Michael Knauth

Recombinant Human Erythropoietin in the Treatment of Acute Ischemic Stroke

Background and Purpose— Numerous preclinical findings and a clinical pilot study suggest that recombinant human erythropoietin (EPO) provides neuroprotection that may be beneficial for the treatment of patients with ischemic stroke. Although EPO has been considered to be a safe and well-tolerated drug over 2 decades, recent studies have identified increased thromboembolic complications and/or mortality risks on EPO administration to patients with cancer or chronic kidney disease. Accordingly, the double-blind, placebo-controlled, randomized German Multicenter EPO Stroke Trial (Phase II/III; ClinicalTrials.gov Identifier: NCT00604630) was designed to evaluate efficacy and safety of EPO in stroke. Methods— This clinical trial enrolled 522 patients with acute ischemic stroke in the middle cerebral artery territory (intent-to-treat population) with 460 patients treated as planned (per-protocol population). Within 6 hours of symptom onset, at 24 and 48 hours, EPO was infused intravenously (40 000 IU each). Systemic thrombolysis with recombinant tissue plasminogen activator was allowed and stratified for. Results— Unexpectedly, a very high number of patients received recombinant tissue plasminogen activator (63.4%). On analysis of total intent-to-treat and per-protocol populations, neither primary outcome Barthel Index on Day 90 (P=0.45) nor any of the other outcome parameters showed favorable effects of EPO. There was an overall death rate of 16.4% (n=42 of 256) in the EPO and 9.0% (n=24 of 266) in the placebo group (OR, 1.98; 95% CI, 1.16 to 3.38; P=0.01) without any particular mechanism of death unexpected after stroke. Conclusions— Based on analysis of total intent-to-treat and per-protocol populations only, this is a negative trial that also raises safety concerns, particularly in patients receiving systemic thrombolysis.

CT and diffusion-weighted MR imaging in randomized order: diffusion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke.

Background and Purpose— Diffusion-weighted MRI (DWI) has become a commonly used imaging modality in stroke centers. The value of this method as a routine procedure is still being discussed. In previous studies, CT was always performed before DWI. Therefore, infarct progression could be a reason for the better result in DWI. Methods— All hyperacute (<6 hours) stroke patients admitted to our emergency department with a National Institutes of Health Stroke Scale (NIHSS) score >3 were prospectively randomized for the order in which CT and MRI were performed. Five stroke experts and 4 residents blinded to clinical data judged stroke signs and lesion size on the images. To determine the interrater variability, we calculated &kgr; values for both rating groups. Results— A total of 50 patients with ischemic stroke and 4 patients with transient symptoms of acute stroke (median NIHSS score, 11; range, 3 to 27) were analyzed. Of the 50 patients, 55% were examined with DWI first. The mean delay from symptom onset until CT was 180 minutes; that from symptom onset until DWI was 189 minutes. The mean delay between DWI and CT was 30 minutes. The sensitivity of infarct detection by the experts was significantly better when based on DWI (CT/DWI, 61/91%). Accuracy was 91% when based on DWI (CT, 61%). Interrater variability of lesion detection was also significantly better for DWI (CT/DWI, &kgr;=0.51/0.84). The assessment of lesion extent was less homogeneous on CT (CT/DWI, &kgr;=0.38/0.62). The differences between the 2 modalities were stronger in the residents’ ratings (CT/DWI: sensitivity, 46/81%; &kgr;=0.38/0.76). Conclusions— CT and DWI performed with the same delay after onset of ischemic stroke resulted in significant differences in diagnostic accuracy. DWI gives good interrater homogeneity and has a substantially better sensitivity and accuracy than CT even if the raters have limited experience.

