Cerebrospinal fluid biomarkers in Parkinson's disease with freezing of gait: an exploratory analysis.

We explore the association between three Alzheimer's disease-related and ten inflammation-related CSF markers and freezing of gait (FOG) in patients with Parkinson's disease (PD). The study population includes PD patients with FOG (PD-FOG, N = 12), without FOG (PD-NoFOG, N = 19), and healthy controls (HC, N = 12). Age and PD duration are not significantly different between groups. After adjusting for covariates and multiple comparisons, the anti-inflammatory marker, fractalkine, is significantly decreased in the PD groups compared to HC (P = 0.002), and further decreased in PD-FOG compared to PD-NoFOG (P = 0.007). The Alzheimer's disease-related protein, Aß42, is increased in PD-FOG compared to PD-NoFOG and HC (P = 0.001). Group differences obtained in individual biomarker analyses are confirmed with multivariate discriminant partial least squares regression (P < 0.001). High levels of Aß42 in PD-FOG patients supports an increase over time from early to advanced state. Low levels of fractalkine might suggest anti-inflammatory effect. These findings warrant replication.

The role of neurotransmitters in the development of Parkinson's disease-related psychosis.

Psychotic symptoms are common, disabling non-motor features of Parkinson's disease (PD). Despite noted heterogeneity in clinical features, natural history and therapy response, current dogma posits that psychosis generally progresses in a stereotypic manner through a cascade of events that begins with minor hallucinations and evolves to severe hallucinations and delusions. Further, the occurrence of psychotic symptoms is believed to indicate a poor prognosis. Here we propose a classification scheme that outlines the pathogenesis of psychosis as it relates to dysfunction of several neurotransmitter systems. We hypothesize that several subtypes exist, and that PD psychosis is not consistently indicative of a progressive cascade and poor prognosis. The literature was reviewed from 1990 to 2017. An overview of the features of PD psychosis is followed by a review of data indicating the existence of neurotransmitter-related subtypes of psychosis. We found that ample evidence exists to demonstrate the presence of multiple subtypes of PD psychosis, which are traced to dysfunction of the following neurotransmitter systems: dopamine, serotonin and acetylcholine. Dysfunction of each of these systems is recognizable through their clinical features and correlates, and the varied long-term prognoses. Identifying which neurotransmitter system is dysfunctional may help to develop targeted therapies. PD psychosis has various subtypes that differ in clinical features, underlying pathology and pathophysiology, treatment response and prognosis. A novel classification scheme is presented that describes the clinical subtypes with different outcomes, which could lead to the development of targeted therapies. Future research should focus on testing the viability of this classification.

LRRK2 levels in immune cells are increased in Parkinson's disease.

Mutations associated with leucine-rich repeat kinase 2 are the most common known cause of Parkinson's disease. The known expression of leucine-rich repeat kinase 2 in immune cells and its negative regulatory function of nuclear factor of activated T cells implicates leucine-rich repeat kinase 2 in the development of the inflammatory environment characteristic of Parkinson's disease. The aim of this study was to determine the expression pattern of leucine-rich repeat kinase 2 in immune cell subsets and correlate it with the immunophenotype of cells from Parkinson's disease and healthy subjects. For immunophenotyping, blood cells from 40 Parkinson's disease patients and 32 age and environment matched-healthy control subjects were analyzed by flow cytometry. Multiplexed immunoassays were used to measure cytokine output of stimulated cells. Leucine-rich repeat kinase 2 expression was increased in B cells (p = 0.0095), T cells (p = 0.029), and CD16+ monocytes (p = 0.01) of Parkinson's disease patients compared to healthy controls. Leucine-rich repeat kinase 2 induction was also increased in monocytes and dividing T cells in Parkinson's disease patients compared to healthy controls. In addition, Parkinson's disease patient monocytes secreted more inflammatory cytokines compared to healthy control, and cytokine expression positively correlated with leucine-rich repeat kinase 2 expression in T cells from Parkinson's disease but not healthy controls. Finally, the regulatory surface protein that limits T-cell activation signals, CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), was decreased in Parkinson's disease compared to HC in T cells (p = 0.029). In sum, these findings suggest that leucine-rich repeat kinase 2 has a regulatory role in immune cells and Parkinson's disease. Functionally, the positive correlations between leucine-rich repeat kinase 2 expression levels in T-cell subsets, cytokine expression and secretion, and T-cell activation states suggest that targeting leucine-rich repeat kinase 2 with therapeutic interventions could have direct effects on immune cell function.

