The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial.

INTRODUCTION: Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. METHODS: The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0-2 vs. 3-6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. RESULTS: The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0-2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). CONCLUSION: GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. TRIAL REGISTRATION: EudraCT-Nr. 2005-003201-81.

Outcome of heparin-treated patients with acute cerebral venous sinus thrombosis: influence of the temporal pattern of intracerebral haemorrhage.

BACKGROUND AND PURPOSE: The influence of temporal patterns of intracerebral haemorrhage (ICH) on the outcome of heparin-treated patients with cerebral venous sinus thrombosis (CVST) has not been examined systematically. METHODS: Temporal patterns of ICH and their influence on survival without disability (modified Rankin Scale score ≤1 point) at hospital discharge were examined in 141 consecutive hospital-admitted patients with acute CVST who were treated with intravenous unfractionated heparin. RESULTS: Of all 141 patients (median age 40 years; 73% women), 59 (42%) had ICH at the time of diagnosis (early ICH). Of these, seven (12%) subsequently had extension of ICH and 13 (22%) had additional ICHs at other locations (delayed ICH). Of 82 patients without early ICH, nine (11%) later had delayed ICH. After a median hospital stay of 26 days, 107 patients (76%) were discharged without disability. Patients with early ICH were less likely to survive without disability until discharge than those without early ICH [63% vs. 85%; risk ratio (RR) 0.73; P = 0.005]. The association was attenuated after adjusting for age, sex and impaired consciousness on admission (RR 0.83; P = 0.03). Taking temporal patterns of ICH into account, early ICH with subsequent complication (extension or delayed ICH) had a larger influence on survival without disability (RR 0.57; 95% confidence interval 0.35-0.95) than early ICH without complications (RR 0.78; 95% confidence interval 0.67-0.91). CONCLUSIONS: Heparin-treated CVST patients were less likely to survive without disability when ICH was present on admission. This association may largely be driven by subsequent extension of haemorrhage or additionally occurring delayed haemorrhage.

EFNS guideline on the treatment of cerebral venous and sinus thrombosis in adult patients.

BACKGROUND: Cerebral venous and sinus thrombosis (CVST) is a rather rare disease which accounts for <1% of all strokes. Diagnosis is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often subacute or lingering onset. Current therapeutic measures which are used in clinical practice include the use of anticoagulants such as dose-adjusted intravenous heparin or body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH), the use of thrombolysis and symptomatic therapy including control of seizures and elevated intracranial pressure. METHODS: We searched MEDLINE (National Library of Medicine), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Library to review the strength of evidence to support these interventions and the preparation of recommendations on the therapy of CVST based on the best available evidence. Review articles and book chapters were also included. Recommendations were reached by consensus. Where there was a lack of evidence but consensus was clear we stated our opinion as good practice points. RESULTS AND CONCLUSIONS: Patients with CVST without contraindications for anticoagulation (AC) should be treated either with body weight-adjusted subcutaneous LMWH or with dose-adjusted intravenous heparin (level B recommendation). Concomitant intracranial haemorrhage (ICH) related to CVST is not a contraindication for heparin therapy. The optimal duration of oral anticoagulant therapy after the acute phase is unclear. Oral AC may be given for 3 months if CVST was secondary to a transient risk factor, for 6-12 months in patients with idiopathic CVST and in those with "mild" thrombophilia, such as heterozygous factor V Leiden or prothrombin G20210A mutation and high plasma levels of factor VIII. Indefinite AC should be considered in patients with recurrent episodes of CVST and in those with one episode of CVST and 'severe' thrombophilia, such as antithrombin, protein C or protein S deficiency, homozygous factor V Leiden or prothrombin G20210A mutation, antiphospholipid antibodies and combined abnormalities (good practice point). There is insufficient evidence to support the use of either systemic or local thrombolysis in patients with CVST. If patients deteriorate despite adequate AC and other causes of deterioration have been ruled out, thrombolysis may be a therapeutic option in selected cases, possibly in those without large ICH and threatening herniation (good practice point). There are no controlled data about the risks and benefits of certain therapeutic measures to reduce an elevated intracranial pressure (with brain displacement) in patients with severe CVST. However, in severe cases with impending herniation craniectomy can be used as a life-saving intervention (good practice point).

