred in < 10 min, as well as the ease of administration. Major side effects, beyond those experienced with levodopa/carbidopa, were limited to nausea and vomiting (three patients) and orthostatic hypotension (one patient); however, only a single patient dropped out of the study as a consequence. These results indicate that intranasal apomorphine is effective in rapidly relieving parkinsonian "off" states and that, for most patients, trimethobenzamide is an effective and well-tolerated antiemetic for use with apomorphine.

Stereotactic neurosurgery for Parkinson's disease.

The Council on Scientific Affairs of the California Medical Association presents the following epitomes of progress in neurosurgery. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and clinical importance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of progress in medicine, whether in their own field of special interest or another. The epitomes included here were selected by the Advisory Panel to the Section on Neurosurgery of the California Medical Association, and the summaries were prepared under the direction of John H. Neal, MD, and the panel.

Isolated eyelid-opening apraxia: report of a new levodopa-responsive syndrome.

Eyelid-opening apraxia (or involuntary levator inhibition) has been described chiefly in the context of basal ganglia disease. We present two novel cases in which apraxia of eyelid opening developed in the absence of any other CNS signs, and which resolved following treatment with levodopa. We suggest that when inability to open the eyes occurs without associated motor impairment, "apraxia" is the correct descriptive term, and a trial of levodopa should be considered.