Nils Henninger

University of Massachusetts Medical School, Worcester, MA, United States

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Publications (49)190.51 Total impact

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    ABSTRACT: Leukoaraiosis is a common finding among patients with ischemic stroke and has been associated with poor stroke outcomes. Our aim was to ascertain whether the severity of pre-existing leukoaraiosis is associated with outcome in patients with acute ischemic stroke who are treated with endovascular stroke therapy.
    AJNR. American journal of neuroradiology. 07/2014;
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    ABSTRACT: It is now well accepted that traumatic white matter injury constitutes a critical determinant of post-traumatic functional impairment. However, the contribution of preexisting white matter rarefaction on outcome following traumatic brain injury (TBI) is unknown. Hence, we sought to determine whether the burden of preexisting leukoaraiosis of presumed ischemic origin is independently associated with outcome after TBI. We retrospectively analyzed consecutive, prospectively enrolled patients of ≥50 years (n = 136) who were admitted to a single neurological/trauma intensive care unit. Supratentorial white matter hypoattenuation on head CT was graded on a 5-point scale (range 0-4) reflecting increasing severity of leukoaraiosis. Outcome was ascertained according to the modified Rankin Scale (mRS) and Glasgow outcome scale (GOS) at 3 and 12 months, respectively. After adjustment for other factors, leukoaraiosis severity was significantly associated with a poor outcome at 3 and 12 months defined as mRS 3-6 and GOS 1-3, respectively. The independent association between leukoaraiosis and poor outcome remained when the analysis was restricted to patients who survived up to 3 months, had moderate-to-severe TBI [enrollment Glasgow Coma Scale (GCS) ≤12; p = 0.001], or had mild TBI (GCS 13-15; p = 0.002), respectively. We provide first evidence that preexisting cerebral small vessel disease independently predicts a poor functional outcome after closed head TBI. This association is independent of other established outcome predictors such as age, comorbid state as well as intensive care unit complications and interventions. This knowledge may help improve prognostic accuracy, clinical management, and resource utilization.
    Neurocritical Care 04/2014; · 3.04 Impact Factor
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    ABSTRACT: Leukoaraiosis (LA) predominantly affects the subcortical white matter, but mounting evidence suggests an association with cortical microvascular dysfunction and potentially decreased cortical ischemic tolerance. Thus, we sought to assess whether preexisting LA is predictive of the cortical infarct volume after middle cerebral artery branch occlusion and whether it relates to a worse outcome. We analyzed data from 117 consecutive patients with middle cerebral artery branch occlusion as documented by admission computed tomography angiography. Baseline clinical, laboratory, and outcome data, as well as final cortical infarct volumes, were retrospectively analyzed from a prospectively collected database. LA severity was assessed on admission computed tomography using the van Swieten scale grading the supratentorial white matter hypoattenuation. Infarct volume predicting a favorable 90-day outcome (modified Rankin Scale score ≤2) was determined by receiver operating characteristic curves. Multivariable linear and logistic regression analyses were used to identify independent predictors of the final infarct volume and outcome. Receiver operating characteristic curve analyses indicated that a final infarct volume of ≤27 mL best predicted a favorable 90-day outcome. Severe LA (odds ratio, 11.231; 95% confidence interval, 2.526-49.926; P=0.001) was independently associated with infarct volume >27 mL. Severe LA (odds ratio, 3.074; 95% confidence interval, 1.055-8.961; P=0.040) and infarct volume >27 mL (odds ratio, 9.156; 95% confidence interval, 3.191-26.270; P<0.001) were independent predictors of a poor 90-day outcome (modified Rankin Scale, 3-6). The presence of severe, subcortical LA contributes to larger cortical infarct volumes and worse functional outcomes adding to the notion that the brain is negatively affected beyond LA's macroscopic boundaries.