Inconsistent trial assessments by the National Institute for Health and Clinical Excellence and IQWiG: standards for the performance and interpretation of subgroup analyses are needed.

OBJECTIVES: The methodology for the critical assessment of medical interventions is well established. Regulatory agencies and institutions adhere, in principle, to the same standards. This consistency, however, is not always the case in practice. STUDY DESIGN AND SETTING: Using the evaluation of the CAPRIE (Clopidogrel versus Aspirin in Patients at risk of Ischemic Events) trial by the British National Institute for Health and Clinical Excellence (NICE) and the German Institute for Quality and Efficiency in Health Care (IQWiG), we illustrate that there was no consensus for the interpretation of possible heterogeneity in treatment comparisons across subgroups. RESULTS: The NICE concluded that CAPRIE demonstrated clinical benefit for the overall intention-to-treat (ITT) population with sufficient robustness to possible sources of heterogeneity. The IQWiG interpreted the alleged heterogeneity as implying that the clinical benefit only applied to the subgroup of patients with a statistically significant result irrespective of the results of the ITT analysis. CONCLUSION: International standards for the performance and interpretation of subgroup analyses as well as for the assessment of heterogeneity between strata are needed.

Prevalence of stroke and stroke symptoms: a population-based survey of 28,090 participants.

BACKGROUND: Stroke is associated with a considerable burden of disease worldwide. Data about prevalence needs regular updating to facilitate health care planning and resource allocation. The purpose of the present study was to determine stroke prevalence in a large urban population in an easy and reliable way. METHODS: In a population survey a total of 75,720 households with at least 1 person >or=50 years received information about stroke symptoms by mail. In addition, the Stroke Symptom Questionnaire assessing the prevalence of stroke and of stroke symptoms was sent. Stroke prevalence was determined by a single physician-diagnosed stroke-screening question or by the combination of the latter with reported visual impairment and/or articulation problems in the past. RESULTS: A total of 28,090 persons responded (37.5%). Mean (+/-SD) age was 64.4 +/- 9.7 years, 62.9 +/- 8.9 for men (43.3%), and 65.5 +/- 10.2 for women. Of all participants 2.7% reported impaired vision, 2.8% facial weakness, 2.8% articulation problems, 3.9% limb weakness, and 5% sensory disturbances. A total of 4.5% reported a physician-diagnosed stroke (women 4.3%; men 4.9%). Combining reported stroke history with reported impaired vision and/or articulation problems, the prevalence of stroke increased to 7.6% (men 8.4%; women 7.2%). Factors associated with higher prevalence were higher age, male gender, non-German nationality, lower education, positive family history of stroke, and living alone. CONCLUSIONS: The combination of questions concerning a prior stroke and stroke symptoms is a useful and easy approach to assess prevalence. It results in prevalence numbers which might compensate for an underestimation of stroke numbers.

Treatment of cerebral venous and sinus thrombosis.

Cerebral venous and sinus thrombosis (CVST) is a rather rare disease which accounts for less than 1% of all strokes. Current therapeutic measures which are used in clinical practice include the use of anticoagulants such as dose-adjusted intravenous heparin or body weight-adjusted subcutaneous low molecular weight heparin, the use of thrombolysis, and symptomatic therapy including control of seizures and elevated intracranial pressure. We reviewed the strength of evidence reported in the literature to support these interventions and provide treatment recommendations based on the best available evidence. Patients with CVST without contraindications for anticoagulation (AC) should be treated either with body weight-adjusted subcutaneous low molecular weight heparin or dose-adjusted intravenous heparin. Concomitant intracranial hemorrhage related to CVST is not a contraindication for heparin therapy. The optimal duration of oral AC after the acute phase is unclear. Oral AC may be given for 3 months if CVST was secondary to a transient risk factor, for 6-12 months in patients with idiopathic CVST and in those with 'mild' hereditary thrombophilia. Indefinite AC should be considered in patients with two or more episodes of CVST and in those with one episode of CVST and 'severe' hereditary thrombophilia. There is insufficient evidence to support the use of either systemic or local thrombolysis in patients with CVST. If patients deteriorate despite adequate AC and other causes of deterioration have been ruled out, thrombolysis may be a therapeutic option in selected cases, possibly in those without intracranial hemorrhage. There are no controlled data about the risks and benefits of certain therapeutic measures to reduce an elevated intracranial pressure (with brain displacement) in patients with severe CVST. Anti-edema treatment (including hyperventilation, osmotic diuretics, craniectomy) should be used as life-saving interventions.

