Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplex-virus-encephalitis (GACHE): a multicenter, multinational, randomized, double-blind, placebo-controlled German, Austrian and Dutch trial [ISRCTN45122933]

Background The treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major unsolved problem in Neurology. Current gold standard for therapy is acyclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains up to 15%, less than 20% of patients are able to go back to work, and the majority of patients suffer from severe disability. This is a discouraging, unsatisfactory situation for treating physicians, the disabled patients and their families, and constitutes an enormous burden to the public health services. The information obtained from experimental animal research and from recent retrospective clinical observations, indicates that a substantial benefit in outcome can be expected in patients with HSVE who are treated with adjuvant dexamethasone. But currently there is no available evidence to support the routine use of adjuvant corticosteroid treatment in HSVE. A randomized multicenter trial is the only useful instrument to address this question. Design GACHE is a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial of treatment with acyclovir and adjuvant dexamethasone, as compared with acyclovir and placebo in adults with HSVE. The statistical design will be that of a 3-stage-group sequential trial with potential sample size adaptation in the last stage. Conclusion 372 patients with proven HSVE (positive HSV-DNA-PCR), aged 18 up to 85 years; with focal neurological signs no longer than 5 days prior to admission, and who give informed consent will be recruited from Departments of Neurology of academic medical centers in Germany, Austria and The Netherlands. Sample size will potentially be extended after the second interim analysis up to a maximum of 450 patients. Trial Registration Current Controlled Trials ISRCTN4512293

Herpesvirus infections of the central nervous system in immunocompromised patients

Human herpesviruses may cause infections of the central nervous system during primary infection or following reactivation from a latent state. Especially in immunosuppressed patients the infection can take a life-threatening course, and therefore early diagnosis of herpesvirus-associated neurological diseases should have high priority. Clinical presentation in these patients is usually without typical features, making diagnosis even more challenging. Therefore general broad testing for different herpesviruses in cerebrospinal fluid samples is highly recommended. In addition, determination of the virus DNA level in the cerebrospinal fluid by quantitative assays seems to be of high importance to determine prognosis. Moreover, it might help to differentiate between specific virus-associated disease and unspecific presence of virus in the cerebrospinal fluid, especially in immunocompromised patients. Polymerase chain reaction analysis of cerebrospinal fluid has revolutionized the diagnosis of nervous system viral infections, particularly those caused by human herpesviruses. This review summarizes the role human herpesviruses play in central nervous system infections in immunocompromised patients, with a focus on the clinical manifestation of encephalitis

Trends in stroke severity at hospital admission and rehabilitation discharge before and during the COVID-19 pandemic in Hesse, Germany: a register-based study

Abstract Background The COVID-19 pandemic has affected acute stroke care, resulting in a decrease in stroke admissions worldwide. We examined trends in stroke severity at hospital admission, including (1) probable need for rehabilitation (National Institutes of Health Stroke Scale score > 6 points) and (2) probable need for assistance (modified Rankin Scale score > 2 points), and discharge to rehabilitation after acute care among inpatients with acute ischemic stroke and intracerebral hemorrhage. Methods We compared quality assurance data for acute ischemic stroke and intracerebral hemorrhage during the pandemic with the period before the pandemic in Hesse, Germany, using logistic regression analyses. Results Fewer inpatients with a probable need for rehabilitation were present at the beginning of the second wave of the COVID-19 pandemic in September 2020 (adjusted OR (aOR) 0.85, 95% CI [0.73, 0.99]), at the end of the second national lockdown in May 2021 (aOR 0.81, 95% CI [0.70, 0.94]), and at the approaching peak of COVID-19 wave 4 in November 2021 (aOR 0.79, 95% CI [0.68, 091]). Rates of probable need for assistance were significantly lower at the beginning of COVID-19 wave 2 in August 2020 (aOR 0.87, 95% CI [0.77, 0.99]) and at the beginning of COVID-19 wave 3 in March 2021 (aOR 0.80, 95% CI [0.71, 0.91]). Rates of discharge to rehabilitation were lower from the beginning in October 2020 to the peak of COVID-19 wave 2 in December 2020 (aOR 0.83, 95% CI [0.77, 0.90]), at the beginning and end of COVID-19 wave 3 in March 2021 and May 2021 (aOR 0.86, 95% CI [0.79, 0.92]), respectively, and at the beginning of COVID-19 wave 4 in October 2021 (aOR 0.86, 95% CI [0.76, 0.98]). Conclusions The results suggest that the COVID-19 pandemic had an impact on stroke management during the pandemic, but the absolute difference in stroke severity at hospital admission and discharge to rehabilitation was small

