Ischemic Stroke Associated With Calcitonin Gene-Related Peptide Inhibitor Therapy for Migraine: A Case Report.

Calcitonin gene-related peptide (CGRP) is involved in nociception and neurogenic inflammation in migraine, but also serves as a potent vasodilator acting on intracranial arteries. This latter effect raises concern about the possibility of drugs inhibiting CGRP precipitating cerebral ischemia. We describe a 41-year-old woman with migraine without aura who developed a right thalamic infarction following a first dose of erenumab, a CGRP-receptor blocker. Stroke onset occurred during a typical migraine. Imaging demonsrated right posterior cerebral artery near-occlusion initially with normalization of the vessel at follow-up imaging 2 months later, suggesting vasospasm as a possible mechanism. Extensive evaluation revealed no other specific cause of stroke or vascular risk factors aside from long-term use of oral contraceptive pills. CGRP inhibitors might be associated with ischemic stroke due to blockade of normal cerebral vasodilatory regulatory function.

Current use of neurotoxins for alleviating symptoms of cervical dystonia.

INTRODUCTION: Cervical dystonia (CD) causes involuntary movements and postures of the head, neck, and shoulders, as well as nonmotor symptoms including pain, mood, and sleep dysfunction, and impacts quality of life. The first-line treatment for CD is botulinum neurotoxin (BoNT) injections. AREAS COVERED: The clinical presentation and diagnosis of CD, as well as where BoNT resides in the treatment landscape, is reviewed first. Next, the mechanism of action and the pharmacological differences in the available preparations of BoNT products are explained. The evidence base for motor and nonmotor efficacy and safety of the available BoNT formulations is reviewed, with attention to duration of benefit as a driver of patient satisfaction. Practical determinants of BoNT efficacy are reviewed including muscle selection, accurate muscle injection, factors related to poor or deteriorating response, and immunogenicity. EXPERT OPINION: BoNT represents a significant advancement in the treatment of CD. More accurate diagnosis, muscle selection and targeting, and dosing can improve outcomes with existing BoNT formulations. Further refinement of BoNT potency, duration of action, safety, and immunogenicity will help reduce unmet needs in the magnitude and duration of benefit. Additional validation of DBS and MRI-guided focused ultrasound may expand options for patients with toxin nonresponse.

A Case Series of Delusional Infestation in Huntington's Disease.

 Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI) is a rare psychotic manifestation of the disease. This report presents two cases of HD patients with DI, both middle-aged females. The first patient achieved remission of DI with olanzapine, later cross-tapered to risperidone, but had spontaneous relapses. The second experienced gradual resolution of DI with risperidone in the setting of iron repletion and amantadine discontinuation, although her other psychotic symptoms remained. These cases shed light on an uncommon condition and may help guide understanding of the most effective treatment for it.

F198S Gerstmann-Sträussler-Scheinker Syndrome With Parkinsonism, Dyskinesia, and Abnormal (I-123)-FP-CIT Single-Photon Emission Computed Tomography: A Case Report.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an autosomal dominant neurodegenerative disease caused by point mutations in the prion protein gene (PRNP). While variable, the clinical presentation typically encompasses progressive cerebellar ataxia, pyramidal signs, and cognitive impairment. Here, we report a case of F198S-associated GSS manifesting levodopa-responsive parkinsonism, levodopa-induced dyskinesia, and an abnormal (I-123)-FP-CIT single-photon emission computed tomography (DaT-SPECT). A 66-year-old male patient presented with six years of progressive recall and language impairment, with an initial impression of primary progressive aphasia. Over time he developed progressive cerebellar ataxia and akinetic parkinsonism. There was a family history of ataxia in multiple family members. Levodopa was prescribed up to 450 mg per day without benefit. Genetic testing at age 69 revealed a heterozygous F198S mutation in the PRNP gene, with MV heterozygosity at codon 129. At age 70, he developed mild generalized choreiform dyskinesia. Levodopa was discontinued, resulting in the resolution of dyskinesia with a concomitant marked worsening of akinetic parkinsonism. DaT-SPECT demonstrated bilaterally reduced putaminal binding. This case highlights that GSS can resemble atypical parkinsonism both clinically and with DaT-SPECT imaging. Taking a salient family history and other clinical features into consideration, GSS should be added to the differential diagnoses of such patients.

Key Features in the Design and Function of Nanocarriers for Intranasal Administration of Gene Therapy in Huntington Disease.

A major obstacle to fulfilling the therapeutic promise of gene therapies for hereditary brain diseases, such as Huntington' Disease (HD), is the requirement for viral vectors and/or an invasive delivery system (stereotaxic injection into brain or infusion into the intrathecal space). HD is an autosomal dominant neurodegenerative disease for which several clinical trials have demonstrated gene-lowering effects following intrathecal administration. These technical limitations have given impetus to the development of alternative non-invasive delivery systems for gene therapy of brain diseases. The overall objective of this review is to discuss the key features in the design of nanocarriers for intranasal administration of gene-therapy for HD, focusing primarily on our series of published work on the use of nanocarriers for gene therapy. Design and development of nanocarriers packaged with gene-lowering agents represents a significant advance towards non-invasive nose-to-brain delivery of gene therapy for HD and other hereditary brain disorders.