Risk and predictors of early epileptic seizures in acute cerebral venous and sinus thrombosis.

We assessed the risk and determined predictors of early epileptic seizures (ES) in patients with acute cerebral venous and sinus thrombosis (CVST). A prospective series of 194 consecutive patients with acute CVST admitted to neurological wards in two German university hospitals was analysed for frequency of ES and in-hospital mortality. Demographic, clinical and radiological characteristics during the acute stage were retrospectively analysed for significant association with ES in univariate and multivariate analyses. During the acute stage, 19 patients (9.8%) died. Early symptomatic seizures were found in 86 patients (44.3%). Status epilepticus occurred in 11 patients (12.8%) of whom four died. Amongst patients with epileptic seizures, mortality was three times higher in those with status than in those without (36.4% and 12%, respectively). In multivariate logistic regression analysis, motor deficit [odds ratio (OR) 5.8; 95% CI 2.98-11.42; P < 0.001], intracranial haemorrhage (OR 2.8; 95% CI 1.46-5.56; P = 0.002) and cortical vein thrombosis (OR 2.9; 95% CI 1.43-5.96; P = 0.003) were independent predictors of early epileptic seizures. Status epilepticus was an important source of morbidity and early mortality in patients with CVST in this study. Patients with focal motor deficits, cortical vein thrombosis and intracranial haemorrhage carried the highest risk for ES. Prophylactic antiepileptic treatment may be an option for these patients.

EFNS guideline on the treatment of cerebral venous and sinus thrombosis.

Cerebral venous and sinus thrombosis (CVST) is a rather rare disease which accounts for <1% of all strokes. Diagnosis is still frequently overlooked or delayed due to the wide spectrum of clinical symptoms and the often subacute or lingering onset. Current therapeutic measures which are used in clinical practice include the use of anticoagulants such as dose-adjusted intravenous heparin or body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH), the use of thrombolysis, and symptomatic therapy including control of seizures and elevated intracranial pressure. We searched MEDLINE (National Library of Medicine), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Library to review the strength of evidence to support these interventions and the preparation of recommendations on the therapy of CVST based on the best available evidence. Review articles and book chapters were also included. Recommendations were reached by consensus. Where there was a lack of evidence, but consensus was clear we stated our opinion as good practice points. Patients with CVST without contraindications for anticoagulation should be treated either with body weight-adjusted subcutaneous LMWH or dose-adjusted intravenous heparin (good practice point). Concomitant intracranial haemorrhage related to CVST is not a contraindication for heparin therapy. The optimal duration of oral anticoagulation after the acute phase is unclear. Oral anticoagulation may be given for 3 months if CVST was secondary to a transient risk factor, for 6-12 months in patients with idiopathic CVST and in those with 'mild' hereditary thrombophilia. Indefinite anticoagulation (AC) should be considered in patients with two or more episodes of CVST and in those with one episode of CVST and 'severe' hereditary thrombophilia (good practice point). There is insufficient evidence to support the use of either systemic or local thrombolysis in patients with CVST. If patients deteriorate despite adequate anticoagulation and other causes of deterioration have been ruled out, thrombolysis may be a therapeutic option in selected cases, possibly in those without intracranial haemorrhage (good practice point). There are no controlled data about the risks and benefits of certain therapeutic measures to reduce an elevated intracranial pressure (with brain displacement) in patients with severe CVST. Antioedema treatment (including hyperventilation, osmotic diuretics and craniectomy) should be used as life saving interventions (good practice point).

Emergency department delays in acute stroke - analysis of time between ED arrival and imaging.

