Evaluation of morning bradykinesia in Parkinson's disease in a United States cohort using continuous objective monitoring.

Introduction: Bradykinesia in Parkinson's disease is a marker for clinical levodopa responsiveness, with persistent bradykinesia reflecting suboptimal response. We objectively measured prevalence and severity of morning bradykinesia using the Personal KinetiGraph® (PKG®). Methods: Retrospective evaluation of a large global database of de-identified PKG assessments from individuals (N=12,840) in routine clinical care in the United States (US; n=3288). Median bradykinesia scores (mBKS) and median dyskinesia scores (mDKS) were calculated using a validated algorithm and previously established targets to evaluate percent time in bradykinesia, levodopa responsiveness, and prevalence and severity (0-5; 5=highest severity) of morning bradykinesia. Results: mBKS was above target (≥26) in 65% of all individuals, and mDKS was above target (≥7) in 3%. Elevated percent time in bradykinesia occurred in 79%. Among individuals where levodopa responsiveness could be evaluated (n=1933), 31% had a significant response (≥1.15 postdose decrease in severity). Morning bradykinesia was identified in 85% of individuals with available morning data (1298/1524), and 64% (954/1501) experienced continued bradykinesia after the first daily levodopa dose. Morning bradykinesia was severe (4.0-4.7) in levodopa-responsive individuals regardless of percent time spent in bradykinesia. Conclusion: Elevated mBKS was very common in the US. Most individuals taking levodopa had morning bradykinesia that persisted even after the first daily dose, and severity was high, indicating a need for additional treatment options.

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 (chi(2) = 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.

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.

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 scale's 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.

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

In a series of consecutively randomized outpatients who had Parkinson's 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.

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 posthypoxic 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.

Poor visual discrimination and visual hallucinations in Parkinson's disease.

This study examined the relationship between deficits in color and contrast discrimination and visual hallucinations (VH) in patients with Parkinson's disease (PD) and normal visual acuity. Thirty-five nondemented and nonpsychotic PD patients with normal visual acuity and without major ophthalmologic disease were interviewed twice and divided into two groups: hallucinators (n = 14) and non-hallucinating controls (n = 21). The groups were compared for color vision (assessed by Lanthony D-15 [LD] and Farnsworth-Munsell 100 hue [FM] tests), and for contrast sensitivity (tested by Vis tech tables [VT] and monocular and binocular Pelli-Robson test [PR]). There was no difference in age, duration or stage of PD, or dosage or duration of levodopa therapy between the two groups. Parkinson's disease patients showed impairment on all visual tests, with the hallucinators performing worse than the controls on all tests. This difference was significant for the LD (p < 0.007), the VT at 1.5 and 3 cycles per degree (p < 0.037 and 0.043, respectively) and the monocular PR tests (p < 0.049). The results led the authors to conclude that in patients with normal visual acuity, those with VH show added visual deficits of color and contrast discrimination. These ophthalmopathies may therefore be facilitating factors for visual hallucinations in PD and justify more focused research on the pathophysiology of visual hallucinations in Parkinson's disease.

5-Hydroxytryptophan-induced myoclonus in guinea pigs: mediation through 5-HT1/2 receptor subtypes.

