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.

Intraoperative clinical testing overestimates the therapeutic window of the permanent DBS electrode in the subthalamic nucleus.

BACKGROUND: Intraoperative test stimulation is established to optimize target localization in STN DBS, but requires a time-consuming awake surgery in off-medication state. The aim of this study was to compare the thresholds of stimulation-induced effects of test stimulation and the permanent electrode. METHODS: Fifty-nine PD patients receiving bilateral STN DBS were clinically examined with stepwise increasing monopolar stimulation during surgery and DBS programming at matched stimulation depths. Thresholds of therapeutic and side effects were obtained from standardized examination protocols. RESULTS: Postoperative stimulation via the permanent electrode caused side effects at a significantly lower threshold than predicted during intraoperative test stimulation (P < 0.001); whereas sufficient therapeutic effects were achieved at significantly higher thresholds (P < 0.001). CONCLUSIONS: Intraoperative testing may lead to an overestimation of the therapeutic window. The two different electrodes lead to distinct spreading of the electric field in the STN and surrounding tissues that causes different volume of tissue activated (VTA). Clinicians involved in DBS surgery and programming should be aware of the differences in both stimulation settings, concerning electrodes geometry, stimulation modes as well as the impact of time. Therapeutic and side effects of permanent stimulation are not predictable by intraoperative test stimulation. Test stimulation may be an orientating test for very low thresholds of side effects instead.

The impact of white matter lesions on the cognitive outcome of subthalamic nucleus deep brain stimulation in Parkinson's disease.

OBJECTIVES: White Matter lesions (WML) are a risk factor for cognitive impairment in Parkinson's disease. There is no clear evidence of reduced general cognitive function after DBS. However, a subgroup of patients develops dementia rapidly after DBS despite careful patient selection processes. The aim of this study was to evaluate the load of WML as a possible risk factor for cognitive decline following STN DBS. PATIENTS AND METHODS: 40 PD-patients receiving bilateral STN-DBS were followed at least three years after surgery to detect dementia. All patients underwent comprehensive neuropsychological assessment and MRI before surgery. The extent of WML was assessed using an automated approach. WML volume was correlated to the onset of dementia and the decline of a cognitive composite score retrospectively. RESULTS: Patients with a rapid onset of dementia within one, respective three following DBS showed significant higher WML volumes compared to cognitive normal and MCI patients (55.8cm3±18.836 vs. 9.3cm3±12.2; p=0.002). The same significant association was found in a multivariable model, including the covariables age, gender and PD disease duration (p=0.01). WML volume was associated to the rate of decline in cognitive composite score within three years after DBS surgery (p=0.006; R2=0.40) after correction for age. CONCLUSIONS: Damaged white matter may lead to a reduced compensation of disconnections in cognitive circuits caused by the implantation of the DBS electrodes or by chronic stimulation. The role of WML as a prognostic factor for the cognitive outcome after DBS may be underestimated. The WML burden should be taken seriously in preoperative risk stratification.

Ocular color-coded sonography - a promising tool for neurologists and intensive care physicians.

Ocular color-coded duplex sonography (OCCS), when performed within the safety limits of diagnostic ultrasonography, is an easy noninvasive technique with high potential for diagnosis and therapy in diseases with raised intracranial pressure and vascular diseases affecting the eye. Despite the capabilities of modern ultrasound systems and its scientific validation, OCCS has not gained widespread use in neurological practice. In this review, the authors describe the technique and main parameter settings of OCCS systems to reduce potential risks as thermal or cavitational effects for sensitive orbital structures. Applications of OCCS are the determination of intracranial pressure in emergency medicine, and follow-up evaluations of idiopathic intracranial hypertension and ventricular shunting by measuring the optic nerve sheath diameter. A diameter of 5.7 - 6.0 mm corresponds well with symptomatically increased intracranial pressure (> 20 cmH2O). OCCS also helps to discriminate between different etiologies of central retinal artery occlusion - by visualization of a "spot sign" and Doppler flow analysis of the central retinal artery - and aids the differential diagnosis of papilledema. At the end perspectives are illustrated that combine established ultrasound methods such as transcranial color-coded sonography with OCCS.

