Inotersen to Treat Polyneuropathy Associated with Hereditary Transthyretin (hATTR) Amyloidosis.

Background: Amyloidosis is a group of diseases with the common pathophysiology of protein misfolding and aberrant deposition in tissue. There are both acquired and hereditary forms of this disease, and this review focuses on the latter hereditary transthyretin-mediated (hATTR). hATTR affects about 50,000 individuals globally and mostly appears as one of three syndromes - cardiac, polyneuropathy, and oculoleptomeningeal. Polyneuropathy is the most common form, and there is usually some overlap in individual patients. Results: Recently, novel therapeutic options emerged in the form of groundbreaking drugs, Patisiran and Inotersen, small interfering RNA molecules that target TTR and reduce the production of this protein. By targeting TTR mRNA transcripts, Inotersen decreases protein translation and production, reducing the deposition of misfolded proteins. It was shown to be both effective and safe for use and specifically formulated to concentrate in the liver - where protein production takes place. Conclusion: hATTR is a rare, progressive, and debilitating disease. Its most common presentation is that of polyneuropathy, and it carries a very poor prognosis and a natural history conveying a median survival of < 12 years. Novel therapeutic options are groundbreaking by providing disease-modifying specific, targeted therapies against TTR production and deposition. The use of RNA interference (RNAi) opens the door to the treatment of hereditary diseases by targeting them at the genetic level.

Ischemic brain infarcts and vasculitis in histoplasmosis of the central nervous system: A case report and review of the literature.

Histoplasmosis is one of the most common endemic mycoses affecting immunocompromised individuals in the United States and Latin America. Involvement of the central nervous system carries higher mortality rates and worse prognosis, given its resemblance to stroke, vasculitis, and meningitis of other etiologies. The diagnosis is challenging, due to its subtle clinical presentation and the poor sensitivity of the cerebrospinal fluid culture. Herein the authors present a case of a middle-aged man with HIV, who presented with intermittent headaches exacerbated by an oculomotor nerve palsy, concerning for acute stroke. A diagnosis of central nervous system histoplasmosis was made, and his neurological deficits subsided after initiation of treatment. The stroke-like syndrome in this scenario may be secondary to granulomatous vasculitis of small caliber cerebral blood vessels. Histoplasmosis of the central nervous system remains a challenging diagnosis, which requires a high index of suspicion by the clinician for an early institution of therapy in order to improve outcomes.

Endovascular Therapy in Mild Ischemic Strokes Presenting Under 6 hours: An International Survey.

BACKGROUND: Endovascular therapy (EVT) for patients with mild ischemic stroke (NIHSS ≤5) and visible intracranial occlusion remains controversial, including within 6 hours of symptom onset. We conducted a survey to evaluate global practice patterns of EVT in this population. METHODS: Vascular stroke clinicians and neurointerventionalists were invited to participate through professional stroke listservs. The survey consisted of six clinical vignettes of mild stroke patients with intracranial occlusion. Cases varied by NIHSS, neurological symptoms and occlusion site. All had the same risk factors, time from symptom onset (5h) and unremarkable head CT. Advanced imaging data was available upon request. We explored independent case and responder specific factors associated with advanced imaging request and EVT decision. RESULTS: A total of 482/492 responders had analyzable data ([median age 44 (IQR 11.25)], 22.7% women, 77% attending, 22% interventionalist). Participants were from USA (45%), Europe (32%), Australia (12%), Canada (6%), and Latin America (5%). EVT was offered in 48% (84% M1, 29% M2 and 19% A2) and decision was made without advanced imaging in 66% of cases. In multivariable analysis, proximal occlusion (M1 vs. M2 or A2, p<0.001), higher NIHSS (p<0.001) and fellow level training (vs. attending; p=0.001) were positive predictors of EVT. Distal occlusions (M2 and A2) and higher age of responders were independently associated with increased advanced imaging requests. Compared to US and Australian responders, Canadians were less likely to offer EVT, while those in Europe and Latin America were more likely (p<0.05). CONCLUSIONS: Treatment patterns of EVT in mild stroke vary globally. Our data suggest wide equipoise exists in current treatment of this important subset of mild stroke.