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Introduction Although a majority of the American public prefer to die at home, a large percentage of Parkinson’s disease patients die in acute care hospitals. We examine trends in the clinical and demographic characteristics of Parkinson’s disease patients who die in a hospital to identify populations potentially vulnerable to unwanted inpatient mortality. Methods Patients with Parkinson’s disease admitted to a hospital from 2002-2016 were identified from the National Inpatient Sample (n = 710,013) along with their associated clinical and demographic characteristics. The main outcome examined was mortality during inpatient admission. From these data, logistic regression models were estimated to obtain the odds ratios of inpatient mortality among clinical and demographic attributes, and their change over time. Results Characteristics significantly associated with increased odds of inpatient mortality included increased age (OR = 1.70 for 55-65, 2.52 for 66-75, 3.99 for 76-85, 5.72 for 86+, all P < 0.001), length of stay ≤5 days (reference; 6 + days OR = 0.37, P < 0.001), white race or ethnicity (reference; Black OR = .84 P < .001, Hispanic OR = 0.91 P = 0.01), male (reference; female OR = 0.93 P < 0.001), hospitalization in Northeast (reference; Midwest OR = 0.78, South 0.84, West OR = 0.82; all P < 0.001), higher severity of illness (moderate OR = 1.50, major OR = 2.32, extreme OR = 5.57; all P < 0.001), and mortality risk (moderate OR = 2.88, major OR = 10.92, extreme OR = 52.30; all P < 0.001). Fitted probabilities overall declined over time. Conclusion Differences exist among PD patient populations regarding likelihood of in-hospital mortality that are changing with time. Insight into which PD patients are most at risk for inpatient mortality may enable clinicians to better meet end-of-life care needs.

Introduction Accumulation of polyglutamine (polyQ) ataxin-3 (ATXN3) contributes to the pathobiology of spinocerebellar ataxia type 3 (SCA3). Recently, we showed that polyQ ATXN3 is elevated in the plasma and cerebrospinal fluid (CSF) of SCA3 patients, and has the potential to serve as a biological marker for this disease [1]. Based on these findings, we investigated whether polyQ ATXN3 can also be detected in urine samples from SCA3 patients. Methods We analyzed urine samples from 30 SCA3 subjects (including one pre-symptomatic subject), 35 subjects with other forms of ataxia, and 37 healthy controls. To quantify polyQ ATXN3 protein levels, we used our previously developed immunoassay. Results PolyQ ATXN3 can be detected in the urine of SCA3 patients, but not in urine samples from healthy controls or other forms of ataxia. There was a significant statistical association between polyQ ATXN3 levels in urine samples and those in plasma. Further, the levels of polyQ ATXN3 urine associated with an earlier age of SCA3 disease onset. Conclusion As clinical trials for SCA3 advance, urine polyQ ATXN3 protein has potential to be a useful, non-invasive and inexpensive biomarker for SCA3.

ObjectivesCurrently utilized clinician-rated symptom scales for tardive dyskinesia (TD) have not kept up with the expanding spectrum of TD phenomenology. The objective of this study was to develop and test the reliability of a new instrument, the CTI.MethodsA movement disorder neurologist devised the outline of the scale. A steering committee (four neurologists and two psychiatrists) provided revisions until consensus was reached. The resulting instrument assesses frequency of abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, limb/trunk, complex movements (e.g., handwringing, self-caressing), and vocalizations. The CTI rates symptoms from 0–3 with 0 = absent, 1 = infrequent/intermittent or only present with activating maneuvers, 2 = frequent intermittent, brief periods without movements, 3 = constant or nearly constant. Functional impairments including activities of daily living (ADL), social impairment, symptom bother, and harm are rated 0–3 with 0 = patient is unaware or unaffected, 1 = symptoms mildly impact patient, 2 = symptoms moderately impact patient, 3 = symptoms severely impact patient. Following institutional review board approval, the CTI underwent inter-rater and test-retest reliability testing. Videos of patient TD examinations were obtained and reviewed by two movement disorder specialists to confirm the diagnosis of TD by consensus and the adequacy to demonstrate a TD-consistent movement. Vignettes were created to include patients’ symptom descriptions and functional, social, or occupational impairments/limitations. Four clinicians rated each video/vignette. Selected videos/vignettes were also subject to an intra-rater retest. Interrater agreement was analyzed via 2-way random-effects interclass correlation (ICC) and test-retest agreement assessment utilizing Kendall’s tau-b.Results45 video/vignettes were assessed for interrater reliability, and 16 for test-retest reliability. ICCs for movement frequency were as follows: abnormal eye movement .89; abnormal tongue/mouth movement .91; abnormal jaw movement .89; abnormal limb movement .76; complex movement .87; abnormal vocalization .77; and functional impairments including harm .82; social embarrassment .88; ADLs .83; and symptom bother .92. Retests were conducted on mean (SD) 15 (3) days later with scores ranging from .66–.87.ConclusionsThe CTI is a new instrument with good reliability in assessing TD symptoms and functional impacts. Future validation study is warranted.FundingNeurocrine Biosciences