In guinea pigs, myoclonus can be induced by 5-hydroxytryptamine (5-HT, serotonin) precursors and synthetic 5-HT receptor agonists, yet the receptor subtype specificity of this behavior is not fully delineated. Guinea pigs were pre-treated with carbidopa (50 mg) followed by one of eight 5-HT antagonists: (-)-N-tert-butyl-3-[4-(2-methoxyphenyl) piperazin-1-yl]-2-phenyl propionamide ((-)-WAY 100135) (5-HT1A), N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridyl)-cy clohexancarboxamide (WAY 100635) (5-HT1A), methiothepin mesylate (5-HT1/2), mesulergine hydrochloride (5-HT2A/2C), N[4-methoxy-3-(4-methyl-L-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2 ,4-oxadizol-3-yl) (GR 127935) (5-HT1D), trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorop hen yl) propen-1-yl]phenol, hemifumarate (SR 46349) (5-HT2), ondansetron hydrochloride (5-HT3), and [1-[2-[methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl-5-fluoro-2-meth oxy-1H-indole-3-carboxylate (GR 125487) (5-HT4). Thirty minutes later, they received 5-hydroxytryptophan (5-HTP) (75 mg/kg, sc) and myoclonic jumping rates were assessed every 10 min for 200 min by a blinded observer. Repeated measures analysis of variance of drug-induced antagonism of 5-HTP-induced myoclonus revealed a significant effect for the 5-HT receptor antagonists methiothepin mesylate, GR127935, and mesulergine hydrochloride compared to placebo, and each of these drugs inhibited 5-HTP-induced myoclonus in a dose-dependent fashion. Based on the receptor profiles of the three effective antagonists, 5-HTP-induced myoclonus is influenced by the 5-HT1/2 receptor systems. The absence of a significant change with any other receptor subtype antagonist suggests that myoclonus is not related to diffuse activation of central serotonergic mechanisms.

Philadelphia Infirmary for Nervous Diseases: America's original model of institutional neurology.

The role and contributions of the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases in the development of neurology in 19th-century America are described. American neurology was largely born during the Civil War through the work of S.W. Mitchell at Turner's Lane Hospital. With the closing of this military facility, the United States was left without an institution dedicated to neurologic research and the treatment of nervous system diseases. Nineteenth century archival data, including original Trustees' minutes, annual board of managers reports, patient case books, and published research from the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases were studied. The Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases promoted the development of neurology in the United States through three main activities. First, it offered patients with primary nervous system diseases, arthritis, and orthopedic disorders specialized care that was unavailable at medical universities. Second, its medical staff, especially Mitchell, provided opportunities for advanced neurologic education. Postgraduate physicians interested in neurologic disease attended formal lectures and directly participated in the operation of outpatient clinics and inpatient rounds. Finally, its formalized record system in the form of case books facilitated neurologic research. These records formed the basis of landmark publications by Mitchell, Sinkler, Osler, and others on rest therapy, spastic palsies, chorea, and other topics. As America's first and comprehensive peacetime neurologic facility, the Philadelphia Orthopedic Hospital and Infirmary for Nervous Diseases fostered the evolution of neurology as a separate, viable specialty in the post-Civil War period and provided a particular focus for the study of interactions among orthopedic, nutritional, and neurologic disorders.

Intravenous levodopa in hallucinating Parkinson's disease patients: high-dose challenge does not precipitate hallucinations.

In five nondemented Parkinson's 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.

Liquid levodopa/carbidopa produces significant improvement in motor function without dyskinesia exacerbation.

We performed the first double-blind, crossover comparison between levodopa/carbidopa (LD/CD) in optimized liquid versus tablet doses to measure plasma LD levels and relative effects on disabilities (motor function, fluctuations, and dyskinesias) in patients with Parkinson's disease. Twenty-three subjects with motor fluctuations were optimized with open-label LD/CD tablets and liquid. In a double-dummy design, patients randomly received 2 weeks of liquid and 2 weeks of tablet LD/CD. Twice during each arm, we evaluated patients hourly 9 AM to 4 PM with the use of plasma LD levels, the Unified Parkinson's Disease Rating Scale, a dyskinesia rating scale, and "on-off" ratings. Patients receiving liquid LD/CD ingested significantly higher doses and had significantly improved motor function and total "on" time, without an increase in dyskinesia severity. The number of motor fluctuations in the two phases was not significantly different. LD levels and variability were also equivalent with the two formulations. At optimized dosing, liquid LD/CD offers a means to significantly improve motor disability in patients with Parkinson's disease without exacerbating dyskinesia.