The retrobulbar "spot sign" as a discriminator between vasculitic and thrombo-embolic affections of the retinal blood supply.

PURPOSE: Sudden retinal blindness is a common complication of temporal arteritis (TA). Another common cause is embolic occlusion of the central retinal artery (CRA). The aim of this prospective study was to examine the diagnostic value of hyperechoic material in the CRA for the exclusion of vasculitis as a cause. The authors used orbital color-coded sonography (OCCS) for the detection of hyperechoic material. MATERIALS AND METHODS: 24 patients with sudden vision loss were included in the study after the exclusion of other causes (e. g. vitreous bleeding, retinal detachment). Parallel to routine diagnostic workup, OCCS was performed in all patients. RESULTS: 7 patients with a diagnosis of TA presented with different degrees of hypoperfusion in the CRA without hyperechoic material (referred to as "spot sign") detected by OCCS. Diagnostic workup in the remaining 17 patients revealed other causes of sudden vision loss, such as central retinal artery occlusion (CRAO) (12), anterior ischemic optic neuropathy (AION) (2), upstream vascular stenosis or occlusion (2) and delayed reperfusion of the CRA (1). The hyperechoic "spot sign" was visible in 10 of 12 patients (83 %) with embolic CRAO. The detection of embolic CRAO using the "spot sign" had a sensitivity of 83 % and a specificity of 100 %. The missing "spot sign" in patients with TA was a highly specific finding (p-value 0.01). CONCLUSION: The detection of the "spot sign" specifically minimizes the probability of TA as a reason for sudden blindness.

[Indications and outcome of ventilated patients treated in a neurological intensive care unit]. / Indikationen und Outcome beatmeter Patienten einer neurologischen Intensivstation.

OBJECTIVE: This study characterized artificially ventilated patients in a neurological intensive care unit (NICU) between 2006-2008 in a purely neurological clinic and a so-called stand-alone situation. In addition the long-term prognoses as well as the quality of life of surviving patients were investigated. METHODS: All ventilated patients from October 2006 to December 2008 were enrolled in this descriptive, retrospective study. The duration of stay in intensive care was analyzed and the current quality of life was prospectively assessed based on the patient records. Final diagnoses, duration of intensive care unit and ventilation as well as the highest score in SAPS II (simplified acute physiology score) and complications during hospitalization were determined. The patients were divided into groups based on the diagnoses as vascular, inflammatory, neurodegenerative, hereditary, epileptogenic and others. Additionally patients were contacted and asked to respond by completing questionnaires on the Barthel index (BI) and the modified Rankin scale (mRS). RESULTS: During the study period a total of 512 patients were treated in the NICU of whom 201 required artificial respiration. Cerebrovascular diseases were the main reason for therapy in the NICU in 96 out of 201 cases (47.8%), followed by inflammatory diseases in 46 (22.8%) and epileptogenic diseases in 26 patients (13%). The median duration of artificial respiration was 9 days with a mean treatment duration of 16 days (range 1-57 days). Of the patients 31 (15.4%) died in the NICU and an additional 32 patients (18.8%) died within a median of 2 months after discharge. Outcome data were available from 67 out of 170 sent questionnaires and rehabilitation reports of 86 patients, which enabled the outcome of 121 surviving patients to be analyzed (71.2%). Of these 42.2% showed no or mild impairment in everyday life. However, the remaining 38% had severe impairments according to the BI. The evaluation of the mRS showed that 49.6% of the patients still had severe symptoms. CONCLUSIONS: More than one third of the patients treated in the NICU required artificial ventilation with an emphasis on cerebrovascular diseases, which illustrates the overlap between stroke unit and NICU care. Despite a lengthy duration of ventilation and a long stay in the intensive care unit more than one third of surviving patients showed no or only mild impairment. However, an additional third suffered from severe disability up to nursing care dependency. The study data differ little from the few publications in this field despite the stand alone situation of the NICU. The case mix index per day averaged around 0.3 and underlines the economic importance with respect to other forms of neurological treatment.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

Selective bilateral hippocampal lesions after theophylline-induced status epilepticus causes a permanent amnesic syndrome.

