Spontaneous Intracranial Hypotension: Case Report and Update on Diagnosis and Treatment.

Spontaneous intracranial hypotension (SIH) is an important cause of daily headaches that occur in young and middle-aged, active persons and is often misdiagnosed, leading to prolonged inactivity and rather high healthcare expenditures. Its diagnosis requires a high degree of clinical suspicion and careful interpretation of imaging studies. We present a case of SIH, which was successfully treated but which posed serious diagnostic challenges, ranging from cerebro-vascular disease and meningitis to granulomatous diseases, and for whom every therapeutic attempt just worsened the patient's condition until we finally reached the correct diagnosis. To raise awareness of this condition, we also present an updated overview of the clinical picture, evaluation, and treatment options for SIH.

Emerging antibody-based therapies for Huntington's disease: current status and perspectives for future development.

INTRODUCTION: Being an inherited neurodegenerative disease with an identifiable genetic defect, Huntington's disease (HD) is a suitable candidate for early intervention, possibly even in the pre-symptomatic stage. Our recent advances in elucidating the pathogenesis of HD have revealed a series of novel potential therapeutic targets, among which immunotherapies are actively pursued in preclinical experiments. AREAS COVERED: This review focuses on the potential of antibody-based treatments targeting various epitopes (of mutant huntingtin as well as phosphorylated tau) that are currently evaluated in vitro and in animal experiments. The references used in this review were retrieved from the PubMed database, searching for immunotherapies in HD, and clinical trial registries were reviewed for molecules already evaluated in clinical trials. EXPERT OPINION: Antibody-based therapies have raised considerable interest in a series of neurodegenerative diseases characterized by deposition of aggregated of aberrantly folded proteins, HD included. Intrabodies and nanobodies can interact with mutant huntingtin inside the nervous cells. However, the conflicting results obtained with some of these intrabodies highlight the need for proper choice of epitopes and for developing animal models more closely mimicking human disease. Approval of these strategies will require a considerable financial and logistic effort on behalf of healthcare systems.

The Involvement of Neuroinflammation in the Onset and Progression of Parkinson's Disease.

Parkinson's disease is a neurodegenerative disease exhibiting the fastest growth in incidence in recent years. As with most neurodegenerative diseases, the pathophysiology is incompletely elucidated, but compelling evidence implicates inflammation, both in the central nervous system and in the periphery, in the initiation and progression of the disease, although it is not yet clear what triggers this inflammatory response and where it begins. Gut dysbiosis seems to be a likely candidate for the initiation of the systemic inflammation. The therapies in current use provide only symptomatic relief, but do not interfere with the disease progression. Nonetheless, animal models have shown promising results with therapies that target various vicious neuroinflammatory cascades. Translating these therapeutic strategies into clinical trials is still in its infancy, and a series of issues, such as the exact timing, identifying biomarkers able to identify Parkinson's disease in early and pre-symptomatic stages, or the proper indications of genetic testing in the population at large, will need to be settled in future guidelines.

Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression.

Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.

Cholesterol Management in Neurology: Time for Revised Strategies?

Statin therapy has been extensively evaluated and shown to reduce the incidence of new or recurrent vascular events, ischemic stroke included. As a consequence, each published guideline pushes for lower low-density cholesterol levels in the population at large, recommending increased statin doses and/or adding new cholesterol-lowering molecules. Neurologists find it sometimes difficult to apply these guidelines, having to confront situations such as (1) ischemic strokes, mainly cardioembolic ones, in patients with already low LDL-cholesterol levels; (2) myasthenic patients, whose lifespan has been extended by available treatment, and whose age and cholesterol levels put them at risk for ischemic stroke; (3) patients with myotonic dystrophy, whose disease often associates diabetes mellitus and heart conduction defects, and in whom blood cholesterol management is also not settled. As such, further trials are needed to address these issues.

Stem Cell- and Cell-Based Therapies for Ischemic Stroke.

Stroke is the second cause of disability worldwide as it is expected to increase its incidence and prevalence. Despite efforts to increase the number of patients eligible for recanalization therapies, a significant proportion of stroke survivors remain permanently disabled. This outcome boosted the search for efficient neurorestorative methods. Stem cells act through multiple pathways: cell replacement, the secretion of growth factors, promoting endogenous reparative pathways, angiogenesis, and the modulation of neuroinflammation. Although neural stem cells are difficult to obtain, pose a series of ethical issues, and require intracerebral delivery, mesenchymal stem cells are less immunogenic, are easy to obtain, and can be transplanted via intravenous, intra-arterial, or intranasal routes. Extracellular vesicles and exosomes have similar actions and are easier to obtain, also allowing for engineering to deliver specific molecules or RNAs and to promote the desired effects. Appropriate timing, dosing, and delivery protocols must be established, and the possibility of tumorigenesis must be settled. Nonetheless, stem cell- and cell-based therapies for stroke have already entered clinical trials. Although safe, the evidence for efficacy is less impressive so far. Hopefully, the STEP guidelines and the SPAN program will improve the success rate. As such, stem cell- and cell-based therapy for ischemic stroke holds great promise.

The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer's Disease: Therapeutic Implications and Future Perspectives.

Alzheimer's disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.

Therapeutic Strategies in Huntington's Disease: From Genetic Defect to Gene Therapy.

Despite the identification of an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 1 as the genetic defect causing Huntington's disease almost 30 years ago, currently approved therapies provide only limited symptomatic relief and do not influence the age of onset or disease progression rate. Research has identified various intricate pathogenic cascades which lead to neuronal degeneration, but therapies interfering with these mechanisms have been marked by many failures and remain to be validated. Exciting new opportunities are opened by the emerging techniques which target the mutant protein DNA and RNA, allowing for "gene editing". Although some issues relating to "off-target" effects or immune-mediated side effects need to be solved, these strategies, combined with stem cell therapies and more traditional approaches targeting specific pathogenic cascades, such as excitotoxicity and bioavailability of neurotrophic factors, could lead to significant improvement of the outcomes of treated Huntington's disease patients.