Flank Pain as a First Symptom of a Diffuse Midline Glioma

Diffuse midline gliomas are a new entity in the WHO Classification of Tumors of the Central Nervous System, corresponding to grade 4 gliomas. The diagnostic pathognomonic feature is the presence of a H3K27M mutation. Although mainly seen in children, cases in adults have also been reported. The symptoms are highly variable and usually dependent on the location and extent of spinal cord compression

Apparent diffusion coefficient in the aging mouse brain: a magnetic resonance imaging study

Novel magnetic resonance imaging sequences have and still continue to play an increasing role in neuroimaging and neuroscience. Among these techniques, diffusion-weighted imaging (DWI) has revolutionized the diagnosis and management of diseases such as stroke, neoplastic disease and inflammation. However, the effects of aging on diffusion are yet to be determined. To establish reference values for future experimental mouse studies we tested the hypothesis that absolute apparent diffusion coefficients (ADC) of the normal brain change with age. A total of 41 healthy mice were examined by T2-weighted imaging and DWI. For each animal ADC frequency histograms (i) of the whole brain were calculated on a voxel-by-voxel basis and region-of-interest (ROI) measurements (ii) performed and related to the animals' age. The mean entire brain ADC of mice <3 months was 0.715(+/-0.016) x 10(-3) mm2/s, no significant difference to mice aged 4 to 5 months (0.736(+/-0.040) x 10(-3) mm2/s) or animals older than 9 months 0.736(+/-0.020) x 10(-3) mm2/s. Mean whole brain ADCs showed a trend towards lower values with aging but both methods (i + ii) did not reveal a significant correlation with age. ROI measurements in predefined areas: 0.723(+/-0.057) x 10(-3) mm2/s in the parietal lobe, 0.659(+/-0.037) x 10(-3) mm2/s in the striatum and 0.679(+/-0.056) x 10(-3) mm2/s in the temporal lobe. With advancing age, we observed minimal diffusion changes in the whole mouse brain as well as in three ROIs by determination of ADCs. According to our data ADCs remain nearly constant during the aging process of the brain with a small but statistically non-significant trend towards a decreased diffusion in older animals

Diabetes, Hypertension, Atrial Fibrillation and Subsequent Stroke-Shift towards Young Ages in Brunei Darussalam

Southeast Asia harbors a young population of more than 600 million people. Socioeconomic transition within the last decades, driven by globalization and rapid economic growth, has led to significant changes in lifestyle and nutrition in many countries of this region. Hence, an increase in the number of non-communicable diseases is seen in most populations of Southeast Asia. Brunei Darussalam is the smallest country in this region, with a population of around 400,000 inhabitants. Vast hydrocarbon resources have transformed Brunei into a wealthy industrialized country within the last few decades. We compared the age distribution and prevalence of cardiovascular risk factors in ischemic stroke patients between the only stroke unit in Brunei Darussalam and a tertiary stroke center from Frankfurt/Germany. Between 2011 and 2016, a total number of 3877 ischemic stroke patients were treated in both institutions. Even after adjusting for age due to different population demographics, stroke patients in Brunei were younger compared to their German counterparts. The prevalence of hypertension and diabetes mellitus was significantly higher in young age groups in Brunei, whereas no difference was observed for older patients. The rapid socioeconomic transition might be a significant risk factor for the development of non-communicable diseases, including stroke

Clinical outcome and cerebrospinal fluid profiles in patients with tick-borne encephalitis and prior vaccination history

Background: Tick-borne encephalitis (TBE) is endemic in southern and eastern districts of Germany. Approximately 10–14% of the infected individuals suffer from long-term disability and in 1.5–3.6% the course is fatal. Two well-tolerated vaccines are available, which provide high protection and which have been confirmed in several field studies. Here we investigate clinical course, long-term outcome and cerebrospinal fluid (CSF) characteristics of TBE cases with a prior history of any vaccination as well as real vaccination breakthrough (VBT). Methods: A case series of 11 patients with a prior history of vaccination, part of a recently published lager cohort of 111 TBE cases. Evaluation included clinical data, degree of disability (modified RANKIN scale, mRS) and analysis of CSF and serum samples. Furthermore, metadata for extended analysis on clinical outcome of TBE with VBT were analysed. Results: One patient had a clear VBT and ten of them had irregular vaccinations schedules (IVS). Infection severity did not differ in patients with IVS as compared to a non-vaccinated control cohort (median mRS: both 3.0) but these patients showed a stronger cellular immune response as measured by CSF pleocytosis (IVS, 205 cells/μL versus non-vaccinated control, 114 cell/μL, P < 0.05) and by differential pattern of CSF (intrathecal) immunoglobulin synthesis. However, shift analysis of VBT metadata using linear-by-linear association revealed a more serious course of TBE in patients with VBT than in a non-vaccinated control cohort (χ2 = 9.95, P = 0.002). Furthermore, ordinal logistic regression analysis showed that VBT patients had an age-corrected, 2.65 fold (CI: 1.110–6.328; χ2 = 4.813; p = 0.028) significant higher risk to suffer from moderate or severe infections, respectively. Conclusion: A history of IVS surprisingly seems to have no impact on the clinical course of TBE but may leave marks in the specific brain immune response. VBT patients, however, carry an age-independent, significant risk to experience a severe infection

