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.

Endovascular Therapy of M2 Occlusion in IMS III: Role of M2 Segment Definition and Location on Clinical and Revascularization Outcomes.

BACKGROUND AND PURPOSE: Uncertainty persists regarding the safety and efficacy of endovascular therapy of M2 occlusions following IV tPA. We reviewed the impact of revascularization on clinical outcomes in 83 patients with M2 occlusions in the Interventional Management of Stroke III trial according to specific M1-M2 segment anatomic features. MATERIALS AND METHODS: Perfusion of any M2 branch distinguished M2-versus-M1 occlusion. Prespecified modified TICI and arterial occlusive lesion revascularization and clinical mRS 0-2 end points at 90 days for endovascular therapy-treated M2 occlusions were analyzed. Post hoc analyses of the relationship of outcomes to multiple baseline angiographic M2 and M1 subgroup characteristics were performed. RESULTS: Of 83 participants with M2 occlusion who underwent endovascular therapy, 41.0% achieved mRS 0-2 at 90 days, including 46.6% with modified TICI 2-3 reperfusion compared with 26.1% with modified TICI 0-1 reperfusion (risk difference, 20.6%; 95% CI, -1.4%-42.5%). mRS 0-2 outcome was associated with reperfusion for M2 trunk (n = 9) or M2 division (n = 42) occlusions, but not for M2 branch occlusions (n = 28). Of participants with trunk and division occlusions, 63.2% with modified TICI 2a and 42.9% with modified TICI 2b reperfusion achieved mRS 0-2 outcomes; mRS 0-2 outcomes for M2 trunk occlusions (33%) did not differ from distal (38.2%) and proximal (26.9%) M1 occlusions. CONCLUSIONS: mRS 0-2 at 90 days was dependent on reperfusion for M2 trunk but not for M2 branch occlusions. For M2 division occlusions, good outcome with modified TICI 2b reperfusion did not differ from that in modified TICI 2a. M2 segment definition and occlusion location may contribute to differences in revascularization and good outcome between Interventional Management of Stroke III and other endovascular therapy studies.

Diagnostic Impact of Bone-Subtraction CT Angiography for Patients with Acute Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Detection and evaluation of ruptured aneurysms is critical for choosing an appropriate endovascular or neurosurgical intervention. Our aim was to assess whether bone-subtraction CTA is capable of guiding treatment for cerebral aneurysms in patients with acute SAH and could replace DSA. MATERIALS AND METHODS: We prospectively studied 116 consecutive patients with SAH with 16-detector row bone-subtraction CTA and DSA before intracranial aneurysm treatment. Two independent neuroradiologists reviewed the bone-subtraction CTA blinded to DSA (reference standard). We determined the accuracy of bone-subtraction CTA for aneurysm detection and the measurement of aneurysm dimensions and compared the radiation doses of the 2 imaging modalities. RESULTS: Seventy-one patients (61%) had 74 aneurysms on DSA. Bone-subtraction CTA detected 73 of these aneurysms, but it detected 1 additional aneurysm. On a per-aneurysm basis, sensitivity, specificity, and positive and negative predictive values for bone-subtraction CTA were 99%, 98%, and 99% and 98%, respectively. For aneurysms of ≤3 mm, sensitivity was 94% (95% CI, 73%-99%). Bone-subtraction CTA slightly overestimated neck and dome diameters by <0.2 mm and overestimated the dome-to-neck ratios by 2% on average. Dose-length product was 565 ± 201 mGy × cm for bone-subtraction CTA and 1609 ± 1300 mGy × cm for DSA. CONCLUSIONS: Bone-subtraction CTA is as accurate as DSA in detecting cerebral aneurysms after SAH, provides similar information about aneurysm configuration and measures, and reduces the average effective radiation dose for vascular diagnostics by 65%. Diagnostic equivalence in association with dose reduction suggests replacing DSA with bone-subtraction CTA in the diagnostic work-up of spontaneous SAH.

Outcome Differences between Intra-Arterial Iso- and Low-Osmolality Iodinated Radiographic Contrast Media in the Interventional Management of Stroke III Trial.