    Stroke 02/2014; · 6.16 Impact Factor
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    ABSTRACT: Current recommendations encourage the use of embolic stroke (ES) models and replication of results across laboratories in preclinical research. Since such endeavors employ different surgeons, we sought to ascertain the impact of injection technique on outcome and response to thrombolysis in an ES model. Embolic stroke was induced in Male Wistar Kyoto rats (n=166) by a fast or a slow clot injection (CI) technique. Saline or recombinant tissue plasminogen activator (rtPA) was given at 1 hour after stroke. Flow rate curves were assessed in 24 animals. Cerebral perfusion was assessed using laser Doppler flowmetry. Edema corrected infarct volume, hemispheric swelling, hemorrhagic transformation, and neurologic outcome were assessed at 24 hours after stroke. Clot burden was estimated in a subset of animals (n=40). Slow CI resulted in significantly smaller infarct volumes (P=0.024) and better neurologic outcomes (P=0.01) compared with fast CI at 24 hours. Unexpectedly, rtPA treatment attenuated infarct size in fast (P<0.001) but not in slow CI experiments (P=0.382), possibly related to reperfusion injury as indicated by greater hemorrhagic transformation (P<0.001) and hemispheric swelling (P<0.05). Outcome and response to thrombolysis after ES are operator dependent, which needs to be considered when comparing results obtained from different laboratories.Journal of Cerebral Blood Flow & Metabolism advance online publication, 15 January 2014; (2014) 0, 000-000. doi:10.1038/jcbfm.2014.1.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 01/2014; · 5.46 Impact Factor
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    ABSTRACT: Factors influencing outcome after cerebral artery occlusion are not completely understood. Although it is well accepted that the site of arterial occlusion critically influences outcome, the majority of studies investigating this issue has focused on proximal large artery occlusion. To gain a better understanding of factors influencing outcome after distal large artery occlusion, we sought to assess predictors of outcome following isolated M2 middle cerebral artery occlusion infarcts. We retrospectively analyzed patients with isolated acute M2 occlusion admitted to a single academic center from January 2010 to August 2012. Baseline clinical, laboratory imaging, and outcome data were assessed from a prospectively collected database. Factors associated with a modified Rankin Scale (mRS) score ≤2 in univariable analyses (p < 0.05) were entered into multivariable logistic regression analysis. The Admission National Institutes of Health Stroke Scale (aNIHSS) score, age, and infarct volume were also entered as dichotomized variables. Receiver operating characteristic curves were plotted to determine the optimal aNIHSS score, infarct volume, and age cut points predicting an mRS score ≤2. Optimal thresholds were determined by maximizing the Youden index. Respective multivariable logistic regression analyses were used to identify independent predictors of a good 90-day outcome (mRS score ≤2; primary analysis) as well as 90-day mortality (secondary outcome). 90 patients with isolated M2 occlusion were included in the final analyses. Of these, 69% had a good 90-day outcome which was associated with age <80 years (p = 0.007), aNIHSS <10 (p = 0.002), and infarct volume ≤26 ml (p < 0.001). Notably, 20% of patients (64% of those with a poor outcome) had died by 90 days. Secondary analysis for 90-day mortality was performed. This analysis indicated that infarct volume >28 ml (OR 11.874, 95% CI 2.630-53.604, p = 0.001), age >80 years (OR 4.953, 95% CI 1.087-22.563, p = 0.039), need for intubation (OR 7.788, 95% CI 1.072-56.604), and history of congestive heart failure (OR 5.819, 95% CI 1.140-29.695) were independent predictors of 90-day mortality (20% of all included patients). While the majority of patients with isolated M2 occlusion stroke has a good 90-day outcome, a substantial proportion of subjects dies by 90 days, as identified by a unique subset of predictors. The knowledge gained from our study may lead to an improvement in the prognostic accuracy, clinical management, and resource utilization in this patient population.
    Cerebrovascular diseases extra. 01/2014; 4(1):52-60.
