Eric J. Pappert

Olanzapine and clozapine Comparative effects on motor function in hallucinating PD patients

Objective: To compare olanzapine and clozapine for safety and efficacy measures of psychosis and motor function in patients with PD and chronic hallucinations. Background: Hallucinations occur in approximately one third of patients with PD treated chronically with dopaminergic drugs. Although clozapine is known to be an effective antipsychotic agent that does not significantly exacerbate parkinsonism, its use requires frequent blood count assessment. Olanzapine is another novel antipsychotic that is not associated with blood dyscrasia, and if equally effective could become the preferred drug for treating hallucinations in subjects with PD. Methods: A randomized, double-blind, parallel comparison of olanzapine and clozapine in patients with PD with chronic hallucinations was conducted. The primary outcome measure was the Scale for the Assessment of Positive Symptoms (SAPS) for psychotic symptoms. The Unified Parkinson’s Disease Rating Scale (UPDRS) motor subscale was used as a secondary outcome measure and as a safety monitoring tool. Results: After 15 patients had completed the study, safety stopping rules were invoked because of exacerbated parkinsonism in olanzapine-treated subjects. UPDRS motor impairment scores from baseline to study end significantly increased with olanzapine treatment, and change scores between the olanzapine and clozapine groups significantly differed. The primary clinical domains responsible for the motor decline were gait and bradykinesia. Even with a smaller patient number than originally anticipated, clozapine significantly improved hallucinations and overall behavioral assessment, whereas olanzapine had no effect. Conclusions: At the doses studied, olanzapine aggravates parkinsonism in comparison with clozapine and should not be regularly used in the management of hallucinations in patients with PD.

Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson's disease.

In a series of consecutively randomized outpatients who had Parkinsons disease (PD), we examined the association of three behaviors: sleep fragmentation, altered dream phenomena, and hallucinations/illusions. Using a log‐linear model methodology, we tested the independence of each behavior. Sixty‐two percent of the subjects had sleep fragmentation, 48% had altered dream phenomena, and 26% had hallucinations/illusions. Eighty‐two percent of the patients with hallucinations/illusions experienced some form of sleep disorder. The three phenomena were not independent. The interaction between sleep fragmentation and altered dream phenomena was strongly statistically significant. Likewise, a significant interaction existed between altered dream phenomena and hallucinations/illusions. No interaction occurred between sleep fragmentation and hallucinations/illusions. Sleep fragmentation, altered dream phenomena, and hallucinations/illusions in PD should be considered distinct but often overlapping behaviors. The close association between altered dream phenomena and hallucinations suggests that therapeutic interventions aimed at diminishing dream‐related activities may have a specific positive impact on hallucinatory behavior.

Objective assessments of longitudinal outcome in Gilles de la Tourette's syndrome.

Objective: To define the long-term outcome in Gilles de la Tourette syndrome (GTS) using objective rating measures. Background: Previous historical studies suggest spontaneous improvement of tic symptoms after adolescence, but objective longitudinal data are limited. Methods: The authors reviewed all videotapes in their database (1978 through 1991) of children with GTS (ages 8 to 14) who were seen in their tertiary care movement disorder center and underwent a standardized 5-minute filming protocol (n = 56). Through multiple contact methods, they successfully located 36 of these patients, who are now adults (age >20 years), and recruited 31 (28 men and 3 women) to volunteer for a second videotape and in-person assessment. A blinded rater evaluated the 62 tapes and rated five tic domains: body areas involved, motor and phonic tic frequency, and motor and phonic tic severity. Using standardized GTS videotape rating scale and Wilcoxon signed-rank tests with Bonferroni correction for multiple comparisons, the authors compared the two videotapes for each tic domain as well as the composite tic disability score. Results: Ninety percent of adult patients still had tics. Adult patients who considered themselves tic-free were often inaccurate in their self-assessment: 50% had objective evidence of tics. Mean objective tic disability diminished in comparison to childhood (mean composite tic disability score childhood 9.58 vs adulthood 7.52, p = 0.014). All domains improved by adulthood, and significant improvements occurred in motor tic severity (p = 0.008). The improvements in tic disability did not relate to medication use, as only 13% of adults received medications for tics, compared with 81% of children. Conclusions: In GTS syndrome, tics objectively improve over time but most adults have persistent tics.