BACKGROUND AND PURPOSE: Intracarotid arterial infusion of nonionic, low-osmolal iohexol contrast medium has been associated with increased intracranial hemorrhage in a rat middle cerebral artery occlusion model compared with saline infusion. Iso-osmolal iodixanol (290 mOsm/kg H2O) infusion demonstrated smaller infarcts and less intracranial hemorrhage compared with low-osmolal iopamidol and saline. No studies comparing iodinated radiographic contrast media in human stroke have been performed, to our knowledge. We hypothesized that low-osmolal contrast media may be associated with worse outcomes compared with iodixanol in the Interventional Management of Stroke III Trial (IMS III). MATERIALS AND METHODS: We reviewed prospective iodinated radiographic contrast media data for 133 M1 occlusions treated with endovascular therapy. We compared 5 prespecified efficacy and safety end points (mRS 0-2 outcome, modified TICI 2b-3 reperfusion, asymptomatic and symptomatic intracranial hemorrhage, and mortality) between those receiving iodixanol (n = 31) or low-osmolal contrast media (n = 102). Variables imbalanced between iodinated radiographic contrast media types or associated with outcome were considered potential covariates for the adjusted models. In addition to the iodinated radiographic contrast media type, final covariates were those selected by using the stepwise method in a logistic regression model. Adjusted relative risks were then estimated by using a log-link regression model. RESULTS: Of baseline or endovascular therapy variables potentially linked to outcome, prior antiplatelet agent use was more common and microcatheter iodinated radiographic contrast media injections were fewer with iodixanol. Relative risk point estimates are in favor of iodixanol for the 5 prespecified end points with M1 occlusion. The percentage of risk differences are numerically greater for microcatheter injections with iodixanol. CONCLUSIONS: While data favoring the use of iso-osmolal iodixanol for reperfusion of M1 occlusion following IV rtPA are inconclusive, potential pathophysiologic mechanisms suggesting clinical benefit warrant further investigation.

Multimodal Computed Tomography Based Definition of Cerebral Imaging Profiles for Acute Stroke Reperfusion Therapy (CT-DEFINE): Results of a Prospective Observational Study.

PURPOSE: To prospectively evaluate the prognostic impact of multimodal computed tomography-based imaging in ischemic stroke patients potentially eligible for reperfusion therapy. METHODS: Anterior circulation stroke patients underwent non-contrast CT (NCCT), CT-angiography, and CT-perfusion within 12 h from symptom-onset. Patients could be treated with intravenous-tissue plasminogen activator (IV-tPA), endovascular or combined reperfusion therapies. Cerebral imaging profiles (IP) were NCCT-Alberta Stroke Program Early CT Score (ASPECTS) > 7 (IP1); NCCT-ASPECTS > 5 and proximal occlusion on CT-angiography (IP2); CT-perfusion mismatch between cerebral blood volume (CBV)-ASPECTS, and cerebral blood flow (CBF)-ASPECTS ≥ 2 (IP3). Favorable outcome was defined as modified Rankin Scale ≤ 2 at 3 months. RESULTS: Of 102 included patients, 62 (61%) received any reperfusion therapy. In IP2 and IP3, favorable outcome was more frequent in patients with reperfusion therapy than in those without; however, this did not reach statistical significance (IP2: 39% vs 15%, p = 0.26; IP3: 50% vs 17 %; p = 0.31). No difference was seen in IP1 (58% vs 58%, p = 1.0). In IP2, patients with IV-tPA alone achieved better functional outcome (50% vs 11%, p = 0.03) and lower mortality (0% vs 28%, p = 0.045) than those without. CONCLUSIONS: Our results suggest a benefit with imaging profile selection based upon the combination of a small-to-moderate-sized infarction and a visible intracranial occlusion in patients receiving IV-tPA. Reperfusion therapy may be futile in patients without proven vessel occlusion.

Prognostic Value of Conventional Magnetic Resonance Imaging for Adult Patients with Brain Tumors.