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    ABSTRACT: To evaluate the relationship between infarct location and QTc-prolongation in patients with posterior circulation strokes. Admission electrocardiograms (ECG) of 131 patients among a prospective sample of 407 consecutive adult patients in the New England Medical Center Posterior Circulation Registry were retrospectively analyzed. The QT interval (ms) was measured and corrected using Bazett's formula (QTcBazett) as well as linear regression functions (QTcLinear). QTcBazett > 440 ms and QTcLinear ≥ 450 ms for men (≥460 ms for women) were considered prolonged. Multivariable linear and logistic regression analyses were used to identify independent predictors of the QTc. Overall, 34 % of patients had a prolonged QTcBazett and 7 % had a prolonged QTcLinear noted on the admission ECG. There was a significant association between temporal lobe infarction and QTcBazett and QTcLinear (p < 0.001 for both) in multivariable linear regression analyses adjusting for demographics, ECG parameters, and preadmission medication use. In multivariable logistic regression analysis, temporal lobe infarction emerged as an independent predictor of prolonged QTcBazett (p = 0.009) and QTcLinear (p = 0.008), respectively. Sensitivity analyses excluding patients with transient ischemic attack yielded similar results. Exploratory analyses indicated that patients with temporal lobe infarction had worse functional 30-day outcomes in multivariable logistic regression (p = 0.022). However, there was no significant association between QTc and 30-day functional outcome. QTc-prolongation is common after posterior circulation stroke and associated with temporal lobe infarction. Prospective studies are needed to confirm these preliminary findings and to examine potential long-term consequences.
    Neurocritical Care 07/2013; · 3.04 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Leukoaraiosis (LA) and male sex have been associated with decreased cerebrovascular reactivity, which potentially adversely affects tissue viability in acute stroke. Therefore, we aimed to elucidate the contribution of LA-severity and sex to the extent of the hyperacute ischemic core volume after intracranial large artery occlusion. METHODS: We analyzed data from 87 patients with acute intracranial large artery occlusion who had acute multimodal computed tomography-imaging. LA-severity was assessed using the van Swieten scale on noncontrast computed tomography. Computed tomography perfusion data were analyzed using automatic calculation of the mean transit time and hyperacute cerebral blood volume defects. Multivariate linear and logistic regression analyses were used to identify independent predictors of the hyperacute infarct-volume. RESULTS: Severe LA (van Swieten Scale, 3-4; odds ratio, 43.22; 95% CI, 6.26-298.42; P<0.001) and male sex (odds ratio, 7.52; 95% CI, 1.38-40.86; P=0.020) were independently associated with a hyperacute cerebral blood volume-lesion >25 mL on multivariate logistic regression analysis. Multivariate linear regression analysis confirmed the association between severe LA (P<0.001) and male sex (P=0.01) with larger cerebral blood volume-lesions. There was no significant difference in the absolute or relative mean transit time-lesion volumes when stratified by LA-severity or sex. Women had significantly smaller cerebral blood volume-lesion volumes compared with men (P=0.036). CONCLUSIONS: Severe LA and male sex are associated with larger infarct cores, which adds to the notion that sex and LA alter the brain's intrinsic susceptibility to acute cerebral ischemia. Future, larger studies are needed to confirm our observation that women have smaller core volumes and its significance.