Predictors, neuroimaging characteristics and long-term outcome of severe european tick-borne encephalitis: a prospective cohort study

Background and Objectives: Tick-borne encephalitis (TBE) still represents a considerable medical and health economic problem in Europe and entails a potential threat to travellers. The aim of this study was to characterise the conditions of severe TBE by precisely recording its clinical variants, the related neuroimaging features, and the variant-specific long-term outcome and by identifying predictors for severe courses. Methods: A cohort of 111 TBE patients (median age 51, range 17–75 years; 42% females) was analysed prospectively. Data were acquired from the department of neurology, University Hospital Heidelberg, and the infectious diseases registry of the Robert-Koch institute Berlin. Neurological status was ascertained by protocol at admission and discharge and the degree of disability was scored using the modified RANKIN Scale (mRS; clinical score addressing neurological disability, range from 0, healthy to 6, dead) at admission and at follow-up. Follow-up examination was conducted by means of a telephone interview. To identify independent predictors for severe TBE and functional outcome, modelled logistic regression was performed. MRI changes were correlated with infection variants. To assess alpha-motor neuron injury patterns, we used high resolution magnetic resonance neurography (hrMRN). Analyses were performed at the Department of Neurology, University Hospital, University of Heidelberg from April 2004 through September 2014 Results: Acute course: 3.6% of patients died during the acute infection. All patients with a lethal course suffered from meningoencephaloradiculitis (MER, 14.4% of the cohort), which is associated with a significantly higher risk of requiring intensive care (p = 0.004) and mechanical ventilation (p<0.001) than menigoencephalitis (ME, 27.9% of the cohort). At admission, both MER and ME groups were severely affected, with the MER group having a statistically higher mRS score (median of 5 in the MER groups versus 4 in the ME group; p<0.001). Long-term outcome: outcome for MER was considerably worse (median mRS = 4) than for ME (mRS = 1, p<0.0001) and meningitis (mRS = 0, 57.7% of the cohort). Risk factors: advanced age (p<0.001) and male gender (p = 0.043) are independent risk factors for a severe infection course. Furthermore, we identified pre-existing diabetes mellitus (p = 0.024) as an independent risk factor for MER. In MER, alpha-motor neuron injury accounts for the poor prognosis confirmed by hrMRN. Conclusion and Relevance: These data provide critical information for neurologists and other health professionals to use in evaluating TBEV patients who live in or travel to endemic areas. This information can be used to classify clinical presentation and estimate infection-associated complications and individual prognosis. Furthermore, the risk for severe, disabling infections in older patients should prompt general practitioners to recommend and encourage vaccination to those patients living in or travelling to endemic areas

In vivo monitoring of acute flavivirus (Modoc) encephalitis with regional and whole-brain quantitative diffusion magnetic resonance imaging

In vivo imaging of structural changes in the brain of patients with encephalitis has become an important aid in diagnostic and therapeutic procedures. Diffusion-weighted magnetic resonance imaging (DWI) was employed to quantitate regional and whole-brain diffusion-weighted MRI changes in a hamster model for acute flavivirus encephalitis. The regional apparent diffusion coefficient (ADC) was determined in hyperintense regions seen on T2-weighted images (i.e., the thalamic area and the temporal lobe), but anatomical variation and structural heterogeneity of encephalitic lesions severely impeded the placement of regions of interest (ROI). Therefore, quantitative whole-brain diffusion-weighted imaging was carried out and revealed a significantly reduced ADC (P = .02) in the brain of hamsters with acute encephalitis (n = 7) as compared to that of healthy, uninfected controls (n = 3). Furthermore, the ADC histogram demonstrated a reduced peak height and center of gravity during the acute encephalitis. Our findings could further support the use of diffusion-weighted imaging for in vivo monitoring of acute flavivirus encephalitis and for the study of therapeutic approaches.status: publishe