Theophylline is known to increase the risk of epileptic seizures and might have a role in seizure-induced brain damage. We present a 55-year-old man who developed an amnesic syndrome after status epilepticus, caused by accidental theophylline intoxication. Imaging studies revealed acute, selective bilateral hippocampal damage, which corresponded to severe disturbances in bilateral temporal functions on neuropsychological testing. Three months later, the memory deficits persisted, while imaging exhibited bilateral atrophy of the hippocampus. Upon his long-term, 18-month follow-up, the patient demonstrated improvements in his daily living abilities, despite the persistence of bilateral temporal deficits. This report provides evidence that theophylline has the potential to provoke permanent seizure-induced neural damage, presumably via inhibition of adenosine receptors, and especially in vulnerable regions of the brain, such as the hippocampus.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

Targeted therapy for high-grade glioma with the TGF-ß2 inhibitor trabedersen: results of a randomized and controlled phase IIb study.

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

Transcranial perfusion sonography using a low mechanical index and pulse inversion harmonic imaging: reliability, inter-/intraobserver variability.

PURPOSE: Transcranial perfusion sonography (TPS) is an emerging noninvasive bedside method for evaluating brain perfusion. The purpose was to assess the feasibility of a low MI/almost real-time frame rate approach and to test its intra-/interobserver variability. MATERIALS AND METHODS: 10 healthy volunteers were investigated 3 times with TPS at a low MI (1.0) and a high frame rate (8.3 Hz). Investigations were performed by 2 sonographers in a cross-over design: 1.) twofold measurements each with 5 volunteers (intraobserver test), and 2.) single measurements of the other 5 volunteers (interobserver test). From 8 established regions of interest (ROI), time-intensity curves (TIC) with the following parameters were calculated: peak intensity (PI), time-to-PI (TTP), area-under-curve (AUC), and cerebral transit time (CTT). The TIC quality was described by the coefficient of determination. TIC parameters were presented descriptively. Intra- and interobserver variability was tested by Spearman's correlation. RESULTS: The overall quality of the TIC was very good (mean r(2) = 0.92, 0.87 - 0.97). TTP (25.7 - 28.1 sec; mean 26.8 sec) and CTT (8.2 - 10.7 sec; mean 9.9 sec) were the most robust parameters. The intraobserver variability was lower with the more experienced sonographer (r = 0.70 vs. r = 0.29). The interobserver reliability was r = 0.34 (p < 0.05). CONCLUSION: Low MI TPS allows for nearly real-time imaging facilitating probe control. Sound sonographer experience allows for a high reliability and makes TPS an interesting tool for the diagnosis and follow-up of perfusion changes, e. g. in stroke or anti-angiogenic brain tumor therapy.

Distinct patterns of functional and structural neuroplasticity associated with learning Morse code.

Learning is based on neuroplasticity, i.e. on the capability of the brain to adapt to new experiences. Different mechanisms of neuroplasticity have been described, ranging from synaptic remodeling to changes in complex neural circuitry. To further study the relationship between changes in neural activity and changes in gray matter density associated with learning, we performed a combined longitudinal functional and morphometric magnetic resonance imaging (MRI) study on healthy volunteers who learned to decipher Morse code. We investigated 16 healthy subjects using functional MR imaging (fMRI) and voxel-based morphometry (VBM) before and after they had learned to decipher Morse code. The same set of Morse-code signals was presented to participants pre- and post-training. We found an increase in task-specific neural activity in brain regions known to be critically involved in language perception and memory, such as the inferior parietal cortex bilaterally and the medial parietal cortex during Morse code deciphering. Furthermore we found an increase in gray matter density in the left occipitotemporal region, extending into the fusiform gyrus. Anatomically neighboring sites of functional and structural neuroplasticity were revealed in the left occipitotemporal/inferior temporal cortex, but these regions only marginally overlapped. Implications of this morpho-functional dissociation for learning concepts are discussed.

