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Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3–6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p<0·0001), and better functional outcome (p=0·010) than was no reperfusion. Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted. National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.

Emerging evidence suggests gut microbiota differences in Parkinson’s Disease (PD) may impact disease progression and treatment. Faecal Microbiota Transplantation (FMT) offers a potential therapeutic approach. We conducted an open-label pilot study to assess the safety, tolerability, and symptom impact of FMT in 12 patients with mild to moderate PD, administered via enema for 6 months. FMT was safe and well tolerated, causing only mild, transient gastrointestinal symptoms. While no significant motor symptom changes were observed, there was a trend toward reduced daily OFF time at 2 months. Whilst no sustained improvement in non-motor symptoms was found after 6 months, transient improvements in quality of life and non-motor scores were noted at 2 months; these gains regressed by study end. Overall, extended FMT therapy in PD appears safe and tolerable, with reduction in daily motor OFF time and self-reported non-motor symptoms that was not sustained throughout the 6-months of treatment

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (−2·75 [0·50] vs −0·96 [0·49] h; difference −1·79 h, −3·03 to −0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild–moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. AbbVie.

Background/ObjectivesThere are many different causes of hemichorea, including both structural and metabolic abnormalities. We describe a rare but reversible cause of hemichorea.MethodsA case report was written.ResultsAn 86-year-old male experienced recurrent subacute onset progressive left upper and lower limb hemichorea worsening over seven days. Prior to this, he experienced acute onset left upper and lower limb hemichorea two months ago which was attributed to diabetic striatopathy, despite lack of supportive MRI imaging (T1 MRI sequences of the basal ganglia was normal). His hemichorea was partially treatment responsive to antiglycaemic therapy and haloperidol.On examination, there was continuous irregular choreiform movements of the left arm and leg which resolved during sleep. The movements were not distractible. The rest of the neurological examination was grossly normal. His blood glucose levels were normal (7 mmol/L); however, serum magnesium was low (Mg 0.27 mmol/L). His hemichorea improved with magnesium replacement. His severe hypomagnesaemia was probably secondary to longterm proton pump inhibitor therapy for gasto-oesophageal reflux disease.Conclusions/DiscussionThis case demonstrates the importance of evaluating serum electrolytes for patients presenting with acute hemichorea.

Recent advances in our understanding of the phenomenology, etiology, pathophysiology, and treatment of Tourette syndrome are discussed. Tourette syndrome appears to involve dysfunction of limbic and somatosensory “traffic” through the basal ganglia, within corticostriatal-thalamocortical circuits. Dynamic alterations in the balance of these inputs may dictate the manifestations (sensory, motor, affective, and behavioral) of the disorder at any given time. Individualized assessment and treatment are the keys to optimal treatment of this condition.

Camptocormia is characterized by abnormal flexion of the thoracolumbar spine that increases during upright posture and abates in the recumbent position and has been reported to occur in patients with Parkinson disease. Camptocormia causes significant spinal and abdominal pain, impairment of balance, and social stigma. A 57-year-old woman with Parkinson disease developed severe camptocormia, which did not improve with trials of antiparkinsonian and muscle relaxant medications. The patient was successfully treated with bilateral globus pallidus interna deep brain stimulation surgery under general anesthesia. High-frequency neuromodulation afforded relief of camptocormia and improvement in Parkinson disease symptoms. Camptocormia in Parkinson disease may represent a form of dystonia and can be treated effectively with chronic pallidal neuromodulation.