PURPOSE: Magnetic resonance imaging (MRI) is the pivotal diagnostic step in patients with brain tumors, and is performed before histological diagnosis is available. We hypothesized that conventional MRI is as accurate as tumor histology in differentiating malignant from benign clinical course. METHODS: Two neuroradiologists blinded to any clinical information evaluated the first diagnostic MRI of 244 brain tumor patients before any treatment, using a self-developed standardized list of image criteria and prospectively determined world health organization (WHO) tumor grade and tumor entity. All patients were examined with at least T1- and T2-weighted spin echo sequences before and after contrast injection on 1 and 1.5-T MRI scanners. Following the patients prospectively for 8-13 years after diagnosis, we were able to use nonsurvival at 5 years as a criterion for malignity and reference for the prognostic accuracy of both MRI and tumor tissue histology. RESULTS: The accuracy for predicting nonsurvival at 5 years was 91% (95% confidence interval (CI): 87-94%) for MRI and 92% (95% CI: 88-95%) for histology. The Kaplan-Meier survival curves of patients with benign and malignant brain tumors as diagnosed by MRI or histology differed significantly (p < 0.001). Histology confirmed benignity or malignity in 201 patients (82%, 95% CI: 77-87%). Sources of misdiagnosis were metastases diagnosed as astrocytoma WHO IV, atypical meningiomas, and low-grade astrocytoma with malignant transformation. CONCLUSION: MRI appears as accurate as histology in predicting survival at 5 years after diagnosis. Histological diagnosis may be more specific, however, and is needed to assess the tumor's specific biology.

Radiochemotherapy-induced changes of tumour vascularity and blood supply estimated by dynamic contrast-enhanced CT and fractal analysis in malignant head and neck tumours.

OBJECTIVE: To investigate radiochemotherapy (RChT)-induced changes of transfer coefficient (K(trans)) and relative tumour blood volume (rTBV) estimated by dynamic contrast-enhanced CT (DCE-CT) and fractal analysis in head and neck tumours (HNTs). METHODS: DCE-CT was performed in 15 patients with inoperable HNTs before RChT, and after 2 and 5 weeks. The dynamics of K(trans) and rTBV as well as lacunarity, slope of log(lacunarity) vs log(box size), and fractal dimension were compared with tumour behaviour during RChT and in the 24-month follow-up. RESULTS: In 11 patients, an increase of K(trans) and/or rTBV after 20 Gy followed by a decrease of both parameters after 50 Gy was noted. Except for one local recurrence, no tumour residue was found during the follow-up. In three patients with partial tumour reduction during RChT, a decrease of K(trans) accompanied by an increase in rTBV between 20 and 50 Gy was detected. In one patient with continuous elevation of both parameters, tumour progressed after RChT. Pre-treatment difference in intratumoral heterogeneity with its decline under RChT for the responders vs non-responders was observed. CONCLUSION: Initial growth of K(trans) and/or rTBV followed by further reduction of both parameters along with the decline of the slope of log(lacunarity) vs log(box size) was associated with positive radiochemotherapeutic response. Increase of K(trans) and/or rTBV under RChT indicated a poor outcome. ADVANCES IN KNOWLEDGE: The modification of K(trans) and rTBV as measured by DCE-CT may be applied for the assessment of tumour sensitivity to chose RChT regimen and, consequently, to reveal clinical impact allowing individualization of RChT strategy in patients with HNT.

18F-labelled CCR1-receptor antagonist is not suitable for imaging of Alzheimer's disease.

Diagnosis of Alzheimer's disease (AD) with positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) relies on typical alterations of brain glucose metabolism which are, however, not disease specific. Amyloid-ß imaging has not entered clinical routine yet. Post mortem histological specimen of brain tissue from AD patients revealed enhanced expression of the chemotactic cytocine receptor 1 (CCR1). PARTICIPANTS, METHODS: CCR1-antagonist ZK811460 was labeled with fluorine-18 to explore its possible use as specific diagnostic tool in AD. Tracer characterization comprising PET imaging of brain and metabolite analysis was performed in AD patients and controls. RESULTS: Neither qualitative evaluation nor quantitative compartment analysis of PET data did show any enhanced binding of the 18F-labeled CCR1-antagonist in the brain of AD patients or controls. CONCLUSION: 18F-ZK811460 did not fulfill the expectation as diagnostic tracer in PET imaging of AD.

[Diagnosis and differential diagnosis of Graves' orbitopathy in MRI]. / Diagnose und Differenzialdiagnose der endokrinen Orbitopathie in der MRT.