Acute disseminated encephalomyelitis: A follow-up study of 40 adult patients

Objectives: To describe the clinical, CSF, and radiologic findings and long-term follow-up in a cohort of patients with acute disseminated encephalomyelitis (ADEM), and to determine possible prognostic factors for progression to MS. Methods: Forty adults (28 women, mean age 33.5 years) diagnosed with ADEM were analyzed. Clinical symptoms, cranial MRI and CSF findings, and the response to a standardized treatment during the acute phase of the disease were analyzed by chart review. The final diagnosis of ADEM or clinically definite MS was established upon follow-up examination after 8 to 137 months. The patients with ADEM and MS were compared to detect differences between the two groups. Results: Fifteen patients had a preceding infection (n = 14) or immunization (n = 1). The most frequent clinical signs were motor deficit (80%), followed by sensory deficits, brainstem signs, and ataxia. CSF findings were highly variable; normal results were present in 20% of patients. Oligoclonal bands were positive in 65% of patients. Ninety-five percent of all patients improved during the acute phase of the disease. Upon follow-up, 14 patients had developed clinically definite MS. Of the 26 patients with the final diagnosis of ADEM, two patients had died, nine had minor deficits, three had moderate deficits, and 12 patients had no remaining symptoms. Patients with the final diagnosis of ADEM were older, and more often had a preceding infection, clinical signs of brainstem involvement, a higher CSF albumin fraction, and infratentorial lesions. Conclusions: Many patients initially diagnosed with ADEM develop clinically definite MS upon long-term follow-up. The authors found no useful diagnostic criteria for the differentiation of a first episode of MS from monophasic ADEM. The term ADEM may still be employed as a description of a clinical syndrome, but should not be used as a distinct entity until reliable diagnostic criteria have been developed.

Intraoperative diagnostic and interventional magnetic resonance imaging in neurosurgery

OBJECTIVE The benefits of intraoperative magnetic resonance (MR) imaging for diagnostic and therapeutic measures are as follows: 1) intraoperative update of data sets for navigational systems, 2) intraoperative resection control of brain tumors, and 3) frameless and frame-based on-line MR-guided interventions. The concept of an intraoperative MR scanner in the sterile environment of operating theater is presented, and its advantages, disadvantages, and limitations are discussed. METHODS A 0.2-tesla magnet (Magnetom Open; Siemens AG, Erlangen, Germany) inside a radiofrequency cabin with a radiofrequency-shielded sliding door was installed adjacent to one of the operating theaters. A specially designed patient transport system carried the patient in a fixed position on an air cushion to the scanner and back to the surgeon. RESULTS In a series of 27 patients, intraoperative resection control was performed in 13 cases, with intraoperative reregistration in 4 cases. Biopsies, cyst aspirations, and catheter placements (mainly frameless) were performed under direct MR visualization with fast image sequences. The MR-compatible equipment and the patient transport system are safe and reliable. CONCLUSION Intraoperative MR imaging is a safe and successful tool for surgical resection control and is clearly superior to computed tomography. Intraoperative acquisition of data sets eliminates the problem of brain shift in conventional navigational systems. Finally, on-line MR-guided interventional procedures can be performed easily with this setting. As with all MR systems, individual testing with phantoms, application of correction programs, and determination of the optimal amount of contrast media are absolute prerequisites to guarantee patient safety and surgical success.

Comparison of Perfusion Computed Tomography and Computed Tomography Angiography Source Images With Perfusion-Weighted Imaging and Diffusion-Weighted Imaging in Patients With Acute Stroke of Less Than 6 Hours’ Duration

Background and Purpose— We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke <6 hours. Methods— Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting <6 hours. We analyzed ischemic lesion volumes on patients’ arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI (Wilcoxon, Spearman, Bland–Altman) and compared them to the infarct extent as shown on day 5 NECT. Results— Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP (P =0.686 for patients who did not undergo thrombolysis/ P =0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV (P =0.893/ P =0.169). CTA-SI volumes did not differ from DWI volumes (P =0.465/ P =0.086). Lesion volumes measured in PCT maps significantly correlated with lesion volumes on PWI (P =0.0047, r =1.0/ P =0.0019, r =0.897 for TTP; P =0.0054, r =0.983/ P =0.0026, r =0.871 for CBV). Also, PCT-CBV lesion volumes significantly correlated with follow-up CT lesion volumes (P =0.0047, r =1.0/ P =0.0046, r =0.819). Conclusions— In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT (NECT), perfusion CT (PCT), and CT angiography (CTA) can render additional information within <15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients.

Clinical evaluation and follow-up results for intraoperative magnetic resonance imaging in neurosurgery.