Association of cognitive domains with postural instability/gait disturbance in Parkinson's disease.

INTRODUCTION: Research suggests an association between global cognition and postural instability/gait disturbance (PIGD) in Parkinson disease (PD), but the relationship between specific cognitive domains and PIGD symptoms is not clear. This study examined the association of cognition (global and specific cognitive domains) with PIGD symptoms in a large, well-characterized sample of individuals with PD. METHODS: Cognitive function was measured with a detailed neuropsychological assessment, including global cognition, executive function, memory, visuospatial function, and language. PIGD symptoms were measured using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III, Motor Examination subscale. Multiple linear regression analyses were performed to assess the relationship between cognition and PIGD symptoms with models adjusting for age, sex, education, enrollment site, disease duration, and motor symptom severity. RESULTS: The analysis included 783 participants, with mean (standard deviation) age of 67.3 (9.7) years and median (interquartile range) MDS-UPDRS Motor Subscale score of 26 (17, 35). Deficits in global cognition, executive function, memory, and phonemic fluency were associated with more severe PIGD symptoms. Deficits in executive function were associated with impairments in gait, freezing, and postural stability, while visuospatial impairments were associated only with more severe freezing, and poorer memory function was associated only with greater postural instability. DISCUSSION: While impairments in global cognition and aspects of executive functioning were associated with more severe PIGD symptoms, specific cognitive domains were differentially related to distinct PIGD components, suggesting the presence of multiple neural pathways contributing to associations between cognition and PIGD symptoms in persons with PD.

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

BACKGROUND/OBJECTIVES: The common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. METHODS: For immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. RESULTS: Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses. CONCLUSIONS: In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression.

Freezing of gait subtypes have different cognitive correlates in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major concern for Parkinson's disease (PD) patients because it is a leading cause of falls and is associated with poor quality of life. The pathophysiology is unknown but it is hypothesized that it relates to cognitive abnormalities; particularly executive and visuospatial dysfunction. However, prior results have been discrepant. Pharmacologic subtypes of FOG include those that are responsive and unresponsive to levodopa. OBJECTIVE: To determine whether executive and visuospatial dysfunction are associated specifically with the levodopa unresponsive subtype of FOG. METHODS: 135 PD subjects completed a single assessment included FOG questionnaire, UPDRS motor scale, comprehensive cognitive battery and measure of hallucinations. Analyses compared unresponsive (n = 16), responsive (n = 20) and no FOG (n = 99) subtypes. RESULTS: The unresponsive subtype had a significantly older age of onset of PD than the responsive group (p = .03) and had worse motor scores (p = .003) than the no FOG group. Longer disease duration was associated with the responsive group compared to the no FOG group (p = .002). The unresponsive FOG group had significantly poorer visuospatial ability (p = .001) and executive functioning (p = .02) than both the no and responsive FOG subgroups. These latter groups were not significantly different. The responsive FOG group was associated with the presence of hallucinations. CONCLUSION: Aside from pharmacological differences, unresponsive FOG is associated with executive and visuospatial dysfunction implicating frontostriatal pathways while responsive FOG is associated with hallucinations suggesting involvement of posterior cortical regions. Further study and treatment of FOG should include appropriate subtype classification.

Severity of depression and anxiety are predictors of response to antidepressant treatment in Parkinson's disease.

BACKGROUND: Antidepressants have appeared to be more effective than placebo treatment in treating depressive syndromes in patients with Parkinson's disease (PD). OBJECTIVE: To identify factors that predict improvement in depressive symptoms during antidepressant treatment in depressed PD patients. METHODS: A secondary analysis was performed on the dataset of the Randomized Placebo-controlled Study of Antidepressants in PD (SAD-PD), in which 76 patients received active treatment with either paroxetine or venlafaxine extended release (XR), and 39 patients received placebo treatment. Backward stepwise regression analyses were conducted with change in 24-item Hamilton Depression Rating Scale (HAMD-24) score between assessments at baseline and week 12 as the main outcome measure, and sex, age, baseline HAMD-24 score, Unified Parkinson's Disease Rating Scale section III (UPDRS-III) score, Mini-Mental State Examination (MMSE), and the Clinical Anxiety Scale (CAS) as independent variables. RESULTS: In both the active treatment and placebo groups, higher baseline HAMD-24 score and lower UPDRS-III score were associated with greater reduction in HAMD-24 score. Higher anxiety scores predicted less response in the active treatment group. Higher MMSE scores predicted greater response only in the placebo-treated group. Sex and age were no predictors of response. CONCLUSIONS: Higher pre-treatment depression scores and lower pre-treatment anxiety scores are the two most important predictors for improvement during antidepressant treatment in depressed PD patients, which is in line with those found in treatment studies of depressed non-PD patients. Furthermore, our results indicate the requirement for different or more intensive treatment for depressed PD patients with more severe anxiety symptoms.

