A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1ß, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

Predictive Factors of Antiparkinsonian Drug Reduction after Subthalamic Stimulation for Parkinson's Disease.

Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor symptoms in individuals with advanced Parkinson's disease (PD) and enables physicians to reduce doses of antiparkinsonian drugs. We investigated possible predictive factors for the successful reduction of antiparkinsonian drug dosage after STN-DBS. We evaluated 33 PD patients who underwent bilateral STN-DBS. We assessed rates of reduction of the levodopa-equivalent daily dose (LEDD) and levodopa daily dose (LDD) by comparing drug doses before vs. 6-months post-surgery. We used correlation coefficients to measure the strength of the relationships between LEDD and LDD reduction rates and preoperative factors including age, disease duration, preoperative LEDD and LDD, unified Parkinson's Disease Rating Scale part-II and -III, levodopa response rate, Mini-Mental State Examination score, dyskinesia score, Hamilton Rating Scale for depression, and the number of non-motor symptoms. The average LEDD and LDD reduction rates were 61.0% and 70.4%, respectively. Of the variables assessed, only the number of psychiatric/cognitive symptoms was significantly correlated with the LEDD reduction rate. No other preoperative factors were correlated with the LEDD or LDD reduction rate. A wide range of preoperative psychiatric and cognitive symptoms may predict the successful reduction of antiparkinsonian drugs after STN-DBS.

Cervical Myelopathy Caused by Intracranial Dural Arteriovenous Fistula with Acute Worsening After Steroid Administration.

Intracranial dural arteriovenous fistulas (DAVFs) draining into the perimedullary venous system are rare and potentially life-threatening lesions often presenting as a myelopathy. The early and proper diagnosis of this rare disease is challenging because the symptoms are nonspecific. Acute clinical deterioration in patients with spinal DAVFs treated with steroid administration has been described. Here we report a case of cervical myelopathy caused by intracranial DAVF with acute worsening after steroid administration. The lesion was successfully treated with endovascular Onyx embolization.

[Peripheral neuropathy as a side effect of chemotherapy and targeted therapy]. / Chemotherapie-induzierte periphere Neuropathie.

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and common side effect induced by a variety of anticancer drugs. CIPN presents as a sensory, motor, and sometimes autonomic dysfunction with a large variability, from a mild tingling sensation and hyperesthesia, to severe neuropathic pain. Up to 40 % of patients will develop CIPN which may lead to dose-reduction or discontinuation of their current treatment and largely affects their quality of life (QoL). This review presents specific clinical features and pathomechanisms and discusses current preventive strategies and therapeutic options.

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has neuroprotective effects in preclinical models of Parkinson's disease. We investigated whether these effects would be apparent in a clinical trial. METHODS: In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25-75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. The study is registered at ClinicalTrials.gov (NCT01971242) and is completed. FINDINGS: Between June 18, 2014, and March 13, 2015, 62 patients were enrolled and randomly assigned, 32 to exenatide and 30 to placebo. Our primary analysis included 31 patients in the exenatide group and 29 patients in the placebo group. At 60 weeks, off-medication scores on part 3 of the MDS-UPDRS had improved by 1·0 points (95% CI -2·6 to 0·7) in the exenatide group and worsened by 2·1 points (-0·6 to 4·8) in the placebo group, an adjusted mean difference of -3·5 points (-6·7 to -0·3; p=0·0318). Injection site reactions and gastrointestinal symptoms were common adverse events in both groups. Six serious adverse events occurred in the exenatide group and two in the placebo group, although none in either group were judged to be related to the study interventions. INTERPRETATION: Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials. FUNDING: Michael J Fox Foundation for Parkinson's Research.

Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

Effect of Antipsychotic Type and Dose Changes on Tardive Dyskinesia and Parkinsonism Severity in Patients With a Serious Mental Illness: The Curaçao Extrapyramidal Syndromes Study XII.