Imaging of Graves' orbitopathy (GO) includes radiological and nuclear medicine procedures. Depending on the method used they provide information about the distribution and activity of the disease. Magnetic resonance imaging (MRI) is not only a helpful tool for making the diagnosis it also enables differentiation of the active and inactive forms of GO due to intramuscular edema. The modality is therefore appropriate to evaluate the disease activity and the course of therapy. The disease leads to the typical enlargement of the muscle bodies of the extraocular muscles. The inferior rectus, medial rectus and levator palpebrae muscles are mostly involved. Signal changes of the intraconal and extraconal fat tissue are possible and a bilateral manifestation is common. The differential diagnosis includes inflammatory diseases and tumors, of which orbital pseudotumor (idiopathic, unspecific orbital inflammation), ocular myositis and orbital lymphoma are the most important. The specific patterns (localization, involvement of orbital structures and signal changes) can be differentiated by MRI.

[Consequences of misdiagnosis: unrecognized acoustic neuroma (vestibular schwannoma) in MRI]. / Konsequenzen einer Fehldiagnose: Akustikusneurinom (Vestibularisschwannom) im MRT nicht erkannt.

This report concerns a 43-year-old male plumber with relapsing acute hearing loss on the right side and vertiginous attacks. Magnetic resonance imaging (MRI) was performed twice after otolaryngology and neurological examinations over an interval of 2 months and according to the reports no evidence of an acoustic neuroma was found. Approximately 2 years later a right-sided hourglass-shaped acoustic neuroma 4 mm in diameter was diagnosed with MRI located in the vestibule and the fundus of the internal auditory canal. In retrospect it had also been visible on the earlier MRI. The tumor was resected via the labyrinth and the diagnosis of a vestibular schwannoma was confirmed histologically. The patient brought a lawsuit against the radiologist who carried out both previous MRI examinations with the wrong interpretation. The lawsuit terminated in a settlement between the parties after presentation of the neuroradiological expert opinion.

CT angiography source images predict final infarct extent in patients with basilar artery occlusion.

BACKGROUND AND PURPOSE: The posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) is a 10-point grading system to quantify ischemic changes in the posterior circulation. We analyzed whether pc-ASPECTS on CT angiography (CTA) source images (CTASI) predicted the final infarct extent and hemorrhagic transformation (HT) rate in patients with basilar artery occlusion. MATERIALS AND METHODS: A pc-ASPECTS score of 10 indicates absence of visible ischemic changes in the posterior circulation, and pc-ASPECTS score of 0 indicates ischemic changes in the midbrain, pons, and bilateral thalami, posterior circulation territories, and cerebellar hemispheres. We retrospectively studied patients with basilar artery occlusion on CTA within 24 hours from symptom onset. We applied pc-ASPECTS to noncontrast CT (NCCT), CTASI, and follow-up images by 3-reader-consensus and assessed HT on follow-up images. We calculated Spearman correlation coefficients and performed linear regression analysis. Final infarct extent and HT rates were compared across dichotomized CTASI pc-ASPECTS groups (>/= 8 vs < 8). RESULTS: Among 43 patients, median (range) onset to CTA time was 5.0 hours (range, 0.7-24 hours). Pc-ASPECTS on CTASI (r = 0.75; P < .001) but not NCCT (r = 0.29; P = .063) correlated with pc-ASPECTS on follow-up scans. Linear regression demonstrated a significant positive relationship between pc-ASPECTS on CTASI and follow-up scans (R(2) = 0.58; P < 01). Median follow-up pc-ASPECTS was lower in patients with a CTASI pc-ASPECTS < 8 compared with patients with a CTASI pc-ASPECTS of 8 or more, respectively (P < .001). HT rates were 27.3% vs 9.5%, respectively (P = .24). None of 8 patients without thrombolysis had HT on follow-up scans. CONCLUSIONS: The extent of hypoattenuation on CTASI predicts the final infarct extent in patients with basilar artery occlusion.

[Computed tomography in acute ischemic stroke. Current developments compared with stroke MRI]. / Computertomographie beim akuten Schlaganfall. Aktuelle Entwicklungen im Vergleich mit dem Schlaganfall-MRT.

