The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

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Diagnosis and management of dementia with Lewy bodies Fourth consensus report of the DLB Consortium

Importance Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. Objective To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. Evidence Review References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. Results Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged Conclusions and Relevance Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=1861807&pdfFileName=jrv140005.pdf

Pharmacological Treatment of Parkinson Disease: A Review

Importance Parkinson disease is the most common form of parkinsonism, a group of neurological disorders with Parkinson disease–like movement problems such as rigidity, slowness, and tremor. More than 6 million individuals worldwide have Parkinson disease. Observations Diagnosis of Parkinson disease is based on history and examination. History can include prodromal features (eg, rapid eye movement sleep behavior disorder, hyposmia, constipation), characteristic movement difficulty (eg, tremor, stiffness, slowness), and psychological or cognitive problems (eg, cognitive decline, depression, anxiety). Examination typically demonstrates bradykinesia with tremor, rigidity, or both. Dopamine transporter single-photon emission computed tomography can improve the accuracy of diagnosis when the presence of parkinsonism is uncertain. Parkinson disease has multiple disease variants with different prognoses. Individuals with a diffuse malignant subtype (9%-16% of individuals with Parkinson disease) have prominent early motor and nonmotor symptoms, poor response to medication, and faster disease progression. Individuals with mild motor-predominant Parkinson disease (49%-53% of individuals with Parkinson disease) have mild symptoms, a good response to dopaminergic medications (eg, carbidopa-levodopa, dopamine agonists), and slower disease progression. Other individuals have an intermediate subtype. For all patients with Parkinson disease, treatment is symptomatic, focused on improvement in motor (eg, tremor, rigidity, bradykinesia) and nonmotor (eg, constipation, cognition, mood, sleep) signs and symptoms. No disease-modifying pharmacologic treatments are available. Dopamine-based therapies typically help initial motor symptoms. Nonmotor symptoms require nondopaminergic approaches (eg, selective serotonin reuptake inhibitors for psychiatric symptoms, cholinesterase inhibitors for cognition). Rehabilitative therapy and exercise complement pharmacologic treatments. Individuals experiencing complications, such as worsening symptoms and functional impairment when a medication dose wears off (“off periods”), medication-resistant tremor, and dyskinesias, benefit from advanced treatments such as therapy with levodopa-carbidopa enteral suspension or deep brain stimulation. Palliative care is part of Parkinson disease management. Conclusions and Relevance Parkinson disease is a heterogeneous disease with rapidly and slowly progressive forms. Treatment involves pharmacologic approaches (typically with levodopa preparations prescribed with or without other medications) and nonpharmacologic approaches (such as exercise and physical, occupational, and speech therapies). Approaches such as deep brain stimulation and treatment with levodopa-carbidopa enteral suspension can help individuals with medication-resistant tremor, worsening symptoms when the medication wears off, and dyskinesias.

https://jamanetwork.com/journals/jama/articlepdf/2760741/jama_armstrong_2020_rv_190013.pdf

Diagnosis and Treatment of Parkinson Disease: A Review

Objective
To update evidence‐based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mds.27602

Update on treatments for nonmotor symptoms of Parkinson's disease—an evidence-based medicine review

This article reviews and summarizes 200 years of Parkinson's disease. It comprises a relevant history of Dr. James Parkinson's himself and what he described accurately and what he missed from today's perspective. Parkinson's disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

https://www.acadia-pharm.com/wp-content/uploads/2015/01/The-Lancet-Pimavanserin-Phase-III-020-Study.pdf

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

OBJECTIVE Our aim was to describe the efficacy and tolerability of pimavanserin, a highly selective serotonin 5-HT2A receptor inverse agonist/antagonist indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (PDP), using the metrics of number needed to treat (NNT) and number needed to harm (NNH). METHODS Categorical efficacy and tolerability data were extracted from the clinical trial databases of the double-blind placebo-controlled studies of pimavanserin in persons with PDP. NNT and NNH values were calculated with their respective 95% confidence intervals. The likelihood to be helped or harmed (LHH) was then calculated contrasting therapeutic response versus discontinuation because of an adverse event. RESULTS NNT values for pimavanserin 34 mg/d versus placebo for several definitions of clinical response are 10, and/or are not statistically significant, and/or show an advantage for pimavanserin over placebo (such as for postural hypotension). In terms of LHH, pimavanserin 34 mg/d is about five times more likely to result in clinical response (as measured by a ≥3 point decrease from baseline on the Scale for the Assessment of Positive Symptoms adapted for Parkinson's disease) versus discontinuation due to an adverse event. CONCLUSIONS Using the metrics of NNT, NNH, and LHH, pimavanserin 34 mg/d for the treatment of PDP appears to have a compelling benefit/risk profile.