We determined the factors leading to emergency department (ED) delays in patients with acute stroke. Data were collected prospectively in four Berlin inner-city hospitals by ED documentation, medical records, imaging files and patient interviews. An extended Cox proportional hazards model was fitted to the data. Analyses were performed in 558 patients with confirmed diagnosis of stroke. Median time from admission at ED to beginning of computed tomography/magnetic resonance imaging (CT/MRI) was 108 min. In a subgroup of patients potentially eligible for thrombolysis with a pre-hospital delay <120 min and a National Institutes of Health Stroke Scale (NIHSS) >4 (n = 74), the median interval to imaging was 68 min. Multivariable analysis revealed that a more severe initial NIHSS, a pre-hospital delay <3 h, admission at two specific hospitals, admission at weekends, and private health insurance were significantly associated with reduced delays. In stroke patients, the time interval between ED admission and imaging depends both on factors that emerge from clinical needs and on factors independent of clinical necessities. Considering the urgency of therapeutic measures in acute stroke, there is necessity and room for both improvement of in-hospital management and of medical and non-medical factors influencing pre-hospital delays.

Vertebral artery dissections after chiropractic neck manipulation in Germany over three years.

Vertebral artery dissection (VAD) has been observed in association with chirotherapy of the neck. However, most publications describe only single case reports or a small number of cases. We analyzed data from neurological departments at university hospitals in Germany over a three year period of time of subjects with vertebral artery dissections associated with chiropractic neck manipulation. We conducted a country-wide survey at neurological departments of all medical schools to identify patients with VAD after chirotherapy followed by a standardized questionnaire for each patient. 36 patients (mean age 40 + 11 years) with VAD were identified in 13 neurological departments. Clinical symptoms consistent with VAD started in 55% of patients within 12 hours after neck manipulation. Diagnosis of VAD was established in most cases using digital subtraction angiography (DSA), magnetic resonance angiography (MRA) or duplex sonography. 90% of patients admitted to hospital showed focal neurological deficits and among these 11 % had a reduced level of consciousness. 50% of subjects were discharged after 20 +/- 14 hospital days with focal neurological deficits, 1 patient died and 1 was in a persistent vegetative state. Risk factors associated with artery dissections (e. g. fibromuscular dysplasia) were present in only 25% of subjects. In summary, we describe the clinical pattern of 36 patients with vertebral artery dissections and prior chiropractic neck manipulation.

Petasites hybridus root (butterbur) is an effective preventive treatment for migraine.

OBJECTIVE: To evaluate the clinical efficacy of a standardized special root extract from the plant Petasites hybridus as a preventive therapy for migraine. METHODS: This is a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine. Eligible patients met International Headache Society criteria for migraine, were ages 18 to 65, and had at least two to six attacks per month over the preceding 3 months. The main outcome measure was the decrease in migraine attack frequency per month calculated as percentage change from baseline over a 4-month treatment period. RESULTS: Over 4 months of treatment, in the per-protocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg bid (p = 0.0012 vs placebo), 36% for Petasites extract 50 mg bid (p = 0.127 vs placebo), and 26% for the placebo group. The proportion of patients with a > or =50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of Petasites 75 mg at 1, 2, and 3 months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. CONCLUSIONS: Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine. Petasites 50 mg PO bid was not significantly more effective than placebo on the primary study endpoints.

High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre.

The aim of this study was to investigate the efficacy of riboflavin for the prevention of migraine. An open label study was performed in a specialized outpatient clinic. Patients received 400 mg riboflavin capsules per day. Headache frequency, duration, intensity and the use of abortive drugs were recorded at baseline and 3 and 6 months after treatment. Headache frequency was significantly reduced from 4 days/month at baseline to 2 days/month after 3 and 6 months (P < 0.05). The use of abortive drugs decreased from 7 units/month to 4.5 units/month after 3 and 6 months of treatment (P < 0.05). In contrast, headache hours and headache intensity did not change significantly. We could demonstrate a significant reduction of headache frequency following riboflavin treatment. In addition, the number of abortive anti-migraine tablets was reduced. In line with previous studies our findings show that riboflavin is a safe and well-tolerated alternative in migraine prophylaxis.

Cerebral venous and sinus thrombosis.