OBJECTIVE: To test the efficacy of current treatment recommendations for parkinsonism and tardive dyskinesia (TD) severity in patients with severe mental illness (SMI). METHODS: We present an 18-year prospective study including all 223 patients with SMI (as defined by the 1987 US National Institute of Mental Health, which were based on DSM-III-R diagnostic criteria) receiving care from the only psychiatric hospital of the former Netherlands Antilles. Eight clinical assessments (1992-2009) focused on movement disorders and medication use. Tardive dyskinesia was measured by the Abnormal Involuntary Movement Scale and parkinsonism by the Unified Parkinson's Disease Rating Scale. Antipsychotics were classified into first-generation antipsychotic (FGA) versus second-generation antipsychotic (SGA) and high versus low dopamine 2 (D2) affinity categories. The effect that switching has within each category on subsequent movement scores was calculated separately by using time-lagged multilevel logistic regression models. RESULTS: There was a significant association between reduction in TD severity and starting/switching to an FGA (B = -3.54, P < .001) and starting/switching to a high D2 affinity antipsychotic (B = -2.49, P < .01). Adding an SGA to existing FGA treatment was associated with reduction in TD severity (B = -2.43, P < .01). For parkinsonism, stopping antipsychotics predicted symptom reduction (B = -7.76, P < .01 in FGA/SGA-switch model; B = -7.74, P < .01 in D2 affinity switch model), while starting a high D2 affinity antipsychotic predicted an increase in symptoms (B = 3.29, P < .05 in D2 affinity switch model). CONCLUSIONS: The results show that switching from an FGA to an SGA does not necessarily result in a reduction of TD or parkinsonism. Only stopping all antipsychotics reduces the severity of parkinsonism, and starting an FGA or a high D2 affinity antipsychotic may reduce the severity of TD.

Subcutaneous interferon ß-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study.

OBJECTIVE: Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) ß-1a 44 µg in patients with an FCDE up to 60 months postrandomisation. METHODS: Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN ß-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported. RESULTS: 402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN ß-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN ß-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies. CONCLUSIONS: Over 5 years in patients presenting with an FCDE, early sc IFN ß-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity. TRIAL REGISTRATION NUMBER: NCT00813709; Results.

[Reversible posterior leukoencephalopathy syndrome in a patient presenting granulomatosis with polyangiitis]. / Syndrome d'encéphalopathie postérieure réversible au cours d'une granulomatose avec polyangéite.

BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is characterised by clinical neurological features of sudden onset and brain MRI findings such as T2/Flair white matter hyperintensities. RPLS can occur in autoimmune diseases, and rarely in systemic vasculitis. We report a case of RPLS in a woman presenting granulomatosis with polyangiitis (Wegener's granulomatosis). PATIENTS AND METHODS: A 22-year-old female patient was treated with methylprednisolone pulses for granulomatosis with polyangiitis and neurological impairment. A few hours after the second pulse, the patient had seizures, blindness and confusion associated with high blood pressure and acute renal failure. MRI revealed a high-intensity area on T2-Flair weighted images of the occipital-temporal lobes. The patient was treated with antiepileptic and antihypertensive medications, oral steroids and cyclophosphamide; the clinical and radiological findings proved reversible over the ensuing days. DISCUSSION: The occurrence of RPLS in systemic vasculitis is rare. Six cases of RPLS associated with granulomatosis and polyangiitis have been reported. It appears important to screen for high blood pressure in patients recently treated with corticosteroids for vasculitis as this condition may represent a precipitating factor for RPLS.

Sex-Specific Alterations of White Matter Developmental Trajectories in Infants With Prenatal Exposure to Methamphetamine and Tobacco.

IMPORTANCE: Methamphetamine is a common illicit drug used worldwide. Methamphetamine and/or tobacco use by pregnant women remains prevalent. However, little is known about the effect of comorbid methamphetamine and tobacco use on human fetal brain development. OBJECTIVE: To investigate whether microstructural brain abnormalities reported in children with prenatal methamphetamine and/or tobacco exposure are present at birth before childhood environmental influences. DESIGN, SETTING, AND PARTICIPANTS: A prospective, longitudinal study was conducted between September 17, 2008, and February 28, 2015, at an ambulatory academic medical center. A total of 752 infant-mother dyads were screened and 139 of 195 qualified neonates were evaluated (36 methamphetamine/tobacco exposed, 32 tobacco exposed, and 71 unexposed controls). They were recruited consecutively from the community. EXPOSURES: Prenatal methamphetamine and/or tobacco exposure. MAIN OUTCOMES AND MEASURES: Quantitative neurologic examination and diffusion tensor imaging performed 1 to 3 times through age 4 months; diffusivities and fractional anisotropy (FA) assessed in 7 white matter tracts and 4 subcortical brain regions using an automated atlas-based method. RESULTS: Of the 139 infants evaluated, 72 were female (51.8%); the mean (SE) postmenstrual age at baseline was 41.5 (0.27) weeks. Methamphetamine/tobacco-exposed infants showed delayed developmental trajectories on active muscle tone (group × age, P < .001) and total neurologic scores (group × age, P = .01) that normalized by ages 3 to 4 months. Only methamphetamine/tobacco-exposed boys had lower FA (group × age, P = .02) and higher diffusivities in superior (SCR) and posterior corona radiatae (PCR) (group × age × sex, P = .002; group × age × sex, P = .01) at baseline that normalized by age 3 months. Only methamphetamine/tobacco- and tobacco-exposed girls showed persistently lower FA in anterior corona radiata (ACR) (group, P = .04; group × age × sex, P = .01). Tobacco-exposed infants showed persistently lower axial diffusion in the thalamus and internal capsule across groups (P = .02). CONCLUSIONS AND RELEVANCE: Prenatal methamphetamine/tobacco exposure may lead to delays in motor development, with less coherent fibers and less myelination in SCR and PCR only in male infants, but these abnormalities may normalize by ages 3 to 4 months after cessation of stimulant exposure. In contrast, persistently less coherent ACR fibers were observed in methamphetamine/tobacco- and tobacco-exposed girls, possibly from increased dendritic branching or spine density due to epigenetic influences. Persistently lower diffusivity in the thalamus and internal capsule of all tobacco-exposed infants suggests aberrant axonal development. Collectively, prenatal methamphetamine and/or tobacco exposure may lead to delayed motor development and white matter maturation in sex- and regional-specific manners.