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Pimavanserin for the Treatment of Parkinson's Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

Antipsychotic efficacy and motor tolerability in a phase III placebo-controlled study of pimavanserin in patients with Parkinson's Disease psychosis (Acp-103-020)

Long-term effectiveness of NUPLAZID™ (pimavanserin) in PD psychosis: Data from 2 open-label studies

OBJECTIVE: To determine the effect of pimavanserin, a selective 5-HT2A inverse-agonist, on caregiver burden. BACKGROUND: Parkinson9s Disease Psychosis (PDP) is associated with functional and cognitive decline, morbidity/mortality, and increased caregiver burden often leading to early institutionalization. Pimavanserin is a potent 5-HT2A inverse-agonist being developed for PDP. Unlike current antipsychotics, it has no dopaminergic, histaminergic, adrenergic or muscarinic activity. Pimavanserin 40mg demonstrated improvements in psychosis, nighttime sleep and daytime wakefulness in randomized controlled trials (RCTs) in PDP. RCT completers could roll into a long-term open-label study (OLS). A consented caregiver had to attend all RCT and OLS visits and complete the Zarit 22-item caregiver burden scale (CBS). METHOD: In an integrated analysis of the 6-week RCTs, CBS scores were evaluated among caregivers of 268 PDP patients in N.America who received pimavanserin 40mg or placebo. Most caregivers were spouses or other family. Continued effect was assessed in the OLS. RESULTS: Mean baseline (pretreatment) CBS scores were 30.6 for placebo (N=133) and 28.8 for pimavanserin 40mg (N=135). Significant improvement in burden was observed for the pimavanserin group (-4.8 points) over placebo (-1.1 points) at 6 weeks (p=0.0009). These results did not strongly correlate with psychosis or sleep improvements, suggesting broader benefits of pimavanserin not captured by other study measures. More caregiver benefit was observed for patients with less dementia and less co-morbid disease. In the OLS, CBS scores remained generally stable (+1-point difference) for up to 9 months.CONCLUSIONS: Improvements on caregiver burden among pimavanserin-treated people with PDP, provide important context around the benefit-risk profile of this selective 5-HT2A inverse-agonist that has shown significant benefit on psychosis and sleep and a well-tolerated safety profile. Disclosure: Dr. Aarsland has nothing to disclose. Dr. Mills has received personal compensation for activities with Acadia Pharmaceuticals, Inc. as an employee. Dr. Williams has received personal compensation for activities with ACADIA Pharmaceuticals Inc. as an employee. Dr. Chi-Burris has nothing to disclose. Dr. Karistedt has nothing to disclose. Dr. Ballard has received personal compensation for activities with Novartis, Eisai, ACADIA Pharmaceuticals, and Lundbeck Research USA, Inc. as a consultant.

Decreased burden among caregivers of patients with Parkinson’s disease psychosis (PDP) treated with pimavanserin, a selective 5-HT2A inverse agonist (P6.044)

Kathy Chi-Burris

Papers

Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial

Pimavanserin for the Treatment of Parkinson's Disease Psychosis: Number Needed to Treat, Number Needed to Harm, and Likelihood to Be Helped or Harmed

Antipsychotic efficacy and motor tolerability in a phase III placebo-controlled study of pimavanserin in patients with Parkinson's Disease psychosis (Acp-103-020)

Long-term effectiveness of NUPLAZID™ (pimavanserin) in PD psychosis: Data from 2 open-label studies

Decreased burden among caregivers of patients with Parkinson’s disease psychosis (PDP) treated with pimavanserin, a selective 5-HT2A inverse agonist (P6.044)