One of the most disabling nonmotor symptoms in persons with Parkinson’s disease is fatigue, which can decrease the quality of life by restricting the function and activities of daily living (ADL). Nonetheless, sufficient evidence for treating fatigue, including drug or nondrug treatment, is not available. In this study, we evaluated the probable effects of vestibular rehabilitation on fatigue and ADL in patients with Parkinson’s disease. Methods. This was a single-blind clinical trial study in which patients with Parkinson’s disease voluntarily participated based on the inclusion and exclusion criteria. The patients were randomly assigned to the case and control groups. The case group received 24 sessions of vestibular rehabilitation protocol, and conventional rehabilitation was performed in the control group (i.e., 3 sessions each week, each lasted about 60 minutes). Both groups were also given fatigue management advice. Fatigue was measured by the Parkinson Fatigue Scale (PFS) and the Modified Fatigue Impact Scale (MFIS). ADL was measured by the Functional Independence Measure (FIM). All changes were measured from the baseline at the completion of the intervention. Results. Both fatigue (P≤0.001) and ADL (P≤0.001) improved significantly more in the vestibular intervention group than in the control one. Conclusion. Vestibular rehabilitation may improve fatigue and ADL and therefore can be used as an effective intervention for patients with Parkinson’s disease, which was also found to be well tolerated.

Pimavanserin is the only medication FDA-approved for the treatment of Parkinson disease (PD) psychosis (PDP), but reports of long-term, real-world clinical experience are lacking.A retrospective chart review of all patients treated with pimavanserin was conducted at our large Movement Disorders practice in Providence, Rhode Island, USA. Demographic and clinical data for each patient were collected and descriptive analyses were performed.We identified 54 patients (23 female) who initiated pimavanserin, whose median age was 70 years (range 44-87 years) and the median duration of pimavanserin therapy was 26 weeks. Initial improvement was seen in 47% of the entire group, and 50% of the DLB patients. Additional antipsychotic medication was needed concomitantly with pimavanserin to maintain a positive response for 40% of patients. Only 15% of the entire group had effective treatment of their condition with pimavanserin monotherapy over a median of 52 weeks. Among the initial responders, 32% continued on pimavanserin monotherapy. Among the non-responders, the mean trial period for patients who did not improve was 27 weeks, for patients who worsened was 16 weeks, and for those who experienced adverse effects was 1-2 weeks. Reported sex was similar across responders (60%), non-responders (56%), and the overall cohort (57%).Our real-world experience shows that pimavanserin is safe and tolerable, with a lower response rate than reported in other publications. While it has been proven to be effective in short-duration clinical trials, our clinical experiences, however, demonstrate less promising results in the long term.

Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing.Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID.PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale.Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Clozapine has been shown to be an effective and well-tolerated treatment for Parkinson disease (PD) psychosis as well as for refractory tremor in PD. Doses used are generally less than one tenth those used in treating schizophrenia. While the risk of leukopenia and agranulocytosis are reported to be independent of dose, that belief is based on the use of doses used in refractory schizophrenia. There are no published data on the risk of agranulocytosis in patients taking extremely low doses of clozapine.This 87-year-old man with diabetes and PD experienced a granulocyte count drop from normal, 3900, at dose initiation, to 0, at the ninth week of treatment taking clozapine 12.5 mg twice daily for refractory tremor. He recovered without developing an infection.This is the first known reported case of agranulocytosis due to clozapine used at an extremely low dose. This report underscores the importance of blood monitoring, even at extremely low doses, although the exact risk remains unknown.

