R. Raman

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.

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.

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.

Placebo-associated improvements in motor function: comparison of subjective and objective sections of the UPDRS in early Parkinson's disease.

The Unified Parkinsons Disease Rating Scale (UPDRS) is primarily composed of an investigator‐derived objective rating of motor function and a patient‐derived assessment of activities of daily living (ADL). Using a stringent definition of placebo effect, we examined the frequency, temporal development, and stability of improvements during placebo treatment over 6 months in a large placebo‐controlled trial of deprenyl and tocopherol in early Parkinsons disease (DATATOP). One hundred ninety‐nine subjects received placebo treatment in the randomized, multicenter, placebo‐controlled DATATOP study. We compared the baseline UPDRS motor section scores with follow‐up scores at 4, 13, and 26 weeks. Placebo‐associated improvement was defined as an improvement over baseline score in motor UPDRS of at least 50% or a change in at least two motor items at any one visit by two or more points. Seventeen percent of the 185 subjects who qualified for analysis met the placebo response criteria. The group prevalence of response was steady (7% to 10%) at any one visit without a marked predominance of an early study effect. Older subjects with more motor impairment at baseline were most likely to show a placebo‐associated improvement. ADL scores were low throughout the study, and ADL improvements did not identify the subjects with objectively defined placebo‐associated improvement. Prominent improvements in investigator‐derived objective measures of Parkinsons disease motor impairment occur during clinical trials, including one that was not aimed at showing improved short‐term efficacy. Although the notion of placebo effect often implies patient‐based perceptions, we found subjective changes to be infrequent in placebo‐treated patients, suggesting that either: (1) the placebo effect was rater‐driven; (2) the ADL questionnaire is insensitive to transient but objectively demonstrable motor changes; or (3) that the objective changes, albeit major, are within the realm of natural variation in the UPDRS motor scale from visit to visit.

Effects of central dopaminergic stimulation by apomorphine on speech in Parkinson’s disease

Objective: To determine the effect of central dopaminergic stimulation with apomorphine on speech in PD. Background: Most patients with PD have a speech disorder. Of those, 89% have involvement of laryngeal function, and 45% have additional articulatory dysfunction. The effect of dopaminergic medications on these two dimensions of speech impairment in PD has not been selectively studied. Methods: In a randomized, double-blind, placebo-controlled crossover design, patients with PD and speech impairment, Hoehn and Yahr stages 2 to 4 “off,” and without severe dyskinesias were given placebo or apomorphine injections 0.05 mg/kg subcutaneously during two consecutive outpatient visits. They were pretreated with domperidone for 48 hours and were tested off their parkinsonian medications for 12 hours. Laryngeal function was assessed by maximum sustained vowel phonations and comfortable vowel phonations. Articulatory function was evaluated by speech intelligibility score, speaking rate, and efficiency ratio. Results: Ten patients, mean age 73.4 years (SD = 6.6), disease duration 8.7 years (SD = 6.3), were tested. The baseline motor score on the Unified Parkinson’s Disease Rating Scale (UPDRSm) and all experimental speech variables were equivalent on both placebo and apomorphine days. At a dose of apomorphine that provoked improvement in UPDRSm (p = 0.0078), no index of either laryngeal or articulatory function improved significantly after apomorphine administration. Conclusion: Laryngeal and articulatory speech components are not under prominent dopaminergic control in PD. Treatment regimens should focus on nondopaminergic pharmacology and other therapies.

Awareness, treatment, and control of vascular risk factors in African Americans with stroke

Objective: To investigate control of risk factors in African American patients with previous stroke. Methods: The baseline history, physical examination, and laboratory data for 1,086 subjects enrolled in the African American Antiplatelet Stroke Prevention Study from 1995 to 1999 were studied. The level of awareness, pharmacologic treatment, and control of diabetes mellitus (casual plasma glucose level ≥200 mg/dL), hypertension (blood pressure ≥140/90 mm Hg), and hypercholesterolemia (serum total cholesterol level ≥240 mg/dL) were determined. Results: Forty percent of subjects reported a history of diabetes mellitus or use of diabetic medication, and 2% of the remaining subjects had a serum glucose level of ≥200 mg/dL. Of those subjects known to be diabetic, 33% had a serum glucose level of ≥200 mg/dL. A history of hypertension or use of antihypertensive medication was reported in 87% of subjects, and 48% of the remaining subjects were found to have a blood pressure of ≥140/90 mm Hg on exam. Of those subjects known to be hypertensive by history, 73% were on antihypertensive medication, but only 30% of the treated subjects had a blood pressure under 140/90 mm Hg. A history of hypercholesterolemia or use of a lipid-lowering agent was reported in 40% of subjects, and 24% of the remaining subjects had a cholesterol level of ≥240 mg/dL. Use of a lipid-lowering agent was reported in 43% of subjects known to be hypercholesterolemic, and 38% of the hypercholesterolemic subjects had a cholesterol level of ≥240 mg/dL. Conclusion: Inadequate rates of awareness and control of cardiovascular disease and stroke risk factors are seen in a clinical trial of African American stroke patients and are comparable with those of previously published reports.

Menstrual-related changes in motoric function in women with Parkinson’s disease

Article abstract Questionnaire studies have found that parkinsonism worsens in women during the premenstrual period, when estrogen and progesterone levels are presumably at their nadir. To assess this patient-based observation and correlate motor signs with hormonal levels, the authors prospectively studied 10 menstruating women with PD in their “off” state, on 5 successive weeks. Although PD severity fluctuated during the study period, there was no significant correlation between the objective or subjective measures of parkinsonism and estrogen and progesterone levels.–1574

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.

Estrogen, progesterone, and tic severity in women with Gilles de la Tourette syndrome

The growing awareness in women’s health issues in neurology has spawned a focus on the neurochemical modulatory effects of female sex hormones.1 Sex-specific variability in the expression of Gilles de la Tourette syndrome (GTS) is likely affecting men much more often than women. Several case reports and one questionnaire-based study have noted a premenstrual increase in tics thought to be secondary to low estrogen levels.2-4⇓⇓ No study has actually measured estrogen and progesterone levels through a menstrual cycle to correlate tic severity and hormonal activity. In families with motor tics, an associated behavioral manifestation, obsessive compulsive disorder (OCD), is also frequently seen in women. Further, men are more likely to present with tics (with or without OCD), and women are more likely to present with OCD (with or without tics).5 We hypothesized that menstruating women with GTS experience subjective and objective worsening of their tics and their OCD symptoms during the premenstrual period, during which both estrogen and progesterone are …