    Stroke 12/2012; · 6.16 Impact Factor
  • Clinical neurology and neurosurgery 11/2012; · 1.30 Impact Factor
  • Diogo C Haussen, Nils Henninger, Magdy Selim
    Acta neurologica Belgica 09/2012; · 0.47 Impact Factor
  • Neurology 08/2012; 79(9):e79. · 8.25 Impact Factor
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    ABSTRACT: Statins have been associated with increased risk of intracerebral hemorrhage (ICH), particularly in elderly patients with previous ICH. Recurrent ICH in the elderly is often related to cerebral amyloid angiopathy. Therefore, we investigated whether statin use is associated with increased prevalence and severity of microbleeds (MB), particularly cortico-subcortical microbleeds (csMB), which are frequently observed in cerebral amyloid angiopathy. We studied 163 consecutive patients with spontaneous ICH who underwent magnetic resonance imaging within 30 days of presentation. We retrieved clinical information and analyzed magnetic resonance imaging for the presence, location, and number of MB, which were divided into csMB or other (other MB). We performed group comparisons stratified by statin use and by the presence vs absence of any MB (csMB and/or other MB) or csMB alone. Sixty-four percent had lobar ICH. Overall, 53% had microbleeds and 39% had csMB. Statin users were older, had significantly lower cholesterol and low-density lipoprotein levels, and higher prevalence of hypertension, diabetes, dyslipidemia, and antiplatelet use. The prevalence and number of other MB were similar in statin-treated and statin-untreated individuals. However, more statin-treated patients had csMB (57% vs 33%; P=0.007), with almost twice as many lesions (4.6±11.3 vs 2.4±8.0; P=0.007) compared with untreated patients. Age and statin use were independently associated with both the presence and increased number of MB (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.00-1.05; P=0.01 and OR, 2.72; 95% CI. 1.02-7.22; P=0.04, respectively) and csMB (OR, 1.03; 95% CI, 1.00-1.06; P=0.01 and OR, 4.15; 95% CI, 1.54-11.20; P<0.01) in multivariate analyses. Statin use in patients with ICH is independently associated with MB, especially csMB. Future studies are needed to confirm our findings and to investigate whether csMB can serve as a surrogate marker for ICH risk in statin-treated patients.
    Stroke 07/2012; 43(10):2677-81. · 6.16 Impact Factor
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    Nils Henninger, Diogo C Haussen, Sandeep Kumar
    Neurology 06/2012; 78(23):e146. · 8.25 Impact Factor
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    ABSTRACT: To date limited information regarding outcome-modifying factors in patients with acute intracranial large artery occlusion (ILAO) in the anterior circulation is available. Leukoaraiosis (LA) is a common finding among patients with ischemic stroke and has been associated with poor post-stroke outcomes but its association with ILAO remains poorly characterized. This study sought to clarify the contribution of baseline LA and other common risk factors to 90-day outcome (modified Rankin Scale, mRS) after stroke due to acute anterior circulation ILAO. We retrospectively analyzed 1,153 consecutive patients with imaging-confirmed ischemic stroke during a 4-year period (2007-2010) at a single academic institution. The final study cohort included 87 patients with acute ILAO subjected to multimodal CT imaging within 24 h of symptom onset. LA severity was assessed using the van Swieten scale on non-contrast CT. Leptomeningeal collaterals were graded using CT angiogram source images. Hemorrhagic transformation (HT) was determined on follow-up CT. Multivariate logistic regression controlling for HT, treatment modality, demographic, as well as baseline clinical and imaging characteristics was used to identify independent predictors of a poor outcome (90-day mRS >2). The median National Institutes of Health Stroke Scale (NIHSS) at baseline was 15 (interquartile range 9-21). Twenty-four percent of the studied patients had severe LA. They were more likely to have hypertension (p = 0.028), coronary artery disease (p = 0.015), poor collaterals (p < 0.001), higher baseline NIHSS (p = 0.003), higher mRS at 90 days (p < 0.001), and were older (p = 0.002). Patients with severe LA had a uniformly poor outcome (p < 0.001) irrespective of treatment modality. Poor outcome was independently associated with higher baseline NIHSS (p < 0.001), worse LA (graded and dichotomized, p < 0.001), reduced leptomeningeal collaterals (graded and dichotomized, p < 0.001), presence of HT (p < 0.001), presence of parenchymal hemorrhages (p = 0.01), baseline mRS (p = 0.002), and older age (p = 0.043). The association between severe LA (p = 0.0056; OR 13.86; 95% CI 1.94-∞) and baseline NIHSS (p = 0.0001; OR 5.11; 95% CI 2.07-14.49 for each 10-point increase) with poor outcome maintained after adjustment for confounders in the final regression model. In this model, there was no significant association between presence of HT and poor outcome (p = 0.0572). Coexisting LA may predict poor functional outcome in patients with acute anterior circulation ILAO independent of other known important outcome predictors such as comorbid state, admission functional deficit, collateral status, hemorrhagic conversion, and treatment modality.