Secondary blepharospasm associated with structural lesions of the brain.

BACKGROUND: Blepharospasm is a form of focal dystonia that manifests as repetitive involuntary closure of the eyes. The pathogenesis of blepharospasm and the neuroanatomic substrates involved are not fully understood. Dysfunction of the basal ganglia traditionally is presumed to be the main cause of most forms of dystonia, but a growing body of evidence suggests that a network of additional cortical and subcortical structures may be involved. METHODS: The medical records of 1114 patients with blepharospasm seen over past 10 years at Emory University were reviewed to identify potentially contributing brain lesions. A systematic review of the published literature was also conducted to identify potentially contributing brain lesions. RESULTS: Among patients with blepharospasm at Emory University, 18 had focal lesions on imaging studies available for review. The literature review revealed 25 articles describing 30 additional cases of blepharospasm associated with focal lesions. Among all 48 cases, lesions were found in multiple regions including the thalamus (n=12), lower brainstem (n=11), basal ganglia (n=9), cerebellum (n=9), midbrain (n=7), and cortex (n=1). CONCLUSIONS: These data in combination with functional imaging studies of primary blepharospasm support a model in which a network of different regions plays a role in the pathogenesis of blepharospasm.

A genetic basis for the variable effect of smoking/nicotine on Parkinson's disease.

Prior studies have established an inverse association between cigarette smoking and the risk of developing Parkinson's disease (PD), and currently, the disease-modifying potential of the nicotine patch is being tested in clinical trials. To identify genes that interact with the effect of smoking/nicotine, we conducted genome-wide interaction studies in humans and in Drosophila. We identified SV2C, which encodes a synaptic-vesicle protein in PD-vulnerable substantia nigra (P=1 × 10(-7) for gene-smoking interaction on PD risk), and CG14691, which is predicted to encode a synaptic-vesicle protein in Drosophila (P=2 × 10(-11) for nicotine-paraquat interaction on gene expression). SV2C is biologically plausible because nicotine enhances the release of dopamine through synaptic vesicles, and PD is caused by the depletion of dopamine. Effect of smoking on PD varied by SV2C genotype from protective to neutral to harmful (P=5 × 10(-10)). Taken together, cross-validating evidence from humans and Drosophila suggests SV2C is involved in PD pathogenesis and it might be a useful marker for pharmacogenomics studies involving nicotine.

A randomized, double-blind, placebo-controlled trial of antidepressants in Parkinson disease.

OBJECTIVE: To evaluate the efficacy and safety of a selective serotonin reuptake inhibitor (SSRI) and a serotonin and norepinephrine reuptake inhibitor (SNRI) in the treatment of depression in Parkinson disease (PD). METHODS: A total of 115 subjects with PD were enrolled at 20 sites. Subjects were randomized to receive an SSRI (paroxetine; n = 42), an SNRI (venlafaxine extended release [XR]; n = 34), or placebo (n = 39). Subjects met DSM-IV criteria for a depressive disorder, or operationally defined subsyndromal depression, and scored >12 on the first 17 items of the Hamilton Rating Scale for Depression (HAM-D). Subjects were followed for 12 weeks (6-week dosage adjustment, 6-week maintenance). Maximum daily dosages were 40 mg for paroxetine and 225 mg for venlafaxine XR. The primary outcome measure was change in the HAM-D score from baseline to week 12. RESULTS: Treatment effects (relative to placebo), expressed as mean 12-week reductions in HAM-D score, were 6.2 points (97.5% confidence interval [CI] 2.2 to 10.3, p = 0.0007) in the paroxetine group and 4.2 points (97.5% CI 0.1 to 8.4, p = 0.02) in the venlafaxine XR group. No treatment effects were seen on motor function. CONCLUSIONS: Both paroxetine and venlafaxine XR significantly improved depression in subjects with PD. Both medications were generally safe and well tolerated and did not worsen motor function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that paroxetine and venlafaxine XR are effective in treating depression in patients with PD.