Potentially Serious Drug-Drug Interactions in Older Patients Hospitalized for Acute Ischemic and Hemorrhagic Stroke.

BACKGROUND: Polypharmacy is very common in older persons and it is associated with inappropriate prescribing and potential drug-drug interactions (DDIs). Aims of this study were to identify prevalence of DDIs in older persons with acute stroke and to evaluate the association between stroke and DDIs. METHODS: One hundred forty-six patients admitted with diagnosis of acute stroke were enrolled. The therapeutic regimen of patients was analyzed at admission to identify the number of DDIs, prevalence and sorts of serious DDIs according to subtype of acute stroke (ischemic or hemorrhagic) and to its recurrence. RESULTS: Five hundred eighty-two DDIs were identified: 18 mild, 415 moderate and 149 serious. Sixty-one percent of patients were exposed to at least one serious DDI. A higher percentage of patients were exposed to at least one serious DDI among those with a recurring ischemic event compared to those with a first event (74 vs. 50%; p < 0.01, respectively). Serious DDIs potentially associated with an increased risk of a cerebral event were identified in 19 (17%) patients with ischemic stroke, and in 7 (19%) patients with hemorrhagic stroke. CONCLUSIONS: The prevalence of serious DDIs was high in aging patients with acute stroke but different according to subtype and recurrence of the cerebrovascular event.

Effects of a 30-mL Epidural Normal Saline Bolus on Time to Full Motor Recovery in Parturients Who Received Patient-Controlled Epidural Analgesia With 0.125% Bupivacaine With 2 µg/mL of Fentanyl.

Previous research suggests that an epidural bolus of 30 mL of normal saline after vaginal delivery may decrease the time for recovery from motor block. A double-blind, randomized controlled study was conducted in 46 parturients to determine if a 30-mL normal saline bolus or sham administered via epidural approach after delivery reduces the time to full motor recovery and the time to 2-dermatome regression. No significant difference was found in time to full motor recovery (saline group 83.18 ± 54 minutes vs control group 100.23 ± 48 minutes, P = .27) or time to 2-dermatome sensory regression (saline group 29.32 ± 16.35 minutes vs control group 36.14 ± 14.39 minutes, P = .15). Results suggest no advantage to the administration of a saline bolus after delivery to hasten the motor recovery in parturients. A post hoc power analysis suggested a sample size of 204 subjects would have been needed to show a difference for this dilute local anesthetic regimen. There were no complications to the technique, which suggests that it is safe to perform, but the difference in recovery (approximately 17 minutes) from a dilute local anesthetic dose may not be clinically significant.

[Practical Use of the Levodopa Pump]. / Praktische Anwendung der Levodopa-Pumpe.

Patients with advanced Parkinson's disease and motor complications undergoing optimized oral therapy can significantly benefit from continuous intrajejunal levodopa/carbidopa infusion applied by means of a medication pump. However, this requires a correctly positioned PEG-J tube and finely adjusted pump settings. Although this method is a routine procedure in specialist centers, no standard procedure has been defined up to now. For this reason, an expert recommendation regarding the practical application has been developed in order to standardize the procedure and facilitate patient access to this treatment option.

Complications after spinal anesthesia in adult tethered cord syndrome.