    Cerebrovascular Diseases 04/2012; 33(6):525-31. · 2.81 Impact Factor
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    ABSTRACT: Preclinical ischemic stroke is at the crossroads in search of reliable and robust simulation models as past experiences with their translation from the laboratory to the standard of clinical care have often been disappointing. The efficacy of neuroprotective agents is still elusive, and the use of thrombolytics alone is limited to the narrow time window of presentation from the onset of the deficit. Hence, the focus has shifted to interventional revascularization to salvage the parenchyma at the risk of infarction. As the burden of disease morbidity and mortality is so enormous, neurointerventionalists have adopted a more aggressive approach to mechanical revascularization with the limited approved tools available-the Penumbra and the MERCI retrieval system, and the recently incorporated stent retrievers. In fact, the interventional space is among the fastest growing fields in stroke research today. Assessing treatment efficacy in these scenarios is infinitely complex as the heterogeneity of the cerebrovasculature, physical and mechanical nature of the occlusive embolus and the time of presentation are all confounders in assessing treatment outcomes. As no single thromboembolic model is apt to address all of these questions, an integrated methodology with a combination of both in vitro and in vivo assessment needs to be adopted. This involves clinically relevant thromboembolic analogs in device evaluation in vascular replicas, thromboembolic stroke induction in large animal gyrencephalic ischemic stroke models for thrombolytic, imaging and neuroprotection research and a native cerebrovascular target for evaluation of the safety and efficacy of mechanical thrombectomy devices.
    Journal of neurointerventional surgery 07/2011; 4(4):307-13. · 1.38 Impact Factor
  • Lucia Rivera-Lara, Nils Henninger
    Archives of neurology 03/2011; 68(3):386-7. · 7.58 Impact Factor
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    ABSTRACT: The purpose of this study was to develop a novel MRI method for imaging clot lysis in a rat embolic stroke model and to compare tissue plasminogen activator (tPA)-based clot lysis with and without recombinant Annexin-2 (rA2). In experiment 1 we used in vitro optimization of clot visualization using multiple MRI contrast agents in concentrations ranging from 5 to 50 μL in 250 μL blood. In experiment 2, we used in vivo characterization of the time course of clot lysis using the clot developed in the previous experiment. Diffusion, perfusion, angiography, and T1-weighted MRI for clot imaging were conducted before and during treatment with vehicle (n=6), tPA (n=8), or rA2 plus tPA (n=8) at multiple time points. Brains were removed for ex vivo clot localization. Clots created with 25 μL Magnevist were the most stable and provided the highest contrast-to-noise ratio. In the vehicle group, clot length as assessed by T1-weighted imaging correlated with histology (r=0.93). Clot length and cerebral blood flow-derived ischemic lesion volume were significantly smaller than vehicle at 15 minutes after treatment initiation in the rA2 plus tPA group, whereas in the tPA group no significant reduction from vehicle was observed until 30 minutes after treatment initiation. The rA2 plus tPA group had a significantly shorter clot length than the tPA group at 60 and 90 minutes after treatment initiation and significantly smaller cerebral blood flow deficit than the tPA group at 90 minutes after treatment initiation. We introduce a novel MRI-based clot imaging method for in vivo monitoring of clot lysis. Lytic efficacy of tPA was enhanced by rA2.
    Stroke 03/2011; 42(4):1110-5. · 6.16 Impact Factor
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    ABSTRACT: Because there is no background signal from xenon in biological tissue, and because inhaled xenon is delivered to the brain by blood flow, we would expect a perfusion deficit, such as is seen in stroke, to reduce the xenon concentration in the region of the deficit. Thermal polarization yields negligible xenon signal relative to hyperpolarized xenon; therefore, hyperpolarized xenon can be used as a tracer of cerebral blood flow. Using a rat permanent right middle cerebral artery occlusion model, we demonstrated that hyperpolarized (129)Xe MRI is able to detect, in vivo, the hypoperfused area of focal cerebral ischemia, that is the ischemic core area of stroke. To the best of our knowledge, this is the first time that hyperpolarized (129)Xe MRI has been used to explore normal and abnormal cerebral perfusion. Our study shows a novel application of hyperpolarized (129)Xe MRI for imaging stroke, and further demonstrates its capacity to serve as a complementary tool to proton MRI for the study of the pathophysiology during brain hypoperfusion.