Quality improvement in neurology: AAN Parkinson disease quality measures: report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology.

BACKGROUND: Measuring the quality of health care is a fundamental step toward improving health care and is increasingly used in pay-for-performance initiatives and maintenance of certification requirements. Measure development to date has focused on primary care and common conditions such as diabetes; thus, the number of measures that apply to neurologic care is limited. The American Academy of Neurology (AAN) identified the need for neurologists to develop measures of neurologic care and to establish a process to accomplish this. OBJECTIVE: To adapt and test the feasibility of a process for independent development by the AAN of measures for neurologic conditions for national measurement programs. METHODS: A process that has been used nationally for measure development was adapted for use by the AAN. Topics for measure development are chosen based upon national priorities, available evidence base from a systematic literature search, gaps in care, and the potential impact for quality improvement. A panel composed of subject matter and measure development methodology experts oversees the development of the measures. Recommendation statements and their corresponding level of evidence are reviewed and considered for development into draft candidate measures. The candidate measures are refined by the expert panel during a 30-day public comment period and by review by the American Medical Association for Current Procedural Terminology (CPT) II codes. All final AAN measures are approved by the AAN Board of Directors. RESULTS: Parkinson disease (PD) was chosen for measure development. A review of the medical literature identified 258 relevant recommendation statements. A 28-member panel approved 10 quality measures for PD that included full specifications and CPT II codes. CONCLUSION: The AAN has adapted a measure development process that is suitable for national measurement programs and has demonstrated its capability to independently develop quality measures.

A comprehensive analysis of deletions, multiplications, and copy number variations in PARK2.

OBJECTIVES: To perform a comprehensive population genetic study of PARK2. PARK2 mutations are associated with juvenile parkinsonism, Alzheimer disease, cancer, leprosy, and diabetes mellitus, yet ironically, there has been no comprehensive study of PARK2 in control subjects; and to resolve controversial association of PARK2 heterozygous mutations with Parkinson disease (PD) in a well-powered study. METHODS: We studied 1,686 control subjects (mean age 66.1 ± 13.1 years) and 2,091 patients with PD (mean onset age 58.3 ± 12.1 years). We tested for PARK2 deletions/multiplications/copy number variations (CNV) using semiquantitative PCR and multiplex ligation-dependent probe amplification, and validated the mutations by real-time quantitative PCR. Subjects were tested for point mutations previously. Association with PD was tested as PARK2 main effect, and in combination with known PD risk factors: SNCA, MAPT, APOE, smoking, and coffee intake. RESULTS: A total of 0.95% of control subjects and 0.86% of patients carried a heterozygous CNV mutation. CNV mutations found in 16 control subjects were all in exons 1-4, sparing exons that encode functionally critical protein domains. Thirteen patients had 2 CNV mutations, 5 had 1 CNV and 1 point mutation, and 18 had 1 CNV mutation. Mutations found in patients spanned exons 2-9. In whites, having 1 CNV was not associated with increased risk (odds ratio 1.05, p = 0.89) or earlier onset of PD (64.7 ± 8.6 heterozygous vs 58.5 ± 11.8 normal). CONCLUSIONS: This comprehensive population genetic study in control subjects fills the void for a PARK2 reference dataset. There is no compelling evidence for association of heterozygous PARK2 mutations, by themselves or in combination with known risk factors, with PD.

Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease.