Since little has been reported about complications of spinal anesthesia in adult tethered cord syndrome (TCS), we sought to delineate the characteristics of the condition.A total of 4 cases of adult TCS after spinal anesthesia were reviewed. The medical charts of the patients were obtained. Anesthesia, which was combined spinal and epidural anesthesia or spinal anesthesia was performed, and follow-up were carried out in all patients.The most common neurological symptom of adult TCS before surgery was occasional severe pain in back, perineal region, or legs. Frequent micturition, diminished knee and ankle reflexes, and difficulty in bending were exhibited in partial patients. Paraesthesia of perineal region or/and lower extremities existed 2 to 3 days after spinal anesthesia in all the cases. Weakness of lower extremities existed in 1 case. Lumbar magnetic resonance imaging showed the low location of conus medullaris. At follow-up, 3 cases recovered completely within 3 weeks, and 1 case underwent permanent disability.These cases suggest anesthesiologists and surgeons alert to the association of adult TCS and spinal anesthesia. Spinal anesthesia should be prohibited in patients with adult TCS to prevent neurological damages.

Akinetic crisis in dementia with Lewy bodies.

BACKGROUND AND PURPOSE: Dementia with Lewy bodies (DLB) is characterised by neuroleptic hypersensitivity. It is unclear, however, whether the neuroleptic hypersensitivity implies an increased incidence of neuroleptic malignant syndrome (NMS) or of akinetic crisis (AC), which are expressions of the same possibly lethal clinical event, and whether AC in DLB can appear independently of neuroleptic treatment. In our prospective study, we assessed the incidence of AC in a cohort of DLB as compared with that in patients with Parkinson disease (PD). METHODS: In total, 614 patients with PD and 236 DLB were recruited and followed during 2005-2013. AC was diagnosed as sudden akinetic state unresponsive to dopaminergic rescue drugs, dysphagia and serological alterations without recovery for 48 h or more requiring hospital admission. Exposure to neuroleptics was specifically evaluated, because of the high implicit risk in DLB. RESULTS: 24 patients with PD (3.9%) and 16 patients with DLB (6.8%) developed AC. 77 (32.6%) DLB and 32 (5.2%) PD were exposed to typical neuroleptics, but only 8 DLB and 3 PD presented with AC. Disease duration before AC was lower in DLB than in PD group (p<0.01). Outcome was fatal in 8 patients with (50%) DLB and 3 (12.5%) PD (p=0.05). When age and use of neuroleptics were adjusted for into a Cox proportional hazards model predicting time to AC, the HR of patients with DLB was 13.0 (95% CI 4.23 to 39.9; p<0.001). CONCLUSIONS: AC in DLB can appear independently of neuroleptic treatment, occurs earlier and is more frequently fatal than in PD.

The Effectiveness of Aripiprazole for Tics, Social Adjustment, and Parental Stress in Children and Adolescents with Tourette's Disorder.

OBJECTIVE: Tourette's syndrome (TS) frequently results in a negative impact on multiple functional domains. This prospective open-label study investigated the potential effectiveness of aripiprazole for tics, social adjustment, and parental stress in children and adolescents with TS. METHODS: Study participants consisted of 26 patients (mean age 10.4 ± 3.0 years; 22 boys and 4 girls) who were prescribed aripiprazole, with each dose ranging from 2.5 to 15 mg/day. At baseline and 2, 4, and 8 weeks from baseline, tic symptoms, social adjustment, and parenting stress were assessed using the Yale Global Tic Severity Scale (YGTSS), the Social Adjustment Inventory for Children and Adolescents (SAICA), and the Parenting Stress Index (PSI). Aripiprazole could be optionally titrated from 2.5 to 30 mg/day at each visit. RESULTS: Of the 26 patients at the initial visit, 22 (84.6%) completed the study. The mean dose of aripiprazole at the endpoint was 8.0 ± 4.0 mg/day. During the 8-week aripiprazole treatment period, motor tics, phonic tics, and impairment on the YGTSS all showed significant improvement. Home behaviors on the SAICA and child domain on the PSI also showed significant improvement. Patients' phonic tics, but not motor tics, showed a positive correlation with their school function and peer relationships. The child domain on the PSI was positively correlated with motor tics, phonic tics, and impairment, as measured by the YGTSS. CONCLUSIONS: An 8-week aripiprazole treatment program for children and adolescents with TS was beneficial to their tic symptoms, behaviors at home, and caregivers' stress with regard to fulfilling parenting roles. A long-term placebo-controlled trial with larger samples is warranted to confirm the effectiveness of aripiprazole for social adjustment and parental stress.