Psychotic symptoms in Parkinson’s disease are relatively common and include hallucinations, illusions, and delusions. Psychosis is a major cause of disability and is one of the most distressing symptoms for both patients and caregivers. The management of psychosis is often complex and challenging and involves determining the degree and severity of psychotic symptoms and whether intervention is required. In this review, the authors describe the phenomenology and risk factors of Parkinson’s disease psychosis (PDP) and current evidence-based treatment options. In randomized, double-blind, placebo-controlled trials, pimavanserin was found to be effective and well-tolerated in PDP but its onset of benefit takes 4–6 weeks. Present reviews of evidence-based medicine suggest that low doses of clozapine can provide benefit without worsening PD motor symptoms. While quetiapine is frequently used, its efficacy is not supported by randomized, double-blind, placebo-controlled trials. Clozapine and pimavanserin have proven efficacy in the treatment of PDP, without impairing motor function. Therefore, these agents should be considered first-line treatment of PDP at this time. Although quetiapine did not show efficacy in PDP, many PD experts use it as it does not worsen motor function and lacks the blood monitoring requirement of clozapine.

Gastrointestinal (GI) symptoms are common in Parkinson disease (PD), often preceding neurological manifestations; however, early diagnostic utility of GI biopsies remains controversial. Studies suggest aberrant deposition of alpha-synuclein (α-syn) follows step-wise progression in central nervous system though histologic interpretation of normal and aberrant staining patterns have shown variable results. This study examines whether GI α-syn mRNA expression combined with standard α-syn immunohistochemical staining enhance the role of GI biopsy in PD.Four groups were examined, including pediatric (21) and adult control patients (18), PD clinic patients (17), and pathologically confirmed PD cases from hospital archives (16). Enteric nervous system α-syn staining was evaluated by immunohistochemistry in 33 PD and 39 controls. α-Syn mRNA levels were compared between patient groups using quantitative polymerase chain reaction and stomach and colon levels in PD.PD patients had Lewy bodies (LB) and diffuse neuronal α-syn staining. GI tissues from elderly controls, children, and young adults exhibited diffuse positivity. LB were limited to PD. Myenteric plexus immunoreactivity varied in different regions. Widespread staining was noted within stomach and colon. Immunoreactivity was present within esophagus, appendix, and small bowel. α-Syn mRNA expression was highest in PD; however, levels varied between proximal and distal GI tract.α-Syn is normally present within young and elderly enteric nervous system; furthermore, while α-syn mRNA is always detectable, levels are highest and most variable in PD. This suggests that enteric α-syn may be altered in neurodegenerative disease. The presence of LB in the GI tract, not solely α-syn expression, may prove useful, distinguishing neurodegenerative disease patients from normal controls.

Background Swallow tail sign (STS), which represents nigrosome-1 in the substantia nigra on 3 Tesla (T) susceptibility-weighted imaging (SWI), has attracted attention as a promising magnetic resonance imaging (MRI) biomarker for idiopathic Parkinson's disease (iPD). Some reports have shown high sensitivity and specificity—both above 94%—for distinguishing iPD from healthy controls. However, abnormal STS has been observed in many neurodegenerative parkinsonisms and even in multiple sclerosis. Methods All patients with parkinsonism who had 3 T MRI were included in a retrospective chart review from a single movement disorders clinic. All subjects were evaluated by a single movement disorder specialist, using Movement Disorders Society diagnostic criteria and American Academy of Neurology consensus guidelines for diagnoses. All MRIs were interpreted by a single neuroradiologist who was blinded to the diagnosis. Results Twenty patients were included in the study. Twelve had abnormal STS: iPD (n = 2), probable multiple system atrophy (n = 3), vascular parkinsonism (n = 1), psychogenic gait disorder (n = 1), neuroleptic parkinsonism (n = 2), cervical dystonia (n = 1), static encephalopathy (n = 1) and gait disorder of unknown etiology (n = 1). Eight had normal STS: iPD (n = 1), probable progressive supranuclear palsy (n = 1), vascular parkinsonism (n = 2), transient parkinsonism of unknown etiology (n = 2), valproic acid induced parkinsonism (n = 1), and essential tremor with parkinsonism (n = 1). 123I-Ioflupane SPECT dopamine transporter (DaT) scan results were available on seven subjects; four subjects had incongruency between DaT and MRI. Conclusion Our results suggest that the abnormal STS is not, in isolation, a reliable biomarker of idiopathic Parkinson's disease.