OBJECTIVE The use of intraoperative magnetic resonance imaging (MRI) in neurosurgery has increased rapidly, and a variety of concepts have recently been presented. Although the feasibility of the procedure has been demonstrated repeatedly, no conclusive analysis of its effects on the surgical procedures, the extent of tumor removal, and outcomes, or its possible problems, has been performed. METHODS Of 242 operations performed with intraoperative MRI, 97 procedures for supratentorial glioma treatment were analyzed with respect to intraoperative imaging results and postoperative outcomes. Analysis of the images included assessment of imaging artifacts, image quality, and extent of tumor removal. Patients were monitored to determine radiological progression, survival times, postoperative complications, and morbidity rates. RESULTS No intraoperative complications related to the imaging procedure were observed. Image quality was good or fair in 85.5% of the cases. Different types of surgically induced imaging changes could be identified. In 56 cases, resection was continued using navigation with intraoperative MRI data sets (rereferencing accuracy, 0.9 mm). For high-grade gliomas, the percentage of cases in which residual tumor was identified by MRI could be significantly reduced from 62% intraoperatively to 33% postoperatively, which was paralleled by a significant increase in survival times for patients without residual tumor. Complication and morbidity rates were within the ranges reported for other studies. CONCLUSION Intraoperative MRI is safe and allows reliable updating of neuronavigational data, with compensation for brain shifting. Surgically induced imaging changes, which have been identified as a possible problem with intraoperative MRI in general, necessitated comparisons with preoperative scans and require future attention. The extent of tumor removal and survival times were increased significantly. Overall, patients seemed to benefit from the method.

Comparison of CT and CT Angiography Source Images With Diffusion-Weighted Imaging in Patients With Acute Stroke Within 6 Hours After Onset

Background and Purpose— Although stroke MRI has advantages over other diagnostic imaging modalities in acute stroke patients, most of these individuals are admitted to emergency units without MRI facilities. There is a need for an accurate diagnostic tool that rapidly and reliably detects hemorrhage, extent of ischemia, and vessel status and potentially estimates tissue at risk. We sought to determine the diagnostic accuracy of the combination of non–contrast-enhanced CT, CT angiography (CTA), and CTA source images (CTA-SI, showing early parenchymal contrast enhancement) in comparison with a multiparametric stroke MRI protocol in patients with acute stroke within 6 hours after onset. Methods— Non–contrast-enhanced CT, CTA, stroke MRI including diffusion-weighted imaging (DWI), and MR angiography (MRA) were performed in patients with symptoms of acute stroke within 6 hours after onset. We analyzed infarct volumes on days 1 and 5 as shown on CTA-SI, DWI, and T2-weighted images (Wilcoxon, Mann-Whitney, Spearman tests), estimated the collateral status, and assessed clinical outcome (modified Rankin Scale, Barthel Index, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale). Results— We analyzed the data of 20 stroke patients who underwent CT and MRI scanning within 6 hours (mean, 2.83 and 3.38 hours, respectively). Vessel occlusion was present in 16 of 20 patients. CTA-SI volumes did not differ from DWI volumes (P =0.601). Furthermore, the CTA-SI lesion volumes significantly correlated with the initial DWI lesion volumes (P <0.0001, r =0.922) and with outcome lesion volumes (P =0.013 r =0.736). Patients with poor collaterals experienced infarct growth (P =0.0058) and had a significantly worse clinical outcome (all P <0.012); patients with good collaterals did not (P =0.176). Conclusions— The combination of non–contrast-enhanced CT (exclusion of intracranial hemorrhage), CTA (vessel status), and early contrast-enhanced CTA-SI (demarcation of irreversible infarct) allows diagnostic assessment of acute stroke with a quality comparable to that of stroke MRI. Furthermore, it is possible to distinguish patients at risk of infarct growth from those who are not according to the collateral status, in analogy with the stroke MRI mismatch concept.

Cohort study of multiple brain lesions in sport divers: role of a patent foramen ovale