Cerebral venous and sinus thrombosis (CVST) can present with a variety of clinical symptoms ranging from isolated headache to deep coma. Prognosis is better than previously thought and prospective studies have reported an independent survival of more than 80% of patients. Although it may be difficult to predict recovery in an individual patient, clinical presentation on hospital admission and the results of neuroimaging investigations are--apart from the underlying condition--the most important prognostic factors. Comatose patients with intracranial haemorrhage (ICH) on admission brain scan carry the highest risk of a fatal outcome. Available treatment data from controlled trials favour the use of anticoagulation (AC) as the first-line therapy of CVST because it may reduce the risk of a fatal outcome and severe disability and does not promote ICH. A few patients deteriorate despise adequate AC which may warrant the use of more aggressive treatment modalities such as local thrombolysis. The risk of recurrence is low (< 10%) and most relapses occur within the first 12 months. Analogous to patients with extracerebral venous thrombosis, oral AC is usually continued for 3 months after idiopathic CVST and for 6-12 months in patients with inherited or acquired thrombophilia but controlled data proving the benefit of long-term AC in patients with CVST are not available.

The management of refractory generalised convulsive and complex partial status epilepticus in three European countries: a survey among epileptologists and critical care neurologists.

OBJECTIVE: To survey the current clinical treatment of refractory status epilepticus and to identify steps in its management which may need further investigation. METHODS: Epileptologists and critical care neurologists were surveyed using a standardised postal questionnaire. RESULTS: Sixty three of 91 participants (69%) returned the questionnaires. Two thirds of the respondents applied another non-anaesthetising anticonvulsant after failure of first line drugs. General anaesthesia for ongoing complex partial status epilepticus (CPSE) was part of the therapeutic regimen of 75% of the interviewees. A non-barbiturate as general anaesthetic of first choice was used by 42%. Up to 70% titrated the anaesthetic to achieve a burst suppression pattern in the electroencephalogram, indicating deep sedation, and 94% reduce anaesthesia within 48 hours. CONCLUSIONS: The management of refractory status epilepticus is heterogeneous in many aspects, even among clinicians who are most familiar with this severe condition. Randomised trials are needed to compare the efficacy, side effects, optimal duration, and depth of general anaesthesia.

Risk of recurrence of cerebral venous and sinus thrombosis during subsequent pregnancy and puerperium.

OBJECTIVE: To assess the risk of recurrence of cerebral venous and sinus thrombosis (CVST) during subsequent pregnancy and puerperium in women with previous cerebral venous occlusive disease. METHODS: The authors retrospectively studied the relapse rate of CVST and the incidence of extracerebral venous thrombosis during subsequent pregnancies in 39 women (from 125 patients with CVST) who suffered a CVST at childbearing age. RESULTS: Mean follow up was 10.25 years (range 1 to 20). Twenty two pregnancies and 19 births were observed in 14 women without evidence of either recurrence of CVST or extracerebral venous thrombosis. One pregnancy occurred during oral anticoagulation and was interrupted and two pregnancies ended with spontaneous abortions. Low dose heparin had been given during five pregnancies. CONCLUSIONS: The risk of recurrence for CVST during pregnancy seems to be low and these data do not justify a negative advice on pregnancy in women with previous CVST. Further studies are needed to evaluate the need for a prophylactic anticoagulation during pregnancy and puerperium.

Matched-pair comparison of three different approaches for thymectomy in myasthenia gravis.

BACKGROUND: Because of the lack of evidence-based data comparing different techniques for thymectomy (Thx), a matched-pair study was conducted to evaluate the role of thoracoscopic Thx (tThx) more objectively. METHODS: Of 182 patients who underwent Thx, 3 groups according to the operation technique were matched for myasthenia gravis (MG) without thymoma, age, gender, and severity of MG. Twenty patients each who had Thx through anterolateral thoracotomy (aThx), extended median sternotomy (sThx), and tThx were compared for length of operation, postoperative morbidity, complete remission, quantification of improvement of MG, and cosmetic results. RESULTS: Complete tThx required 197 +/- 35 min as compared to 113 +/- 43 min for sThx and 82 +/- 27 min for aThx (P <0.001). With zero mortality the overall postoperative morbidity rate was 25% for sThx versus 15% for aThx and 5% for tThx (P <0.05). There was no difference in complete remission of MG. The median activities of daily living (ADL) scores improved by 6.0 (1-19) after tThx, 5.5 (2-4) after sThx, and 7.5 (0-12) after aThx. Best cosmetic results were achieved after tThx. CONCLUSIONS: There was adequate cumulative medium-term improvement of MG and less postoperative morbidity after tThx, which may become the preferred technique for Thx.