OBJECTIVE: To evaluate the efficacy of ropinirole 24-hour prolonged release (ropinirole 24-hour) as an adjunct to levodopa in patients with Parkinson disease (PD) and motor fluctuations. METHODS: In a double-blind, placebo-controlled, 24-week study, 393 subjects with PD were randomized to ropinirole 24-hour (n = 202) or placebo (n = 191). The primary outcome measure was reduction in hours of daily "off" time. RESULTS: At week 24, the mean dose of ropinirole 24-hour was 18.8 mg/day with a mean reduction in daily levodopa of 278 mg. There was a mean reduction in daily "off" time of 2.1 hours in the ropinirole 24-hour group and 0.3 hours with placebo. Secondary outcome measures including change in hours and percent of daily "on" time and "on" time without troublesome dyskinesia, Unified PD Rating Scale motor and activities of daily living subscales, Beck Depression Inventory-II, PDQ-39 subscales of mobility, activities of daily living, emotional well-being, stigma and communication, and PD Sleep Scale were significantly improved at week 24 with ropinirole 24-hour. The most common adverse events (AE) with ropinirole 24-hour were dyskinesia, nausea, dizziness, somnolence, hallucinations, and orthostatic hypotension and AEs led to study withdrawal in 5% of both the active and placebo groups. CONCLUSION: Ropinirole 24-hour was effective and well tolerated as adjunct therapy in patients with Parkinson disease (PD) not optimally controlled with levodopa. Ropinirole 24-hour demonstrated an improvement in both motor and non-motor PD symptoms, while permitting a reduction in adjunctive levodopa dose.

Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based treatment recommendations for the medical and surgical treatment of patients with Parkinson disease (PD) with levodopa-induced motor fluctuations and dyskinesia. To that end, five questions were addressed. 1. Which medications reduce off time? 2. What is the relative efficacy of medications in reducing off time? 3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia, and antiparkinsonian medication usage and improve motor function? 5. Which factors predict improvement after DBS? METHODS: A 10-member committee including movement disorder specialists and general neurologists evaluated the available evidence based on a structured literature review including MEDLINE, EMBASE, and Ovid databases from 1965 through June 2004. RESULTS, CONCLUSIONS, AND RECOMMENDATIONS: 1. Entacapone and rasagiline should be offered to reduce off time (Level A). Pergolide, pramipexole, ropinirole, and tolcapone should be considered to reduce off time (Level B). Apomorphine, cabergoline, and selegiline may be considered to reduce off time (Level C). 2. The available evidence does not establish superiority of one medicine over another in reducing off time (Level B). Sustained release carbidopa/levodopa and bromocriptine may be disregarded to reduce off time (Level C). 3. Amantadine may be considered to reduce dyskinesia (Level C). 4. Deep brain stimulation of the STN may be considered to improve motor function and reduce off time, dyskinesia, and medication usage (Level C). There is insufficient evidence to support or refute the efficacy of DBS of the GPi or VIM nucleus of the thalamus in reducing off time, dyskinesia, or medication usage, or to improve motor function. 5. Preoperative response to levodopa predicts better outcome after DBS of the STN (Level B).

Longitudinal outcome of Parkinson's disease patients with psychosis.

OBJECTIVES: To examine the long-term outcome of PD patients with psychosis requiring antipsychotic therapy; to explore predictors of mortality, nursing home placement, dementia, and persistent psychosis; and to compare outcomes of those with persistent psychosis vs those whose psychosis resolved. METHODS: Baseline data available from 59 patients enrolled in the PSYCLOPS (PSychosis and CLOzapine in PD Study) trial included age, age at onset of PD, duration of PD and psychosis, character of psychosis, medications, living setting, and scores for Mini-Mental State Examination (MMSE), Unified Parkinson's Disease Rating Scale, Hoehn and Yahr Scale, and Clinical Global Impression Scale. Longitudinal data were collected 26 months later regarding four outcomes: death, nursing home placement, diagnosis of dementia, and persistence of psychosis. Logistic regression was used to explore whether any baseline characteristics were associated with an increased likelihood of one of these outcomes. RESULTS: At baseline, 56% of patients had an MMSE score of <25, 12% were in a nursing home, 95% had hallucinations, and 60% had paranoia. On follow-up, 25% were dead, nursing home placement occurred in 42%, psychosis was persistent in 69%, and dementia was diagnosed in 68%. Select baseline characteristics predicted individual outcomes: Nursing home placement was associated with the presence of paranoia and older age; persistent psychosis was associated with younger age at onset of PD and longer disease duration; dementia was associated with older age at PD onset and lower initial MMSE score; no characteristics predicted death. Whether psychosis persisted or not had no significant effect on the development of the other three outcomes. The prevalence of hallucinations at follow-up was not different between groups currently receiving antipsychotics vs those on no treatment. CONCLUSIONS: Psychosis in PD requiring antipsychotic therapy is frequently associated with death, nursing home placement, development and progression of dementia, and persistence of psychosis. Still, it appears the prognosis has improved with atypical antipsychotic therapy based on the finding that 28% of NH patients died within 2 years compared with 100% in a previous study done prior to availability of this treatment.

