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.

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.

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.

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.

What is a clinically important change in the Unified Dyskinesia Rating Scale in Parkinson's disease?

INTRODUCTION: Dyskinesia remain a significant problem in Parkinson Disease (PD). The translation process of novel drug targets for dyskinesia has proven difficult with several failures at phase III level. Determining the 'clinically important change' (CIC) for dyskinesia rating scales in phase II clinical trials may assist in optimizing drug development of new anti-dyskinetic treatments. We used a standard phase IIa acute levodopa infusion paradigm to determine for the first time the CIC for dyskinesia using the new UDysRS. METHODS: We performed a randomized, double-blind, placebo-controlled crossover study with eleven PD patients with stable bothersome dyskinesia. We used the following patient-reported clinically important events as CIC anchors: onset, maximum intensity, remission of dyskinesia. Objective dyskinesia scores using the UDysRS part III Impairment were determined at these same events by blinded video-rating. The CIC was determined using the 'within-patient' score change and a sensitivity- and specificity-based approach. RESULTS: Patients were most aware of 'onset of dyskinesia', followed by 'remission of dyskinesia'. An 11.1-point median change (UDysRS Part III Impairment, p < 0.0001) was the CIC for patient-reported remission of dyskinesia from a practically defined-OFF state. A 2.32-point change (UDysRS Part III Impairment) had the best specificity and sensitivity to distinguish between patient-reported remission and perception of dyskinesia. CONCLUSIONS: In this study, we provide the first report of a CIC for the UDysRS Part III Impairment. Early knowledge of a CIC may help inform the decision to advance into phase III trials and contribute for a higher yield of success in finding new anti-dyskinetic treatments.

Axial disability and deep brain stimulation in patients with Parkinson disease.

Axial motor signs-including gait impairment, postural instability and postural abnormalities-are common and debilitating symptoms in patients with advanced Parkinson disease. Dopamine replacement therapy and physiotherapy provide, at best, partial relief from axial motor symptoms. In carefully selected candidates, deep brain stimulation (DBS) of the subthalamic nucleus or globus pallidus internus is an established treatment for 'appendicular' motor signs (limb tremor, bradykinesia and rigidity). However, the effects of DBS on axial signs are much less clear, presumably because motor control of axial and appendicular functions is mediated by different anatomical-functional pathways. Here, we discuss the successes and failures of DBS in managing axial motor signs. We systematically address a series of common clinical questions associated with the preoperative phase, during which patients presenting with prominent axial signs are considered for DBS implantation surgery, and the postoperative phase, in particular, the management of axial motor signs that newly develop as postoperative complications, either acutely or with a delay. We also address the possible merits of new targets-including the pedunculopontine nucleus area, zona incerta and substantia nigra pars reticulata-to specifically alleviate axial symptoms. Supported by a rapidly growing body of evidence, this practically oriented Review aims to support decision-making in the management of axial symptoms.

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.

Restless genital syndrome in Parkinson disease.

IMPORTANCE: Symptoms in the genital region, such as pain, discomfort, tingling, and burning sensations, have rarely been reported in Parkinson disease (PD), and the previous cases were attributed to nonmotor off symptoms. We report a patient with PD and severe genital discomfort unrelated to motor fluctuations but compatible with restless genital syndrome. OBSERVATIONS: A 65-year-old woman with PD experienced a disabling discomfort in her pelvis and genital region for 3 years. The episodes occurred in the evening and were triggered by sitting or lying down for a period. Gynecological investigation was unrevealing. She experienced improvement with a low dose of a dopamine agonist. CONCLUSION AND RELEVANCE: Restless genital syndrome is a rare disorder that can be a source of distress and disability. In patients with PD, restless genital syndrome should be included in the differential diagnosis of genital symptoms and restlessness, along with nonmotor wearing off and akathisia. A detailed clinical history is essential for this diagnosis and treatment with dopamine agonists can provide benefit.

Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. a preliminary observation.