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 Parkinson's 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 microM/l (SD +/- 4.69) versus mean CSF level 0.114 microM/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.

Early American professorships in neurology.

American universities recognized and institutionalized the emerging importance of neuroscience in medicine by establishing neurological professorships as early as the 1860s. Nearly 20 years before Charcot assumed his celebrated chaired professorship for Diseases of the Nervous System in France, Harvard University created a professorship of Physiology and Pathology of the Nervous System (1864), naming Brown-Sequard as its recipient. In 1867, the new Bellevue Hospital Medical School established a combined neurology/psychiatry chair with William A. Hammond as professor, and the University of Pennsylvania created a clinical professorship devoted specifically to neurology in 1875, naming Horatio C. Wood. Although modest in their university power base and their clinical research/laboratory programs, these American posts were internationally unique for their time and solidly entrenched neurology as a specific division in early US medical education.

Levodopa stability in solution: time course, environmental effects, and practical recommendations for clinical use.

We defined the temporal stability characteristics of levodopa/carbidopa (LD/CD) solution, and determined the effects of temperature, ascorbate, and light on LD stability over 7 days. At room temperature and without ascorbate, LD levels significantly declined by 48 h. Ascorbate prolonged stability to 72 h. Refrigeration and freezing prevented a significant decline in LD levels for the full 7 days. Light or darkness had no effect on stability. LD/CD solution, if made daily, requires no special handling and longer stability is maintained with ascorbate, refrigeration, or freezing.

Training opportunities for the nineteenth-century American neurologist: preludes to the modern neurology residency.

During the nineteenth century, two parallel developments, a surge in neuroscience discovery and the advent of medical specialization, resulted in new educational demands for advanced, postgraduate neurologic training in the United States. Archival data, including trustees' reports, school charters, and instructional plans from medical institutions in New York, Boston, Philadelphia, and Chicago, document three comparative models for early postgraduate neurologic training. First, senior physicians with an interest in neurologic disease incorporated postgraduates directly into their practice and as laboratory assistants; second, medical universities, as well as distinct postgraduate schools, organized advanced general medical curricula with optional opportunities for focused neurologic training; and third, separate neurologic hospitals provided physicians with full-time clinical instruction specifically in neurology. As a result, although neurology residencies were not established until the 1900s, postgraduate neurologic training was firmly institutionalized in nineteenth-century America. These programs provided doctors in the United States with advanced neurologic educational opportunities and expertise and fostered the development of a distinct American neurologic school.

Early American neurologic textbooks.

Although European treatises were translated and available to American doctors interested in neurology during the 19th century, the early American neurologic textbooks were distinctive in their comprehensive integration of basic and clinical science. William A. Hammond, in 1871, published the first comprehensive American textbook of neurology, preceding the manuals by Gowers (1886) and Oppenheim (1894) by more than a decade. Four other American adult neurologic textbooks expanded on Hammond's model and incorporated other important topics, including neurologic anatomy, the formal examination, neurochemistry, and complete bibliographies. Bernard Sachs' 1895 textbook was the first pediatric neurologic textbook published in America and made significant contributions to the organization of childhood neurologic disorders. These works functioned as centralized resources for neurologic information, were influential educational tools, and helped foster a growing appreciation of the American neurologic school both nationally and internationally.

Inclusion body myositis: treatment with intravenous immunoglobulin.

We report the results of nine patients with inclusion body myositis treated with intravenous immunoglobulin in an open-label uncontrolled study. None of our patients improved on objective manual muscle testing or functional disability scores. One patient developed mild neutropenia, complicating the intravenous immunoglobulin treatment. Our results do not exclude the possibility that intravenous immunoglobulin could be beneficial in some patients by slowing the rate of deterioration or perhaps stabilizing the disease. However, given the lack of objective improvement and high cost of treatment, we would not recommend intravenous immunoglobulin in the treatment of inclusion body myositis unless a blinded, controlled trial demonstrates clear benefit.