Modern multimodal acute stroke computed tomography (CT) includes noncontrast cranial CT (NCT), CT angiography (CTA), and CT perfusion imaging (CTP). Compared to stroke MRI, NCT is faster and easier. Multimodal CT can determine acute stroke etiology: Is arterial occlusion or intracerebal hemorrhage present? How extensive are the perfusion disturbance and infarct core, respectively? The information from NCT is sufficient for making acute stroke thrombolysis decisions within 4.5 h from symptom onset. The therapeutic effect of CTA and CTP--as well as acute stroke MRI--on improved functional outcome has still not been established.

Disappearing hyperdense middle cerebral artery sign in ischaemic stroke patients treated with intravenous thrombolysis: clinical course and prognostic significance.

BACKGROUND AND PURPOSE: Hyperdense middle cerebral artery sign (HMCAS) on CT is a well known indication of thromboembolic arterial occlusion. Its disappearance after thrombolytic therapy is poorly described. Taking the rate of HMCAS disappearance as a surrogate for MCA recanalisation, its prognostic value after intravenous thrombolysis was examined. METHODS: 1905 stroke patients with HMCAS on admission CT scan in the Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR) were studied. On follow-up CT scans 22-36 h after thrombolysis, HMCAS disappeared in 831 cases, persisted in 788 and was uncertain in 122; follow-up CT was not done in 164 cases. RESULTS: Patients whose HMCAS disappeared were younger (median age 67 years vs 69 years for persistent; p = 0.03), with milder stroke (admission National Institute of Health Stroke Scale (NIHSS) score was 16 vs 17; p<0.005) and were less likely to have early infarct signs on admission CT (26% vs 33%; p<0.005). Patients with disappearing HMCAS were more likely to have early improvement in NIHSS score (median improvement 2 vs 0 at 2 h; 4 vs 1 at 24 h), be independent at 3 months (42% vs 19%), with fewer deaths (15% vs 30%) than those with persistent HMCAS. In multivariate analysis, HMCAS disappearance independently predicted functional independence and survival. Early NIHSS improvement independently predicted HMCAS disappearance. CONCLUSIONS: HMCAS disappeared after intravenous thrombolysis in about half of cases and these patients had twice as good outcomes compared with those with persistent HMCAS. The prognosis in patients with MCA occlusion that persists after intravenous thrombolysis is poor, which may indicate the need for an alternative treatment approach to this subgroup.

Endovascular therapy of symptomatic intracranial stenosis in patients with impaired regional cerebral blood flow or failure of medical therapy.

BACKGROUND AND PURPOSE: Symptomatic intracranial stenoses have a high risk for a recurrent stroke if treated medically. Although angioplasty and stent placement are proposed treatment options, data on longer-term outcome are limited. MATERIALS AND METHODS: We analyzed all endovascular procedures on symptomatic intracranial stenosis at our institution from January 1998 to December 2005. We retrospectively assigned patients to group A (symptoms despite antithrombotic therapy) or group B (impaired regional cerebral blood flow [rCBF]). Primary outcome events were periprocedural major complications or recurrent ischemic strokes in the territory of the treated artery. We used the Kaplan-Meier method to calculate survival probabilities. RESULTS: The procedural technical success rate was 92% (35/38) with periprocedural major complications in 4 cases (10.5%; group A [8.3%, 2/24], group B [14.3%, 2/14]). Median (range) follow-up for the 33 patients with technically successful procedures was 21 (0-72) months. Recurrent ischemic strokes occurred in 15% (3/20) of patients in group A and 0% (0/13) of patients in group B. Overall, there were 21% (7/33) primary outcome events (group A [25%, 5/20], group B [15%, 2/13]). There was a nonsignificant trend for better longer-term survival free of a major complication or recurrent stroke in patients with impaired rCBF compared with patients who were refractory to medical therapy treatment (Kaplan-Meier estimate 0.85 [SE 0.10] vs 0.72 [SE 0.11] at 2 years, respectively). CONCLUSION: Interventional treatment of symptomatic intracranial stenosis carries significant risk for complications and recurrent stroke in high-risk patients. The observation that patients with impaired rCBF may have greater longer-term benefit than medically refractory deserves further study.