Outcomes for studies assessing the efficacy of hemostatic therapies in persons with congenital bleeding disorders.

INTRODUCTION: Management strategies and hemostatic treatments to achieve control of bleeding are relevant across many disease areas. Identification of primary outcomes for studies assessing hemostatic intervention was the objective of a National Heart, Lung and Blood Institute (NHLBI) sponsored multidisciplinary initiative. The aim of this report is to summarize the evidence reviewed, and the outcomes identified by the subgroup tasked to assess outcomes for inherited bleeding disorders. METHODS: The subgroup decided to focus on haemophilia, the prototypal congenital bleeding disorder and the one with the largest available body of evidence. MEDLINE, EMBASE and PsycINFO, The Cochrane Review, CINAHL, and Web of Science were searched for systematic and narrative reviews on outcomes used in haemophilia clinical trials. Three different clinical goals were identified as typical objectives of future research. RESULTS: Out of 1322 unique citations, 24 reviews published in the period 2002-2019 were included. We identified 113 outcome measures, categorized in 6 domains: health-related quality of life (HRQoL), comorbidities and mortality, overall physical functioning and participation, bleeding and hemostasis, joint health, and costs and resource use. Three different clinical goals were identified as typical objectives of future research: Episodic 'on demand' replacement therapy, prevention of bleeding (Prophylaxis), and long-term and overall impact of bleeding. For each of these scenarios, specific outcomes were recommended. CONCLUSIONS: Primary outcomes for clinical trials assessing the efficacy of hemostatic treatment in achieving control, prevention and limiting long-term consequences of bleeding in inherited bleeding disorders are suggested, and their strength and limitations discussed.

Interleaved deep brain stimulation for dyskinesia management in Parkinson's disease.

BACKGROUND: In patients with Parkinson's disease, stimulation above the subthalamic nucleus (STN) may engage the pallidofugal fibers and directly suppress dyskinesia. OBJECTIVES: The objective of this study was to evaluate the effect of interleaving stimulation through a dorsal deep brain stimulation contact above the STN in a cohort of PD patients and to define the volume of tissue activated with antidyskinesia effects. METHODS: We analyzed the Core Assessment Program for Surgical Interventional Therapies dyskinesia scale, Unified Parkinson's Disease Rating Scale parts III and IV, and other endpoints in 20 patients with interleaving stimulation for management of dyskinesia. Individual models of volume of tissue activated and heat maps were used to identify stimulation sites with antidyskinesia effects. RESULTS: The Core Assessment Program for Surgical Interventional Therapies dyskinesia score in the on medication phase improved 70.9 ± 20.6% from baseline with noninterleaved settings (P < 0.003). With interleaved settings, dyskinesia improved 82.0 ± 27.3% from baseline (P < 0.001) and 61.6 ± 39.3% from the noninterleaved phase (P = 0.006). The heat map showed a concentration of volume of tissue activated dorsally to the STN during the interleaved setting with an antidyskinesia effect. CONCLUSION: Interleaved deep brain stimulation using the dorsal contacts can directly suppress dyskinesia, probably because of the involvement of the pallidofugal tract, allowing more conservative medication reduction. © 2019 International Parkinson and Movement Disorder Society.

Novel RAB39B variant associated intellectual disability and levodopa-responsive young-onset parkinsonism.

We report a 37-year-old Caucasian male with history of developmental delay, childhood onset Intellectual Disability (ID) and attention deficit hyperactivity disorder (ADHD) who presented at the age of 34 with tremor-dominant parkinsonism. Next Generation Sequencing (NGS) revealed pathogenic hemizygous sequence variant, c.200G > T, in the RAB39B gene. This report expands the number of described individuals with young onset PD associated with RAB39B mutation.

Interactive mobile application for Parkinson's disease deep brain stimulation (MAP DBS): An open-label, multicenter, randomized, controlled clinical trial.

INTRODUCTION: Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), but its efficacy is tied to DBS programming, which is often time consuming and burdensome for patients, caregivers, and clinicians. Our aim is to test whether the Mobile Application for PD DBS (MAP DBS), a clinical decision support system, can improve programming. METHODS: We conducted an open-label, 1:1 randomized, controlled, multicenter clinical trial comparing six months of SOC standard of care (SOC) to six months of MAP DBS-aided programming. We enrolled patients between 30 and 80 years old who received DBS to treat idiopathic PD at six expert centers across the United States. The primary outcome was time spent DBS programming and secondary outcomes measured changes in motor symptoms, caregiver strain and medication requirements. RESULTS: We found a significant reduction in initial visit time (SOC: 43.8 ± 28.9 min n = 37, MAP DBS: 27.4 ± 13.0 min n = 35, p = 0.001). We did not find a significant difference in total programming time between the groups over the 6-month study duration. MAP DBS-aided patients experienced a significantly larger reduction in UPDRS III on-medication scores (-7.0 ± 7.9) compared to SOC (-2.7 ± 6.9, p = 0.01) at six months. CONCLUSION: MAP DBS was well tolerated and improves key aspects of DBS programming time and clinical efficacy.

Surgical Management of Parkinson's Disease in the Elderly.