    NMR in Biomedicine 02/2011; 24(2):170-5. · 3.45 Impact Factor
  • Nils Henninger, Rajat Kumar, Marc Fisher
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    ABSTRACT: Data from the European Cooperative Acute Stroke Study (ECASS) III trial demonstrated that tissue plasminogen activator given up to 4.5 h after stroke onset improves outcome and treatment guidelines support its use during this time window. Intra-arterial therapy with tissue plasminogen activator or devices is commonly used at large tertiary centers up to 6–8 h after stroke onset, but conclusive evidence of efficacy remains lacking. During the acute phase after stroke onset, blood pressure elevations should be reduced as should substantial elevations in blood glucose. Statins are recommended in essentially all non-cardioembolic stroke patients. The most important future directions for acute stroke therapy are to extend the therapeutic time window and to increase the proportion of patients treated within the currently documented 4.5-h time window. Imaging-guided selection of appropriate patients will likely be a key factor for extending the therapeutic time window and both diffusion/perfusion MRI and perfusion computed tomography will be useful imaging modalities in this effort.
    Expert Review of Cardiovascular Therapy 10/2010; 8(10):1389-98.
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    ABSTRACT: Granulocyte Colony-Stimulating Factor (G-CSF) has remarkable neuroprotective properties. Due to its proven safety profile, G-CSF is currently used in clinical stroke trials. As neuroprotectants are considered to be more effective in the early phase of cerebral ischemia and during reperfusion, G-CSF should to be tested in combination with thrombolysis. Therefore, combination therapy was investigated in an experimental model of thromboembolic stroke. Male Wistar rats (n = 72) were subjected to a model of thromboembolic occlusion (TE) of the middle cerebral artery. Different groups (n = 12 each) treated by recombinant tissue-plasminogen activator (rt-PA) or/and G-CSF: group control (control), group early G-CSF (G-CSF 60 min after TE), group rt-PA (rt-PA 60 min after TE), group com (combination rt-PA/G-CSF), group delayed rt-PA (rt-PA after 180 min), group deco (G-CSF after 60 min, rt-PA after 180 min). Animals were investigated by magnetic resonance imaging (MRI) and silver infarct staining (SIS) 24 hours after TE. Early G-CSF or rt-PA reduced the infarct size compared to all groups (p < 0.05 to p < 0.01) with the exception of group com, (p = n.s.) as measured by T2, DWI, and SIS. Late administration of rt-PA lead to high mortality and larger infarcts compared to all other groups (p < 0.05 to p < 0.01). Pre-treatment by G-CSF (deco) reduced infarct site compared to delayed rt-PA treatment (p < 0.05). G-CSF did not significantly influence PWI when combined with rt-PA. All animals treated by rt-PA showed improved parameters in PWI indicating reperfusion. G-CSF was neuroprotective when given early after TE. Early combination with rt-PA showed no additional benefit compared to rt-PA or G-CSF alone, but did not lead to side effects. Pretreatment by G-CSF was able to reduce deleterious effects of late rt-PA treatment.
    Experimental and Translational Stroke Medicine 04/2010; 2:9.
  • Nils Henninger, Nabil Ahmad, Jane G Morris
    The American journal of emergency medicine 01/2010; 28(1):117.e1-3. · 1.54 Impact Factor

Publication Stats

581 Citations
190.51 Total Impact Points


  • 2007–2013
    • University of Massachusetts Medical School
      • Department of Neurology
      Worcester, MA, United States
  • 2012
    • Beth Israel Deaconess Medical Center
      • Department of Neurology
      Boston, MA, United States
  • 2010
    • Universitätsklinikum Erlangen
      • Department of Neurology
      Erlangen, Bavaria, Germany
  • 2004–2005
    • Universität Heidelberg
      • Neurological Clinic
      Heidelberg, Baden-Wuerttemberg, Germany