Traditional Chinese Patent Medicine for Acute Ischemic Stroke: An Overview of Systematic Reviews Based on the GRADE Approach.

The aim of the study is to conduct an overview of systematic reviews (SRs) to provide a contemporary review of the evidence for delivery of Traditional Chinese Patent Medicine (TCPMs) for patients with acute ischemic stroke.SRs were assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) tool and the Oxman-Guyatt Overview Quality Assessment Questionnaire (OQAQ). We assessed the quality of the evidence of high methodological quality (an AMSTAR score ≥9 or an OQAQ score ≥7) for reported outcomes using the GRADE (the Grading of Recommendations Assessment, Development and Evaluation) approach.(1) Dan Shen agents: tiny trends toward the improvement in different neurological outcomes (RR = 1.16, 1.10, 1.23, 1.08, 1.12); (2) Mailuoning: a tiny trend toward improvement in the neurological outcome (RR = 1.18); (3) Ginkgo biloba: tiny trends toward improvement in the neurological outcome (RR = 1.18, MD = 0.81); (4) Dengzhanhua: a tiny trend toward an improvement in neurological (RR = 1.23); (5) Acanthopanax: a small positive (RR = 1.17, 1.31) result on neurological improvement reported; (6) Chuanxiong-type preparations: neurological functional improved (MD = 2.90);(7) Puerarin: no better effect on the rate of death or disability (OR = 0.81, 95% CI 0.35-1.87); (8) Milk vetch: no better effect on the rate of death (OR = 0.66, 95% CI: 0.11-2.83);(9) Qingkailing: rate of death reduced (OR = 0.66, 95% CI: 0.11-2.83). Limitations in the methodological quality of the RCTs, inconsistency and imprecision led to downgrading of the quality of the evidence, which varied by review and by outcome. Consequently, there are currently only weak evidences to support those TCPMs.The 9 TCPMs may be effective in the treatment of acute ischemic stroke, as the GRADE approach indicated a weak recommendation for those TCPMs' usage.

Effectiveness and Tolerability of Aripiprazole in Children and Adolescents with Tourette's Disorder: A Meta-Analysis.

OBJECTIVE: Aripiprazole, an atypical antipsychotic drug, has shown potential as a promising candidate for the treatment of Tourette's disorder (TD). However, the effectiveness and the tolerability profile of aripiprazole in the reduction of tics in children and adolescents with TD have not been systematically analyzed. This meta-analysis aimed to evaluate the effectiveness and tolerability of aripiprazole in children and adolescents with TD. METHODS: We searched for clinical trials that investigated the effect of aripiprazole in children and adolescents with TD in PubMed and Web of Science. The outcomes of interest comprised the Yale Global Tic Severity Score (YGTSS) total tic scores and the Clinical Global Impressions Scale for Tic Severity (CGI-S) scores. The pooled effect size (ES) and 95% confidence interval (CI) were calculated to assess the effectiveness of aripiprazole in children and adolescents with TD. RESULTS: Ten studies were retrieved from 122 citations for the analysis, and in total, 302 patients (mean age, 11.6 years; median follow-up, 9 weeks) were included in the analysis. After synthesis of the data, the meta-analysis showed significantly greater improvement in the mean change in the YGTSS total tic scores (ES = -1.99, 95% CI = [-2.26]-[-1.72]; p = 0.001) and the mean CGI-S scores (ES = -2.34, 95% CI = [-2.96]-[-1.73]; p = 0.001) from pretreatment to posttreatment. Adverse events were reported in nine trials. Drowsiness (28.5%), nausea (20.2%), and headache (13.8%) were common adverse events. CONCLUSIONS: The use of aripiprazole is safe, and shows therapeutic effectiveness in children and adolescents with TD.

[Anticonvulsive Therapy after the First Unprovoked Seizure ­ Pros and Cons]. / Antikonvulsive Therapie nach dem ersten epileptischen Anfall - pro und contra.

A first seizure is a critical life time event with severe consequences. A very thorough work-up is needed to find out the cause of the seizure and to number the risk of recurrence. Reasons for an anticonvulsive therapy are a pathologic EEG, a pathologic neurologic examination, the proof of a structural lesion, focal seizure onset or seizure onset while sleeping or classification as an epilepsy syndrome with high recurrence risk like juvenile myoclonic epilepsy or juvenile absence epilepsy. Psychological and social aspects like the patients or relatives fear of a further seizure, the risk of injury and occupational and recreational aspects must be considered as well. Reasons against an anticonvulsive therapy are mainly related to adverse effects like gain of weight and osteoporosis.