HIV-associated dementia presenting predominantly with clinical motor deficits: A case report.

HIV-associated dementia is commonly seen in older individuals and presents as a subcortical dementia associated with concentration, attention, and memory impairments. Motor signs, such as difficulty with gait, and mood changes are less prominent findings but are considered during diagnosis. We present a case of HIV-associated dementia in a young 29-year-old man who presented with progressive lower extremity weakness and difficulty ambulating.

Predicting Severity of Huntington's Disease With Wearable Sensors.

The Unified Huntington's Disease Rating Scale (UHDRS) is the primary clinical assessment tool for rating motor function in patients with Huntington's disease (HD). However, the UHDRS and similar rating scales (e.g., UPDRS) are both subjective and limited to in-office assessments that must be administered by a trained and experienced rater. An objective, automated method of quantifying disease severity would facilitate superior patient care and could be used to better track severity over time. We conducted the present study to evaluate the feasibility of using wearable sensors, coupled with machine learning algorithms, to rate motor function in patients with HD. Fourteen participants with symptomatic HD and 14 healthy controls participated in the study. Each participant wore five adhesive biometric sensors applied to the trunk and each limb while completing brief walking, sitting, and standing tasks during a single office visit. A two-stage machine learning method was employed to classify participants by HD status and to predict UHDRS motor subscores. Linear discriminant analysis correctly classified all participants' HD status except for one control subject with abnormal gait (96.4% accuracy, 92.9% sensitivity, and 100% specificity in leave-one-out cross-validation). Two regression models accurately predicted individual UHDRS subscores for gait, and dystonia within a 10% margin of error. Our regression models also predicted a composite UHDRS score-a sum of left and right arm rigidity, total chorea, total dystonia, bradykinesia, gait, and tandem gait subscores-with an average error below 15%. Machine learning classifiers trained on brief in-office datasets discriminated between controls and participants with HD, and could accurately predict selected motor UHDRS subscores. Our results could enable the future use of biosensors for objective HD assessment in the clinic or remotely and could inform future studies for the use of this technology as a potential endpoint in clinical trials.

Istradefylline - a first generation adenosine A2A antagonist for the treatment of Parkinson's disease.

Introduction It is now accepted that Parkinson's disease (PD) is not simply due to dopaminergic dysfunction, and there is interest in developing non-dopaminergic approaches to disease management. Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of PD.Areas covered In this narrative review, we summarize the literature supporting the utility of adenosine A2A antagonists in PD with a specific focus on istradefylline, the most studied and only adenosine A2A antagonist currently in clinical use.Expert opinion: At this time, the use of istradefylline in the treatment of PD is limited to the management of motor fluctuations as supported by the results of randomized clinical trials and evaluation by Japanese and USA regulatory authorities. The relatively complicated clinical development of istradefylline was based on classically designed studies conducted in PD patients with motor fluctuations on an optimized regimen of levodopa plus adjunctive dopaminergic medications. In animal models, there is consensus that a more robust effect of istradefylline in improving motor function is produced when combined with low or threshold doses of levodopa rather than with high doses that produce maximal dopaminergic improvement. Exploration of istradefylline as a 'levodopa sparing' strategy in earlier PD would seem warranted.

Medical Management and Prevention of Motor Complications in Parkinson's Disease.

Levodopa is the most effective medication for the treatment of the motor symptoms of Parkinson's disease. However, over time, the clinical response to levodopa becomes complicated by a reduction in the duration and reliability of motor improvement (motor fluctuations) and the emergence of involuntary movements (levodopa-induced dyskinesia). Strategies that have been attempted in an effort to delay the development of these motor complications include levodopa sparing and continuous dopaminergic therapy. Once motor complications occur, a wide array of medical treatments is available to maximize motor function through the day while limiting dyskinesia. Here, we review the clinical features, epidemiology, and risk factors for the development of motor complications, as well as strategies for their prevention and medical management.

The challenge of developing adenosine A2A antagonists for Parkinson disease: Istradefylline, preladenant, and tozadenant.

Laboratory and clinical experience have pointed to the value of targeting motor pathways emerging from the striatum to treat problems arising in advanced Parkinson's disease (PD). These pathways are selectively populated with a subtype of adenosine binding sites (A2A receptors) that offer a target for improving PD symptomatology. Several compounds were developed that possess high selectivity and potency for blocking this receptor. Three of these compounds - istradefylline, preladenant, and tozadenant - were chosen for clinical development programs that culminated in Phase 3 multicenter randomized clinical trials. Each of these drugs exert virtually no off-target neurochemical effects. Clinical trials with these drugs focused upon reducing OFF time when administered adjunctly to levodopa and other antiparkinsonian medications. Despite promising Phase 2 data, preladenant did not show efficacy when tested in a randomized placebo-controlled Phase 3 clinical trial. Reports of hematological toxicity necessitated ceasing an ongoing Phase 3 investigation of tozadenant. Following a challenging approval process, based on the results of randomized clinical trials carried out in the U.S. and Japan, istradefylline received approval in these countries for treatment of OFF episodes.