BACKGROUND: Deep Brain Stimulation (DBS) is an increasingly popular therapy for Parkinson's Disease (PD). Despite the experience gained over time with DBS of either the subthalamus or the globus pallidus pars interna, there is still no consensus regarding the age limit for DBS indication. OBJECTIVES: This narrative review of the literature discusses the issues of age and DBS, emphasizing the critical need for good quality evidence to support the surgical management of elderly patients with PD. METHODS: We searched PubMed using the terms Parkinson's Disease; Parkinson's Disease therapy; deep brain stimulation; antiparkinsonian agents therapeutic use; age factors; aged; aged, 80 and over; middle aged; treatment outcome; and risk assessments. RESULTS: We identified several limitations of the available evidence, such as under-representation of older patients in DBS studies, small sample sizes in studies with older participants, heterogeneity of outcomes, and conflicting results. CONCLUSIONS: Despite preliminary suggestions that age might affect the outcomes of DBS, the evidence to support the hypothesis of age as an independent predictor of DBS outcomes is limited and results are controversial. Ultimately, finding an age-independent biomarker predicting DBS outcome is the final goal to expand this powerful treatment to all patients age in an effective and safe manner.

The Relationship Between Serotonin-2A Receptor and Cognitive Functions in Nondemented Parkinson's Disease Patients with Visual Hallucinations.

BACKGROUND: There is growing evidence that the serotonergic system, in particular serotonin 2A receptors, is involved in neuropsychiatric symptoms in Parkinson's disease (PD), including cognitive processing and visual hallucinations. However, the relationship between serotonin 2A receptor availability, visual hallucinations, and cognitive profile is unknown. The objective of this study was to investigate the level of serotonin 2A receptor availability in brain regions affected by visual hallucinations and to test the association with cognitive/behavioral changes in patients who have PD with visual hallucinations. METHODS: Nondemented patients who had PD with (n = 11) and without (n = 8) visual hallucinations and age-matched controls (n = 10) were recruited. All participants completed neuropsychological testing, which consisted of visuoperceptual, executive, memory, language, and frontal-behavioral function. Positron emission tomography scans using [18F]setoperone, a serotonin 2A antagonist radioligand, were acquired in patients with PD, and a parametric binding potential map of [18F]setoperone was calculated with the simplified reference tissue model using the cerebellum as a reference. RESULTS: Patients who had PD with visual hallucinations exhibited significantly lower scores on measures of executive and visuoperceptual functions compared with age-matched controls. These changes were paralleled by decreased [18F]setoperone binding in the right insula, bilateral dorsolateral prefrontal cortex, right orbitofrontal cortex, right middle temporal gyrus, and right fusiform gyrus. The psychometric correlation analysis revealed significant relationships among tests associated with visuoperceptual function, memory and learning, and serotonin 2A binding in different prefrontal and ventral visual stream regions. There was also reduced serotonin 2A receptor binding in patients who had PD with depression. CONCLUSIONS: These findings support a complex interaction between serotonin 2A receptor function and cognitive processing in patients who have PD with visual hallucinations.

Prevalence and impact of headache and migraine among Pomeranians in Espirito Santo, Brazil.

This is the first study to assess the prevalence of headache and migraine among Pomeranian descendents in Brazil. A high prevalence of headache in the last 6 months was found (53.2%). Most headache sufferers were diagnosed as having migraine (55%). More women reported to have headache than men (65% and 33.8%, respectively). Migraine was the most common headache found among women (62.2%). Among men migraine was responsible for only 37.8% of the cases of headache. A high impact of headache was found, especially among migraineurs. Most of the headache sufferers declared to seek medical assistance for headache (67%) and most of them used to take common analgesics for headache relief. None of them was under prophylactic therapy.

Deep Brain Stimulation in Rare Inherited Dystonias.

BACKGROUND: Rare causes of inherited movement disorders often present with a debilitating phenotype of dystonia, sometimes combined with parkinsonism and other neurological signs. Since these disorders are often resistant to medications, DBS may be considered as a possible treatment. METHODS: Patients with identified genetic diseases (ataxia-telangiectasia, chorea-achantocytosis, dopa-responsive dystonia, congenital nemaline myopathy, methylmalonic aciduria, neuronal ceroid lipofuscinosis, spinocerebellar ataxia types 2 and 3, Wilson's disease, Woodhouse-Sakati syndrome, methylmalonic aciduria, and X trisomy) and disabling dystonia underwent bilateral GPi DBS (bilateral thalamic Vim nucleus in 1 case). The primary outcome was the difference in the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) between baseline, 1 year and last available follow-up. Preoperative factors such as age at surgery, disease duration at surgery, proportion of life lived with dystonia and severity of dystonia were correlated to the primary outcome. RESULTS: Eleven patients were operated between February 2003 and December 2013. Age and duration of disease at time of surgery were 30 ± 19 and 12.5 ± 15.7 years, respectively. DBS effects on dystonia severity were variable but overall marginally effective, with a mean improvement of 7.9% (p = 0.39) at 1-year follow-up and 16.7% (p = 0.46) at last follow-up (mean 47.3 ± 19.9 months after surgery). No preoperative factors were identified to predict the surgical outcome. CONCLUSION: Our findings support the current knowledge that DBS is modestly effective in treating rare inherited dystonias with a combined phenotype. However, the BFMDRS might not be the best tool to measure outcome in these severely affected patients.

Dystonic Pseudo Foot Drop.

The most common presentation of foot dystonia in patients with Parkinson's disease (PD) or dystonia is inversion of the foot accompanied by flexion of the toes, with or without extension of the hallux. Less commonly, foot dystonia may mimic foot drop, as occurs with weakness of the dorsiflexors muscles, resulting in a pseudo foot drop. This has rarely been reported in the literature and has been poorly recognized, often leading to misdiagnosis and unnecessary investigations and treatment. We report 5 patients with dystonic pseudo foot drop, one of them diagnosed with early-onset PD, 2 with sporadic PD, and 2 with dystonia. Despite the steppage gait, their physical exam revealed normal strength, and no other explanation for a "foot drop" was found. It is important to recognize this phenomenology, which can be a clue to the diagnosis of early-onset PD, and may be responsive to levodopa in selected patients.