Prospective longitudinal assessment of hallucinations in Parkinson’s disease

Objective: To monitor the evolution of hallucinations over 4 years in a stratified sample of patients with PD. Methods: Using a modified version of the Unified PD Rating Scale (UPDRS) Thought Disorder question, the authors stratified patients into five baseline behavioral groups. They recruited up to 20 patients for each group to participate in sequential interviews (Rush Hallucination Inventory) at baseline and 6, 18, and 48 months. UPDRS motor examinations and Mini Mental State Examinations (MMSE) were obtained at baseline and 48 months. Data were analyzed with Wilcoxon rank sum tests, Mantel-Haenszel tests, and Spearman correlations. To determine features that influenced the new development of hallucinations, a cumulative logit regression model of hallucination severity over time was fit using generalized estimating equations. Results: Based on the design stratification, 60 patients had no hallucinations at baseline (20 with no behavioral problems, 20 with sleep fragmentation, 20 with altered dream phenomena). Twenty-nine patients had hallucinations (20 with retained insight and 9 with loss of insight). At 48 months, the authors could account for all but two subjects (98% retrieval). In 4 years, the presence of hallucinations increased (33% at baseline, 44% at 18 months, and 63% at 48 months, p < 0.0001). The presence of frequent hallucinations (at least three times weekly) also increased (p = 0.0002). Having hallucinations at baseline or at any given assessment was a strong predictor at all follow-up evaluations of continued hallucinations (p < 0.0001). Hallucinations were not associated with increased mortality (χ2 = 0.59, df (1), p = 0.47). Among the 60 subjects without hallucinations at baseline, time was the only significant factor influencing the development of hallucination over 48 months. Baseline age, PD duration, sex, medications, and UPDRS or MMSE scores did not influence the incidence of hallucinations. Conclusions: This prospective, longitudinal study documents the persistent and progressive nature of hallucinations in PD patients on chronic dopaminergic therapy. The consistent association of hallucinations with combined levodopa/agonist therapy suggests that these drugs may play a role in the pathophysiology of hallucinations.

Intravenous levodopa in hallucinating Parkinson's disease patients High‐dose challenge does not precipitate hallucinations

In five nondemented Parkinsons disease patients with daily visual hallucinations, we tested whether high-dose IV levodopa (LD) infusions precipitated hallucinations. Two infusion paradigms were studied, each with 1.5—mg/kg hourly dose for 4 hours—steady infusion and pulse infusion of the full hour dose over 5 minutes each hour. In both protocols, plasma LD levels changed significantly during the infusion protocol. The cumulative area under the curve was equivalent for the two infusions. All patients remained alert, and none developed visual hallucinations. The two patients with peak-dose dyskinesias on oral LD developed prominent dyskinesias during the infusion. Visual hallucinations do not relate simply to high levels of LD or to sudden changes in plasma levels.

Advantages of a Modified Scoring Method for the Rush Video-Based Tic Rating Scale

Previously, we published a video‐based objective rating scale of tics that met reliability and validity criteria for measurement of five domains of tic disability. In the original form, the scales metric properties did not permit internal comparison of each of the five domains of impairment and did not provide a total score for use as a primary outcome measure. In this study, we retained the original scale and videotape protocol but tested whether a modified scoring system corrected these limitations. The new scoring method rated assigned tic data to ratings of 0–4 on five disability categories: number of body areas, frequency of motor tics, frequency of phonic tics, severity of motor tics, and severity of phonic tics. The sums of these ratings yielded a total score of overall tic disability (0–20). In a series of 31 patients with Gilles de la Tourette syndrome, we assessed Spearman correlation coefficients for the old and new scoring systems as well as the correlation of the new ratings with the objectively derived sections of the Yale Global Tic Severity Scale (YGTSS), another valid and reliable scale used in clinical practice and research. For each domain, the rank order for the scores on the original scale was well retained in the new scores. Likewise, for each domain, ranking with the new scoring system correlated well with scores on the comparable objective item from the YGTSS. The new total score accurately captured the rank order of the combined five domains from the original scale and correlated well with the total objective motor plus phonic tic score from the YGTSS and the YGTSS Tourette Syndrome Overall Impairment Rating. These data demonstrate that the modified videotape‐based scoring system retains the essential information gathered in the original Rush scale. The modification provides comparisons among the five assessed domains and a total objectively based disability score that can be used as a single outcome measure for assessing tic disability.

