Wolfgang Müllges

Effect of a Novel Free Radical Scavenger, Edaravone (MCI-186), on Acute Brain Infarction

Edaravone, a novel free radical scavenger, demonstrates neuroprotective effects by inhibiting vascular endothelial cell injury and ameliorating neuronal damage in ischemic brain models. The present study was undertaken to verify its therapeutic efficacy following acute ischemic stroke. We performed a multicenter, randomized, placebo-controlled, double-blind study on acute ischemic stroke patients commencing within 72 h of onset. Edaravone was infused at a dose of 30 mg, twice a day, for 14 days. At discharge within 3 months or at 3 months after onset, the functional outcome was evaluated using the modified Rankin Scale. Two hundred and fifty-two patients were initially enrolled. Of these, 125 were allocated to the edaravone group and 125 to the placebo group for analysis. Two patients were excluded because of subarachnoid hemorrhage and disseminated intravascular coagulation. A significant improvement in functional outcome was observed in the edaravone group as evaluated by the modified Rankin Scale (p = 0.0382). Edaravone represents a neuroprotective agent which is potentially useful for treating acute ischemic stroke, since it can exert significant effects on functional outcome as compared with placebo.

Anticoagulant Reversal, Blood Pressure Levels, and Anticoagulant Resumption in Patients With Anticoagulation-Related Intracerebral Hemorrhage

IMPORTANCE Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of ≥1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs ≥160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01829581.

Cognitive performance after coronary artery bypass grafting: A follow-up study

Abstract—The authors studied 52 of an initial cohort of 91 patients who underwent coronary artery bypass grafting and survived the perioperative period without stroke or other comorbidities, after a median follow-up of 55 months. Baseline data of the followed patients were comparable to those lost for follow-up. No patient showed a decline in neuropsychological test performance as compared to baseline. Vascular risk factor control was good in all patients, possibly contributing to the favorable outcome.

CT perfusion predicts secondary cerebral infarction after aneurysmal subarachnoid hemorrhage.

Objective: To prospectively assess the diagnostic accuracy of CT perfusion (CTP) and transcranial Doppler sonography (TCD) for the prediction of secondary cerebral infarction (SCI) after aneurysmal subarachnoid hemorrhage (SAH). Methods: During 2 weeks after SAH, 38 consecutive patients completed an average of 3.5 CT/CTP and 10.7 TCD examinations at regular intervals as required by the study protocol. SCI was defined as delayed infarction on native CT between 3 and 14 days after SAH and developed in n = 14 patients (n = 24 without SCI). Analysis was based on examination dates before SCI. Common measures of diagnostic accuracy were calculated for qualitative CTP (visual color-map ratings from two blinded observers) and TCD assessments (mean flow velocity >120 cm/s in anterior, middle, and posterior cerebral artery territories). Quantitative measures, which for CTP were obtained from cortical a priori regions of interest corresponding to the vascular territories, were analyzed by binary logistic regression. Results: Time of prediction for SCI by CTP was at a median of 3 days (range 2 to 5 days) before manifestation of complete infarction on native CT. Visual assessment of time-to-peak (TTP) color maps performed best for the prediction of SCI with 0.93 sensitivity (95% CI: 0.7 to 1.0) and 0.67 specificity (95% CI: 0.53 to 0.7). On quantitative analysis, the odds ratio (OR) for 1 second of side-to-side delay in TTP was 1.4 (p = 0.01, Wald χ2 = 8.57, CI: 1.07 to 1.82). Daily TCD measures were not significantly related to SCI at any time before complete infarction on native CT. Conclusions: Time to peak as indicated by CT perfusion is a sensitive and early predictor of secondary cerebral infarction.

Early natural course of transient encephalopathy after coronary artery bypass grafting.

Objective A decline of neuropsychological performance is an unwanted side effect of coronary artery bypass grafting (CABG) with extracorporeal circulation. There is little data on the neuropsychological changes during the first 2 wks after CABG. Design, Setting, Patients In this prospective observational study at our university medical center, a group of 67 patients who underwent routine CABG was selected for absence of comorbidity (such as carotid stenosis, previous stroke, dementia, and advanced general medical disorders) and examined. In this selected group of patients, no focal deficit was seen throughout the study. A total of 20 hospitalized patients with different types of peripheral neuropathy and free from drugs interfering with cognition served as a control group for the practice effects of the neuropsychological testing. Measurements and Main Results Seven standard tests covering different neuropsychological domains were used as a composite battery. Examinations took place before surgery and serially at days 3, 6, and 9 after CABG; general neurologic examination was done every day, including the first postoperative day. We observed a definite decline in all tests at day 3 (p < .01) and progressive recovery thereafter up to or even beyond preoperative values within 9 days (p < .01). Transient depression as indicated by self-rated scores occurred in some patients. Conclusion We observed a uniform, but transient, deterioration in performance on a battery of frequently repeated standardized neuropsychological tests early after CABG. Our data on the early natural course may help to better evaluate treatment efforts aimed at preventing or reducing after-surgery neuropsychological alterations.

Selective degeneration of sudomotor fibers in Ross syndrome and successful treatment of compensatory hyperhidrosis with botulinum toxin

We report a 5‐year follow‐up of a patient with Ross syndrome. A biopsy of the anhidrotic skin immunostained with protein gene product 9.5 visualized by confocal microscopy revealed selective loss of sudomotor fibers, whereas epidermal innervation remained intact, providing the first morphologic evidence of selective loss of sudomotor fibers in this syndrome. Among the different treatment strategies employed for the patients disabling segmental hyperhidrosis, intracutaneous injection of botulinum toxin A was the most helpful.