OBJECTIVE: Hyperechogenicity of the substantia nigra is a frequent observation on transcranial sonography in Parkinson's disease and Machado-Joseph disease patients. Additionally, restless legs syndrome is a sleep disorder that is also frequently found in both diseases. Autopsy studies have demonstrated increased SN iron content in hyperechogenic substantia nigra. Iron storage is also known to be involved in restless legs syndrome. We formally compared echogenicity of the substantia nigra with restless legs syndrome in Parkinson's disease and Machado-Joseph disease patients. METHODS: Transcranial brain sonography was performed in a sample of Parkinson's disease and Machado-Joseph disease patients, and findings then correlated with the presence and severity of restless legs syndrome. RESULTS: There was a continuum of substantia nigra echogenicity among groups (Parkinson's disease versus Machado-Joseph disease versus controls) and sub-groups (Parkinson's disease with and without restless legs syndrome versus Machado-Joseph disease with and without restless legs syndrome) as well as a statistically significant negative correlation between restless legs syndrome severity and substantia nigra echogenicity (p<0.001). CONCLUSIONS: These preliminary observations demonstrate that the severity of RLS may be influenced by nigral iron load reflected by substantia nigra echogenicity in different neurodegenerative movement disorders.

Sleep disorders in cerebellar ataxias.

Cerebellar ataxias comprise a wide range of etiologies leading to central nervous system-related motor and non-motor symptoms. Recently, a large body of evidence has demonstrated a high frequency of non-motor manifestations in cerebellar ataxias, specially in autosomal dominant spinocerebellar ataxias (SCA). Among these non-motor dysfunctions, sleep disorders have been recognized, although still under or even misdiagnosed. In this review, we highlight the main sleep disorders related to cerebellar ataxias focusing on REM sleep behavior disorder (RBD), restless legs syndrome (RLS), periodic limb movement in sleep (PLMS), excessive daytime sleepiness (EDS), insomnia and sleep apnea.

Sleep disorders in cerebellar ataxias / Distúrbios do sono nas ataxias cerebelares

Cerebellar ataxias comprise a wide range of etiologies leading to central nervous system-related motor and non-motor symptoms. Recently, a large body of evidence has demonstrated a high frequency of non-motor manifestations in cerebellar ataxias, specially in autosomal dominant spinocerebellar ataxias (SCA). Among these non-motor dysfunctions, sleep disorders have been recognized, although still under or even misdiagnosed. In this review, we highlight the main sleep disorders related to cerebellar ataxias focusing on REM sleep behavior disorder (RBD), restless legs syndrome (RLS), periodic limb movement in sleep (PLMS), excessive daytime sleepiness (EDS), insomnia and sleep apnea.

As ataxias cerebelares se caracterizam por uma enorme variedade de etiologias, cursando tanto com sintomas motores como também com sintomas não motores. Recentemente, várias evidências têm demonstrado uma frequência elevada de sintomas não motores nas ataxias cerebelares, especialmente nas ataxias espinocerebelares autossômicas dominantes (SCA). Dentre os sintomas não motores, estão os distúrbios do sono, que muitas vezes são sub-diagnosticados ou pouco valorizados. Nessa revisão, enfatizamos os principais distúrbios do sono relatados nas ataxias cerebelares, como transtorno comportamental do sono REM, síndrome das pernas inquietas, movimentos periódicos das pernas no sono, sonolência diurna excessiva, insônia e apnéia do sono.

Prevalence and impact of headache and migraine among Pomeranians in Espirito Santo, Brazil / Prevalência e impacto da cefaléia entre pomeranos do interior do Espírito Santo

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 percent). Most headache sufferers were diagnosed as having migraine (55 percent). More women reported to have headache than men (65 percent and 33.8 percent, respectively). Migraine was the most common headache found among women (62.2 percent). Among men migraine was responsible for only 37.8 percent 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 percent) and most of them used to take common analgesics for headache relief. None of them was under prophylactic therapy.

Este estudo é o primeiro a avaliar a prevalência da cefaléia e da migrânea entre descendentes de pomeranos no Brasil. Demonstrou-se alta prevalência de cefaléia (53,2 por cento), sendo que a migrânea foi responsável por 55 por cento das cefaléias. Houve maior prevalência de cefaléia entre as mulheres (65 por cento) do que entre os homens (33,8 por cento). Entre as mulheres verificou-se maior prevalência de migrânea (62,2 por cento) sobre as outras cefaléias (37,8 por cento). Entre os homens a migrânea foi responsável por apenas 34,6 por cento dos casos de cefaléia. Verificou-se importante impacto da cefaléia nesta população, especialmente entre os portadores de migrânea. A maior parte (67 por cento) dos portadores de cefaléia recebia algum tipo de orientação médica em relação ao problema, e a maioria fazia uso de medicamentos analgésicos comuns. Nenhum dos indivíduos estava em tratamento profilático.

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.