Stroke thrombolysis with alteplase is currently recommended 0–4·5 h after stroke onset. We aimed to determine whether perfusion imaging can identify patients with salvageable brain tissue with symptoms 4·5 h or more from stroke onset or with symptoms on waking who might benefit from thrombolysis. In this systematic review and meta-analysis of individual patient data, we searched PubMed for randomised trials published in English between Jan 1, 2006, and March 1, 2019. We also reviewed the reference list of a previous systematic review of thrombolysis and searched ClinicalTrials.gov for interventional studies of ischaemic stroke. Studies of alteplase versus placebo in patients (aged ≥18 years) with ischaemic stroke treated more than 4·5 h after onset, or with wake-up stroke, who were imaged with perfusion-diffusion MRI or CT perfusion were eligible for inclusion. The primary outcome was excellent functional outcome (modified Rankin Scale [mRS] score 0–1) at 3 months, adjusted for baseline age and clinical severity. Safety outcomes were death and symptomatic intracerebral haemorrhage. We calculated odds ratios, adjusted for baseline age and National Institutes of Health Stroke Scale score, using mixed-effects logistic regression models. This study is registered with PROSPERO, number CRD42019128036. We identified three trials that met eligibility criteria: EXTEND, ECASS4-EXTEND, and EPITHET. Of the 414 patients included in the three trials, 213 (51%) were assigned to receive alteplase and 201 (49%) were assigned to receive placebo. Overall, 211 patients in the alteplase group and 199 patients in the placebo group had mRS assessment data at 3 months and thus were included in the analysis of the primary outcome. 76 (36%) of 211 patients in the alteplase group and 58 (29%) of 199 patients in the placebo group had achieved excellent functional outcome at 3 months (adjusted odds ratio [OR] 1·86, 95% CI 1·15–2·99, p=0·011). Symptomatic intracerebral haemorrhage was more common in the alteplase group than the placebo group (ten [5%] of 213 patients vs one [<1%] of 201 patients in the placebo group; adjusted OR 9·7, 95% CI 1·23–76·55, p=0·031). 29 (14%) of 213 patients in the alteplase group and 18 (9%) of 201 patients in the placebo group died (adjusted OR 1·55, 0·81–2·96, p=0·66). Patients with ischaemic stroke 4·5–9 h from stroke onset or wake-up stroke with salvageable brain tissue who were treated with alteplase achieved better functional outcomes than did patients given placebo. The rate of symptomatic intracerebral haemorrhage was higher with alteplase, but this increase did not negate the overall net benefit of thrombolysis. None.

ObjectivesTo characterize infusion site events (ISEs) in patients with advanced Parkinson’s disease (aPD) treated with foslevodopa/foscarbidopa (LDp/CDp).MethodsThis post hoc analysis was conducted in patients receiving LDp/CDp in a 12-week, phase 3, randomized study (NCT04380142). ISEs were recorded by investigators, including median time to onset/resolution and severity. Clinical management of presumed infusion site infections were summarised for the 3 most commonly reported preferred terms (infusion site infection, infusion site cellulitis, and infusion site abscess). Infections were presumed in most cases due to infrequently performed site cultures.ResultsOf 74 patients receiving LDp/CDp, infusion site reactions were reported in 46 (62.2%) and presumed infusion site infections in 21 (28.4%). Of these, most experienced infusion site reactions/infections that were mild or moderate in severity (45/46 [97.8%] and 20/21 [95.2%], respectively); 2 patients experienced serious infusion site infections. The median time to onset of infusion site reactions/infections was 5 and 32 days, respectively; median time to resolution was 7 and 18 days, respectively. Most patients who experienced ISEs continued LDp/CDp. Roughly half of presumed infections were empirically treated with oral antibiotics and resolved with or without treatment.ConclusionsPresumed infusion site infections represented a small subset of ISEs; most were non-serious, mild to moderate in severity, did not result in discontinuation, and resolved with or without antibiotics. Better outcomes may result when patients/care partners use aseptic techniques, rotate infusion sites more often than every third day, use a new infusion set upon changes in the skin, and monitor for early infection signs.

Abstract BACKGROUND AND IMPORTANCE: Camptocormia is characterized by abnormal flexion of the thoracolumbar spine that increases during upright posture and abates in the recumbent position and has been reported to occur in patients with Parkinson disease. Camptocormia causes significant spinal and abdominal pain, impairment of balance, and social stigma. CLINICAL PRESENTATION: A 57-year-old woman with Parkinson disease developed severe camptocormia, which did not improve with trials of antiparkinsonian and muscle relaxant medications. The patient was successfully treated with bilateral globus pallidus interna deep brain stimulation surgery under general anesthesia. High-frequency neuromodulation afforded relief of camptocormia and improvement in Parkinson disease symptoms. CONCLUSION: Camptocormia in Parkinson disease may represent a form of dystonia and can be treated effectively with chronic pallidal neuromodulation.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb + ) children and adults who are at risk of (confirmed single IAb + ) or living with (multiple IAb + ) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb + ; (2) when people who are IAb + are initially identified there is a need for confirmation using a second sample; (3) single IAb + individuals are at lower risk of progression than multiple IAb + individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care. Graphical Abstract