[Severe tick-borne encephalomyelitis with lack of cerebrospinal fluid pleocytosis]. / Schwere Frühsommer-Meningo-Enzephalomyelitis ohne Liquor-Pleozytose.

Tick borne encephalitis (TBE) is an important viral encephalitis in central and eastern Europe. Cerebrospinal fluid (CSF) pleocytosis has been described in all published patients so far. This may be due to selection bias, however, as CSF pleocytosis is often used as a case definition parameter. The frequency of TBE without CSF pleocytosis is unknown. We report two cases who developed severe TBE without CSF pleocytosis. A normal CSF cell count should therefore not discourage from the differential diagnosis of TBE and deter from serological testing in patients with a clinical constellation suggesting TBE.

Ageing abolishes the effects of fluoxetine on neurogenesis.

Depression constitutes a widespread condition observed in elderly patients. Recently, it was found that several drugs employed in therapies against depression stimulate hippocampal neurogenesis in young rodents and nonhuman primates. As the rate of neurogenesis is dramatically reduced during ageing, we examined the influences of ageing on neurogenic actions of antidepressants. We tested the impact of fluoxetine, a broadly used antidepressant, on hippocampal neurogenesis in mice of three different age groups (100, 200 and over 400 days of age). Proliferation and survival rate of newly generated cells, as well as the percentage of cells that acquired a neuronal phenotype were analyzed in the hippocampus of mice that received fluoxetine daily in a chronic manner. Surprisingly, the action of fluoxetine on neurogenesis was decreasing as a function of age and was only significant in young animals. Hence, fluoxetine increased survival and the frequency of neuronal marker expression in newly generated cells of the hippocampus in the young adult group (that is 100 days of age) only. No significant effects on neurogenesis could be detected in fluoxetine-treated adult and elderly mice (200 and over 400 days of age). The data indicate that the action of fluoxetine on neurogenesis is highly dependent on the age of the treated individual. Although the function of neurogenesis in the clinical manifestation of depression is currently a matter of speculation, this study clearly shows that the therapeutic effects of antidepressants in elderly patients are not mediated by neurogenesis modulation.

Biological activity of two botulinum toxin type A complexes (Dysport and Botox) in volunteers: a double-blind, randomized, dose-ranging study.

Despite extensive clinical experience and published data regarding botulinum toxin, questions remain about the clinical substitution of one botulinum toxin formulation for another. In the case of Dysport and Botox, dose-equivalence ratios ranging from 1:1 to 6:1 (Dysport:Botox) have been advocated. This dose-ranging, electroneurographic study investigated the dose equivalence, diffusion characteristics (spread) and safety of these two type-A toxins in 79 volunteers. Dysport and Botox caused significant and similar reductions in compound muscle action potential (CMAP) amplitude in the target muscle (extensor digitorum brevis, EDB) 2 weeks after injection, with effects persisting to the 12-week timepoint. For both products, the reduction in amplitude was increased with increasing doses and with increasing concentration. The effects of toxin on neighbouring muscles were much smaller and of a shorter duration than those on the target muscle, implying a modest spread of toxin. Unlike the target muscle, the effects were greater with the higher volume, suggesting this volume led to greater diffusion from the EDB. No adverse events were reported. Statistical modelling with CMAP amplitude data from the target muscle gave a bioequivalence of 1.57 units of Dysport:1 unit of Botox (95 % CI: 0.77-3.20 units). The data indicate that a dose-equivalence ratio of 3:1 was within the statistical error limits, but ratios over 3:1 are too high.