INTRODUCTION: Many patients with advanced dementia and Parkinson’s disease and related disorders (PDRD) are receiving gastrostomy tube (GT) placement annually, despite its lack of proven benefit for preventing aspiration, enhancing nutrition, or prolonging survival. Given clinical practice variability in the care of people with neurodegenerative disorders, we sought to examine racial and geographic disparities in GT placement for these populations in the United States. METHOD: Data were extracted from a nationally available database using diagnostic and procedural codes from 2006 to 2010. GT placement rates and odds ratios were calculated for two groups: PDRD and non-parkinsonian dementia (NPD). RESULTS: In the PDRD group, odds of GT placement were higher among patients coded as Black (OR 1.69, CI .80-3.56, p=.17) and Asian (OR 2.17, CI 0.70-6.78, p=.18) than Whites; although these tendencies did not reach statistical significance. In the NPD group, GT placement among Black patients was significantly more likely (OR 2.88, CI 1.90-4.36, p

IMPORTANCE: Schizophrenia is associated with cognitive dysfunction and cardiovascular risk factors, including metabolic syndrome (MetS) and its constituent criteria. Cognitive dysfunction and cardiovascular risk factors can worsen cognition in the general population and may contribute to cognitive impairment in schizophrenia. OBJECTIVE: To study the association between cognitive dysfunction and cardiovascular risk factors and cognitive impairment in individuals with schizophrenia. DATA SOURCES: A search was conducted of Embase, Scopus, MEDLINE, PubMed, and Cochrane databases from inception to February 25, 2020, using terms that included synonyms of schizophrenia AND metabolic adversities AND cognitive function. Conference proceedings, clinical trial registries, and reference lists of relevant publications were also searched. STUDY SELECTION: Studies were included that (1) examined cognitive functioning in patients with schizophrenia or schizoaffective disorder; (2) investigated the association of cardiovascular disease risk factors, including MetS, diabetes, obesity, overweight, obesity or overweight, hypertension, dyslipidemia, and insulin resistance with outcomes; and (3) compared cognitive performance of patients with schizophrenia/schizoaffective disorder between those with vs without cardiovascular disease risk factors. DATA EXTRACTION AND SYNTHESIS: Extraction of data was conducted by 2 to 3 independent reviewers per article. Data were meta-analyzed using a random-effects model. MAIN OUTCOMES AND MEASURES: The primary outcome was global cognition, defined as a test score using clinically validated measures of overall cognitive functioning. RESULTS: Twenty-seven studies involving 10 174 individuals with schizophrenia were included. Significantly greater global cognitive deficits were present in patients with schizophrenia who had MetS (13 studies; n = 2800; effect size [ES] = 0.31; 95% CI, 0.13-0.50; P = .001), diabetes (8 studies; n = 2976; ES = 0.32; 95% CI, 0.23-0.42; P

Highlights • Rate of gastrostomy tube down trended during the study period. • Thousands of patients are still undergoing gastrostomy tube placement. • Gastrostomy tube is associated with longer hospital stay. • Gastrostomy tube is associated with a higher odds of discharge to nursing facility., Introduction Dysphagia causing aspiration pneumonia is a common complication in the advanced stages of neurodegenerative disorders. Historically, physicians attempted to prevent this complication with gastrostomy tube (GT) placement. Its use is supported in amyotrophic lateral sclerosis (ALS), not supported in Alzheimer’s disease (AD), and without disease-specific guidelines in Parkinson’s disease (PD). Method The rate of GT placement in these three populations over two decades, from 1990 to 2010, was calculated using a binomial regression model with the data extracted using diagnosis and procedural codes from a national database. The median length-of-stay (LOS) and discharge destinations were compared. Results The rate of GT placement was 6.0% lower annually in AD, 3.4% in PD, and 0.2% in ALS (all p ≤ 0.007). The analysis of hospital LOS and discharge destination showed 3.2 to 5.5 days longer LOS with GT placement in all groups (all p ≤ 0.01), and three to four times lower odds of going home with GT placement in AD and PD groups (OR 0.28, 95% CI 0.14–0.55, and OR 0.22, CI 0.11–0.42 respectively), while unchanged in ALS group (OR 1.1, 95% CI 0.6–1.9). Conclusion Despite the downward trend of GT placement over two decades, thousands of AD and PD patients still underwent GT placement annually, and this was associated with longer LOS in all groups and increased likelihood of being discharged to a nursing facility in AD and PD. Further research is necessary to understand the effects of GT on physician practices and patient expectations in advanced AD and PD.