Long-term comparative experience with tolcapone and entacapone in advanced Parkinson's disease.

The objective of this study was to compare the long-term tolerability and efficacy of tolcapone and entacapone in patients with fluctuating Parkinson's disease (PD). Tolcapone and entacapone are two currently available catechol- O -methyltransferase inhibitors that have demonstrated efficacy in the treatment of advanced PD. There are little published data on long-term experience and no direct comparisons. We compared the results of two separate, simultaneous, long-term open label extensions, one for tolcapone and the other for entacapone. The inclusion/exclusion criteria were similar. Data were collected prospectively at 6, 12, 24, and 36 months. Efficacy measures included the Unified Parkinson's Disease Rating Scale (UPDRS) total score, subscores, items 32 (duration of dyskinesia) and 39 (duration of "off" time), and levodopa dose. The two groups were compared using a Mann-Whitney U test for change from baseline and analysis of variance. Tolerability was defined as the ability of patients to maintain therapy and was compared using a Kaplan-Meier analysis. Eleven patients enrolled in the entacapone study and 14 in the tolcapone study. The tolcapone group had more severe disease with significantly higher UPDRS motor score, duration of "off," and levodopa dose requirement. Tolcapone was more effective in lowering UPDRS motor and complication subscores, duration of "off" time, and levodopa doses. UPDRS motor scores and change in levodopa dose in the tolcapone group remained below baseline level for 36 months; however, they were above baseline in the entacapone group from 6 months on. Tolerability was the same for both treatments. Tolcapone appears to have greater and longer efficacy with regard to motor symptoms, "off" time, and change in levodopa requirements than entacapone. These findings indicate that tolcapone continues to have a place in the treatment of advanced PD. However, the risks associated with this drug, particularly hepatic injury, and the requirement for rigorous blood monitoring, need to be considered when choosing an appropriate treatment for patients with advanced PD.

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.

Focal myopathy as a cause of anterocollis in Parkinsonism.

We present a patient with levodopa-responsive Parkinsonism who developed disproportionate anterocollis over a period of 4 to 5 weeks. A neurological evaluation, including EMG and muscle biopsy, demonstrated the presence of a focal myopathy typical of the so-called "dropped head syndrome" or "isolated neck extensor myopathy." Parkinsonian patients presenting with disproportionate anterocollis should be evaluated for focal myopathy, as this may represent one possible cause.

The long-term safety and efficacy of pramipexole in advanced Parkinson's disease.

Objective: To assess the long-term safety and efficacy of pramipexole in advanced Parkinson's disease over a four year time period.Methods: This study is an open-label extension trial of pramipexole for Parkinson's disease open to patients completing a double-blind placebo controlled safety and efficacy trial of this drug. Three hundred and six patients entered the trial. These patients had moderate to severe PD (stage II-IV Hoehn and Yahr during off time) and were experiencing motor fluctuations. Patients were titrated over a six week period and then entered a maintenance phase which lasted up to 50 months. Patients were evaluated every 3 months using the Unified Parkinson's Disease Rating Scale (UPDRS II, III and IV) and modified Schwab and England scale (S/E).Results: Sixty-four percent (197) of the 306 patients who entered this study completed it. Patients showed steady improvement over the 6 week ascending dose interval when pramipexole was reintroduced into the trial as the open-label study medication. Over the duration of the trial patients slowly returned to their baseline levels. This was true for all measures evaluated except for the UPDRS part IV. On UPDRS part IV patients remained below their baseline score which indicated an improvement for the duration of the study. Patterns similar to the overall scores were seen when the individual components of the UPDRS scale part II for "on" and "off" periods and part III were evaluated. However tremor during "on" periods showed improvement over baseline for the duration of the trial. The most common adverse events secondary to pramipexole occurring in greater than 10% of patients included dyskinesias, asymptomatic orthostatic hypotension, dizziness, insomnia, and hallucinations.Conclusion: Pramipexole was well tolerated for up to 4 years. Pramipexole treatment appeared to show continued efficacy in the treatment of Parkinson's disease for 3 years in this open-label descriptive study. After 3 years there was a gradual return to baseline motor states perhaps suggesting progression of Parkinson's disease.