Abstract Objective: To investigate the role of a patent foramen ovale in the pathogenesis of multiple brain lesions acquired by sport divers in the absence of reported decompression symptoms. Design: Prospective double blind cohort study. Setting: Diving clubs around Heidelberg and departments of neuroradiology and neurology. Subjects: 87 sport divers with a minimum of 160 scuba dives (dives with self contained underwater breathing apparatus). Main outcome measures: Presence of multiple brain lesions visualised by cranial magnetic resonance imaging and presence and size of patent foramen ovale as documented by echocontrast transcranial Doppler ultrasonography. Results: 25 subjects were found to have a right-to-left shunt, 13 with a patent foramen ovale of high haemodynamic relevance. A total of 41 brain lesions were detected in 11 divers. There were seven brain lesions in seven divers without a right-to-left shunt and 34 lesions in four divers with a right-to-left shunt. Multiple brain lesions occurred exclusively in three divers with a large patent foramen ovale (P=0.004). Conclusions: Multiple brain lesions in sport divers were associated with presence of a large patent foramen ovale. This association suggests paradoxical gas embolism as the pathological mechanism. A patent foramen ovale of high haemodynamic relevance seems to be an important risk factor for developing multiple brain lesions in sport divers. Key messages An increased prevalence of multiple brain lesions has been reported in scuba divers compared with non-diving controls It has been suggested that the brain lesions were due to arterial gas embolism and that the gas emboli could have entered the arterial circulation via a patent foramen ovale We investigated this hypothesis in volunteer sport divers who had made at least 160 scuba dives Brain lesions occurred in divers even in the absence of reported decompression sickness Multiple brain lesions occurred exclusively in divers with a large patent foramen ovale The association of multiple brain lesions with a large patent foramen ovale suggests paradoxical gas embolism as the pathological mechanism

Role of CT Angiography in Patient Selection for Thrombolytic Therapy in Acute Hemispheric Stroke

BACKGROUND AND PURPOSE It has been shown that thrombolytic therapy can improve clinical outcome in a subgroup of patients with acute cerebral ischemia. This subgroup was characterized by certain clinical and imaging findings (eg, moderate to severe neurological deficit for less than 3 to 6 hours, occlusion of the middle cerebral artery, lack of extended infarct signs on CT, and efficient leptomeningeal collaterals). Although not part of published prospective randomized rtPA trials, information about the status of the brain vessels would be helpful in the selection of patients who may benefit the most. Our purpose was to determine the feasibility of CT angiography (CTA) in patients with acute hemispheric ischemia and to evaluate its relevance for thrombolytic therapy. METHODS CTA was performed in 40 consecutive patients (11 women and 29 men; age range, 19 to 80 years) with moderate or severe symptoms (National Institutes of Health Stroke Scale score of > or =8) of acute hemispheric ischemia. CTA findings were compared with Doppler ultrasonography (US; n=22) and intra-arterial digital subtraction angiography (DSA; n=7). Twenty patients received thrombolytic therapy, the remaining patients received intravenous heparin. RESULTS Images and 3-dimensional reconstructions of diagnostic quality could be obtained in all patients. Thirty-four patients had a vessel occlusion. The extent of leptomeningeal collaterals correlated significantly with the outcome after thrombolytic therapy (rs=0.46, P<0.05). The evaluation of diagnostic accuracy showed a high agreement with US (22 of 22) and DSA (6 of 7). CONCLUSIONS CTA can provide important information for the initiation of therapy in patients with acute hemispheric ischemia. Identification of patients with autolyzed thrombi, occlusion of the internal carotid artery bifurcation, and poor leptomeningeal collaterals is feasible with the use of CTA. These patients may have little potential for benefit from thrombolytic therapy.

Intraoperative Magnetic Resonance Imaging to Update Interactive Navigation in Neurosurgery: Method and Preliminary Experience

We report on the first successful intraoperative update of interactive image guidance based on an intraoperatively acquired magnetic resonance imaging (MRI) date set. To date, intraoperative imaging methods such as ultrasound, computerized tomography (CT), or MRI have not been successfully used to update interactive navigation. We developed a method of imaging patients intraoperatively with the surgical field exposed in an MRI scanner (Magnetom Open; Siemens Corp., Erlangen, Germany). In 12 patients, intraoperatively acquired 3D data sets were used for successful recalibration of neuronavigation, accounting for any anatomical changes caused by surgical manipulations. The MKM Microscope (Zeiss Corp., Oberkochen, Germany) was used as navigational system. With implantable fiducial markers, an accuracy of 0.84 +/- 0.4 mm for intraoperative reregistration was achieved. Residual tumor detected on MRI was consequently resected using navigation with the intraoperative data. No adverse effects were observed from intraoperative imaging or the use of navigation with intraoperative images, demonstrating the feasibility of recalibrating navigation with intraoperative MRI.