Respiratory complaints are not uncommon in patients with Parkinson's disease (PD). While many are explained by pulmonary and cardiovascular problems unrelated to PD, secondary effects of PD, such as kyphoscoliosis, respiratory muscle rigidity, repeated pneumonias, or side effects of medication such as dyskinesias, there is a small group of patients with paroxysmal dyspnea for whom neither anxiety or other explanation has been found. This Point of View was written to call attention to this neglected, uncommon, but very distressing symptom.

Background Non-motor symptoms (NMSs) of Parkinson's disease (PD) were often overlooked and less studied. Little is known about NMSs in Ethiopia. The aim of the study was to determine the prevalence of NMSs and associated factors. Methods A multi-center cross-sectional observational study was conducted. NMS questionnaire was used to screen for the NMSs. Both descriptive and analytical statistics were used to analyze the data. Results Total of 123 PD patients with median of 4 years were investigated. The mean age of PD patients was 62.9 years. The mean age of PD onset was 58.3 years. In 23.6% the age of onset was below age 50. Males accounted 72.4%. Majority of the patients were on Levodopa alone and 31.7% were on levodopa plus trihexyphenidyl. Longer duration of illness was associated with frequent occurrence of NMSs. Constipation was the commonest NMS (78%), followed by urinary urgency (67.5%) and nocturia (63.4%). An unexplained pain was reported by 45.5 %, cognitive impairment (45.5%), and sleep disturbance was reported by 45.5% of the study participants. Neurophysciatric symptoms were reported by small proportion of the patients. Lower monthly earning was associated with swallowing problem, unexplained weight change, and lighheadness. Conclusion The prevalence of NMS was high among PD patients in Ethiopia. Constipation was the commonest NMS. Longer duration of illness was associated with frequent occurrence of NMSs. Lower monthly earning was associated with swallowing problem, unexplained weight change, and lighheadness.

Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.

Most movement disorders in psychiatric patients are induced by neuroleptic antipsychotic medications, all of which are dopamine D2 receptor blocking drugs. These include: acute onset disorders: dystonic reactions, akathisia and the neuroleptic malignant syndrome (NMS); non-acute onset parkinsonism; and the tardive syndromes. However, many other medications, when used at recommended doses, also induce movement disorders, with tremor being the most common. With the exception of serotonin syndrome, they are rarely as severe or disabling as the neuroleptic extrapyramidal syndromes may be. The serotonin reuptake inhibiting (SSRI) drugs are associated with the serotonin syndrome, a life-threatening disorder, but may also cause tremor and akathisia. While SSRI's have been thought to occasionally cause a tardive dyskinesia-like syndrome, this almost never occurs without prior or concurrent neuroleptic exposure as well. There also are few reliable data to support an association between antidepressants and parkinsonism. Valproic acid has been shown to cause parkinsonism, and lithium may as well, in addition to both having the well-known side effect of tremors. Myoclonus and asterixis are usually induced by toxic levels of medications but may appear with therapeutic levels, particularly with anticonvulsant mood stabilizers, and clozapine. Ataxia rarely occurs with non-toxic levels of drug, particularly anticonvulsants, benzodiazepines and lithium.

Anxiety is a severe problem for at least one-third of people living with Parkinson's disease (PD). Anxiety appears to have a greater adverse impact on quality of life than motor impairment. Despite its high prevalence and impact on daily life, anxiety is often undiagnosed and untreated. To better address anxiety in PD, future research must improve knowledge about the mechanism of anxiety in PD and address the lack of empirical evidence from clinical trials. In response to these challenges, the Parkinson's Foundation sponsored an expert meeting on anxiety on June 13th and 14th 2018. This paper summarizes the findings from that meeting informed by a review of the existing literature and discussions among patients, caregivers, and an international, clinician-scientist, expert panel working group. The goal is to provide recommendations to improve our understanding and treatment of anxiety in PD.

Subjective memory impairment (SMI) is a common complaint among older people. We performed a double-blind, placebo-controlled study1 which showed that deuterated two carbon fragments ameliorated the condition but at the expense of objective memory function. Future studies are needed to confirm the results before endorsing the treatment of SMI with deuterated ethyl alcohol.