Eyeball pressure testing in the evaluation of serious bradyarrhythmias in Guillain-Barre syndrome

Objective: To investigate the usefulness of eyeball pressure testing (EP) as an indicator for impending serious bradyarrhythmias in patients with Guillain-Barre syndrome (GBS) and its relationship to motor disability. Background: Autonomic dysfunction is a common complication in GBS and accounts for a significant number of deaths. Serious bradyarrhythmias are thought to occur only in severe cases but are difficult to predict. Methods/Design: In 13 consecutive patients with GBS aged 29 to 70 years, 156 EP (6 to 19 per patient) were done serially for up to 1 year. Bilateral moderate pressure was manually applied and sustained for 25 seconds or until abnormal bradycardia developed, defined as heart rate below 40 beats per minute. Disability was graded by a score from 0 to 5 (DS). Results: Four of 13 patients (DS 2/2/3-4/5) showed abnormal sensitivity to EP at least once. In two of them, vagal overreactivity could be demonstrated repeatedly, which gradually resolved within 4 and 10 days. In one patient with a rapid progressive course requiring early cardiopulmonary resuscitation, a highly abnormal EP could be recorded until 1 day after heart arrest. Another patient (DS 3-4) with abnormal EP required cardiac pacing twice because of significant bradycardia. The only other event necessitating pacing occurred in a severely disabled patient (DS 5-4) who never showed abnormal EP. Conclusions: Vagal overreactivity could be demonstrated in approximately 30% of our patients. It was not restricted to severe motor impairment and was also present in mild-to-moderately disabled patients. In this regard, EP may be a simple and useful bedside test to indicate an increased risk of developing serious bradyarrhythmias in patients with GBS. NEUROLOGY 1996;47: 102-108

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany – A national case collection:

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran that reverses its anticoagulant effects within minutes. It may exhibit the potential for patients under dabigatran therapy suffering ischemic stroke to regain eligibility for thrombolysis with rt-PA and may inhibit lesion growth in patients with intracerebral hemorrhage on dabigatran. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January to August 2016 were used. Results Thirty-one patients presenting with signs of stroke received idarucizumab in 22 stroke centers. Nineteen patients treated with dabigatran presented with ischemic stroke and 12 patients suffered from intracranial bleeding. In patients receiving rt-PA thrombolysis following idarucizumab, 79% benefitted from i.v. thrombolysis with a median improvement of five points in NIHSS. No bleeding complications occurred. Hematoma growth was observed in 2 out of 12 patients with intracranial hemorrhage. The outcome was favorable with a median NIHSS improvement of 5.5 points and mRS 0–3 in 67%. Overall, mortality was low with 6.5% (one patient in each group). Conclusion Administration of rt-PA after reversing dabigatran activity with idarucizumab in case of ischemic stroke is feasible, easy to manage, effective, and appears to be safe. In dabigatran-associated intracranial hemorrhage, idarucizumab has the potential to prevent hematoma growth and improve outcome. Idarucizumab represents a new therapeutic option for patients under dabigatran treatment presenting with ischemic stroke or intracranial hemorrhage.

Cerebral arteriovenous transit time (cTT): a sonographic assessment of cerebral microcirculation using ultrasound contrast agents

Transcranial color-coded sonography (TCCS) has been used to investigate major brain-supplying arteries, draining veins and brain parenchyma. Here, we describe a contrast-enhanced TCCS analysis of cerebral arteriovenous transit time (cTT) as a measure of cerebral microcirculation. We evaluate its reproducibility and its correlation with clinical impairment of brain function and neuropsychological tests. A total of 27 patients with cerebral microangiopathy and 30 healthy controls were examined. CTT is defined by the time an ultrasound contrast agent requires to pass from the P2-segment of the posterior cerebral artery to the vein of Galen. This was measured by comparison of power Doppler intensity in two off-line defined regions of interest. Serial intraindividual cTT measurements within several min showed a good reproducibility of this parameter. cTT was significantly longer in patients with cerebral microangiopathy than in controls (Mann-Whitney U test,p < 0.001) and related to cognitive impairment measured by the Mini-Mental-State examination. We conclude that it is a quick and reliable parameter related to increased vascular resistance of the microcirculation or a rarefaction of microvessels. Further studies are needed to show the sensitivity and specificity of cTT in the diagnosis of small vessel disease and the interference of important circulation factors, such as heart failure or blood viscosity.

Noninvasive assessment of intracranial fistulas and other small arteriovenous malformations

Twenty patients in whom the diagnosis of an intracranial arteriovenous malformation was suspected either by the history and clinical findings or by abnormal periorbital Doppler flow are discussed. Sixteen patients had only minor complaints or inconclusive signs or were clinically asymptomatic; 4 others presented with the syndrome of a carotid cavernous fistula. Patients were further examined by means of transcranial Doppler sonography, computed tomographic scanning, and cerebral angiography. In 17 patients, the diagnosis of an arteriovenous malformation could be established by transcranial Doppler sonography and could be confirmed by angiography. Transcranial Doppler sonography gave false negative results in 1 and false positive results in 2 patients. Our findings demonstrate the usefulness of modern ultrasound techniques in the assessment of small or even occult intracranial arteriovenous shunts before subjecting patients to more invasive procedures.