Alpha-tocopherol in the ventricular cerebrospinal fluid of Parkinson's disease patients: Dose-response study and correlations with plasma levels

Objective: To determine if ventricular cerebrospinal fluid (vCSF) alpha-tocopherol levels in Parkinsons disease (PD) patients can be increased by oral alpha-tocopherol supplementation and whether vCSF levels are linearly related to plasma alpha-tocopherol levels. Background: In spite of its putative neuroprotective properties, alpha-tocopherol has failed to alter PD clinical progression. However, the ability of supplemental alpha-tocopherol to affect brain or vCSF levels has never been assessed in humans nor has a dose-response curve for alpha-tocopherol in vCSF been established. Methods: Five PD patients with Ommaya catheters received oral dl-alpha-tocopherol over 5 months. Each patient ingested alpha-tocopherol daily with monthly dosage increases (400, 800, 1,600, 3,200, 4,000 IU/day). Plasma and vCSF samples were obtained at baseline and at the end of each month. Alpha-tocopherol levels were determined in triplicate by high-pressure liquid chromatography with fluorometric and electrochemical detection. Results: At baseline, endogenous alpha-tocopherol was detected in plasma and vCSF, with a greater than one-hundred-fold difference between the fluid compartments (mean plasma level 18.76 micro Meter/l (SD +/- 4.69) versus mean CSF level 0.114 micro Meter/l (SD +/- 0.084). A clear dose-response curve occurred in plasma, with statistically significant increases over baseline developing even with 400 IU/d. With higher doses, a significant increase continued without evidence of saturation. However, there was no significant increase in vCSF alpha-tocopherol levels at any dose, including the supraclinical (4,000 IU/d). There was no correlation between plasma and vCSF alpha-tocopherol levels. Conclusion: Oral alpha-tocopherol supplementation, even at supraclinical doses, fails to increase vCSF alpha-tocopherol levels. This lack of change may be due to limited passage across the blood-brain barrier or very rapid alpha-tocopherol metabolism. All prior negative studies on efficacy of alpha-tocopherol in PD may need reevaluation in light of these pharmacologic data. NEUROLOGY 1996;47: 1037-1042

Animal model of posthypoxic myoclonus Effects of serotonergic antagonists

Objective: To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus. Background: Although serotonergic system dysfunction is implicated in post-hypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated. Methods: The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague–Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at −30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose–response study with six doses across a range from the original dose studied to 10% of that dose. Results: Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose–response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. Conclusions: 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance–Adams syndrome.

Flu-like symptoms following botulinum toxin therapy.

This paper reviews the relevant literature on flu-like symptoms (FLS) in patients treated with botulinum toxin (BoNT) type A and B. We conducted a systematic search in PubMed and Medline of publications on BoNT and FLS. FLS were defined as the presence of symptoms of an upper respiratory tract infection associated with fever, general malaise or fatigue, within one month after BoNT injections and not secondary to any other identified condition. FLS have been reported in between 1.7 and 20% of patients treated with various preparations of BoNT/A. Most patients have a mild to moderate symptoms lasting less than 2 weeks, but 66 serious AEs related to FLS were reported to the Food and Drug Administration between 1989 and 2003. No significant differences in the frequency of FLS have emerged when different BoNT/A commercial products were compared, although no well-designed head-to-head comparison trials focusing on FLS have been published. For BoNT/B preparations, FLS have been reported in 5-55% of cases. We concluded that the frequency of FLS in patients treated with BoNT/A and BoNT/B varies widely between studies and no clear risk factors have been identified for this complication. We suggest potential treatments like analgesics/antipyretics or switching to less antigenic preparations in case of persistent symptoms.

Botulinum Toxin Therapy for Cervical Dystonia: The Science of Dosing

The first-line treatment for cervical dystonia (CD) is botulinum toxin type A (BoNT-A), which has been established as a highly effective and well-tolerated therapy. However, this treatment is also complex and challenging to apply in clinical practice. Approximately 20% of patients discontinue therapy due to treatment failure, adverse effects, and other reasons. In addition, expert consensus recommendations are lacking to guide physicians in the optimal use of BoNT-A for CD. Among the issues still to be clarified is the optimal dosing frequency. The generally accepted standard for intervals between BoNT-A injections is ≥12 weeks; however, this standard is based primarily on the methodology of pivotal trials for the BoNT-A products, rather than on evidence that it is optimal in comparison to other intervals. While some retrospective, observational studies of BoNT-A used in clinical practice appear to support the use of ≥12-week dosing intervals, it is often unclear in these studies how the need for reinjection was determined. In contrast, a prospective dose-ranging trial in which patients were allowed to request reinjection as early as 8 weeks showed that about half of patients receiving abobotulinumtoxinA, at the currently recommended initial dose of 500 U, requested reinjection at 8 weeks. Moreover, results from an open-label, 68-week extension phase of the pivotal trial of incobotulinumtoxinA showed that 47.1% of patients had received reinjection at ≤12 weeks. Ongoing studies, such as the Cervical Dystonia Patient Registry for Observation of BOTOX® Efficacy (CD PROBE), may help clarify this question of optimal dosing intervals for BoNT-A in CD.