Background: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. Objective: To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive‐enhancing medications. Methods: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21‐24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive‐enhancing medications. The primary outcome measure was change in the PD‐adapted Scale for the Assessment of Positive Symptoms. Results: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; –6.62 vs. –0.91; P = 0.002) versus the cognitively unimpaired (n = 135; –5.50 vs. –3.23; p = 0.046) group. The comparable change was –6.04 versus –2.18 (P = 0.012) and –5.66 versus –3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive‐enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive‐enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. Conclusions: The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive‐enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Background Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. Objectives To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. Methods Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. Results Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. Conclusion Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

Introduction Pimavanserin (Pim) is a 5HT2A inverse agonist that is the only Food and Drug Administration-approved treatment for Parkinson disease (PD) psychosis. The published open-label experience is limited. Methods This report is a chart review of all patients who were started on the drugs since the one earlier report on 15 patients. All patients were included, whether or not they completed 6 weeks of treatment, the time required for maximum benefit found in the published phase 3 trial. Results Twenty-six patients are reported. Three patients had dementia with Lewy bodies; one had an atypical parkinsonism; 22 had PD, including one with schizophrenia and neuroleptic exacerbated, dopamine transporter scan-positive idiopathic PD; and another had PD complicated by strokes. Six stopped before 6 weeks due to adverse effects, including 1 with worsened psychosis. Eighteen completed at least 6 weeks of treatment. Of these, 3 stopped due to lack of efficacy and 3 due to worsened psychosis. Twelve found it helpful. Of the 18 who took Pim for at least 6 weeks, 12 improved and continue to take it. Conclusions Almost 50% of parkinsonian patients with psychotic symptoms found Pim to be a useful medication, which they continue to take. Reasons for intolerance varied and were thought to be unrelated to the drug.

Background Management of tardive syndromes (TS) is challenging, with only a few evidence-based therapeutic algorithms reported in the American Academy of Neurology (AAN) guideline in 2013. Objective To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2) Does switching from typical to atypical DRBAs reduce TS symptoms? 3) What is the efficacy of pharmacologic agents in treating TS? 4) Do patients with TS benefit from chemodenervation with botulinum toxin? 5) Do patients with TS benefit from surgical therapy? Methods Systematic reviews were conducted by searching PsycINFO, Ovid MEDLINE, PubMed, EMBASE, Web of Science and Cochrane for articles published between 2012 and 2017 to identify new evidence published after the 2013 AAN guidelines. Articles were classified according to an AAN 4-tiered evidence-rating scheme. To the extent possible, for each study we attempted to categorize results based on the description of the population enrolled (tardive dyskinesia [TD], tardive dystonia, tardive tremor, etc.). Recommendations were based on the evidence. Results and recommendations New evidence was combined with the existing guideline evidence to inform our recommendations. Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) and must be recommended as treatment. Clonazepam and Ginkgo biloba probably improve TD (Level B) and should be considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C). Pallidal deep brain stimulation possibly improves TD and might be considered as a treatment for intractable TD (Level C). There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Psychosis is a common problem for people treated for Parkinson's disease. The syndrome is quite stereotypic, with hallucinations being the most common, followed by delusions. While the hallucinations are usually not very bothersome, the delusions are typically paranoid in nature. Treatment is often, but not always, required.This article reviews the therapeutic approaches of this syndrome focusing on drug treatments used once contributory factors have been removed. This includes a review of the evidence supporting the use of clozapine and, most recently, pimavanserin, the first drug with antipsychotic efficacy that has no effect on dopamine. Treatment with second generation antipsychotic drugs and cholinesterase inhibitors are also reviewed.Clozapine and pimavanserin have proven efficacy for Parkinson's disease psychosis (PDP), without impairing motor function. In clozapine's favor are its antipsychotic benefits seen within 1 week and its effectiveness in improving tremor in PD. However, this is counterbalanced by the need for blood monitoring, despite the extremely low doses used, and sedation. Pimanvanserin is well tolerated, without sedation or other significant side effects. Its onset of benefit, however takes 4-6 weeks. While quetiapine is also frequently used, its efficacy is not supported by double blinded, randomized trials.

Nonmotor symptoms (NMSs) in Parkinson's disease (PD) have become increasingly recognized as major determinants of quality of life across cultures worldwide. Behavioral symptoms include dementia, depression, anxiety, apathy, and fatigue. Somatic symptoms include hypotension, constipation, diaphoresis, and pain. However, somatic symptoms may also be intrinsic, such as dementia, and iatrogenic, such as compulsive disorders. The authors address some of the more common disorders, yet few have been the target of clinical trials.