Axel Petzold

VU University Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (208)958.71 Total impact

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    ABSTRACT: Increased expression of glial fibrillary acidic protein (GFAP) is a characteristic of gliotic activation (Müller cells and astrocytes) in the retina. This study assessed vitreous body GFAP levels in various forms of retinal pathology. This prospective study included 82 patients who underwent vitrectomy (46 retinal detachments (RDs), 13 macular hole (MHs), 15 epiretinal glioses (EGs), 8 organ donors). An established enzyme-linked immunosorbent assay (ELISA, SMI26) was used for quantification of GFAP. The highest concentration of vitreous body GFAP in organ donors was 20 pg/mL and it was used as the cutoff. A significant proportion of patients suffering from RD (65 %) to EG (53 %) had vitreous body GFAP levels above this cutoff when compared to organ donors (0 %, p < 0.0001, p = 0.0194, respectively, Fisher's exact test) and MH (8 %, p < 0.0001, p = 0.0157, respectively). In RD and EG, vitreous body GFAP levels were correlated with axial length (R = 0.69, R = 0.52, p < 0.05 for both). The data suggest that human vitreous body GFAP is a protein biomarker for glial activation in response to retinal pathologies. Vitreous body GFAP levels may be of interest as a surrogate outcome for experimental treatment strategies in translational studies.
    Albrecht von Graæes Archiv für Ophthalmologie 08/2015; DOI:10.1007/s00417-015-3127-7 · 2.33 Impact Factor
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    ABSTRACT: To test blood and CSF neurofilament light chain (NfL) levels in relation to disease progression and survival in amyotrophic lateral sclerosis (ALS). Using an electrochemiluminescence immunoassay, NfL levels were measured in samples from 2 cohorts of patients with sporadic ALS and healthy controls, recruited in London (ALS/control, plasma: n = 103/42) and Oxford (ALS/control, serum: n = 64/36; paired CSF: n = 38/20). NfL levels in patients were measured at regular intervals for up to 3 years. Change in ALS Functional Rating Scale-Revised score was used to assess disease progression. Survival was evaluated using Cox regression and Kaplan-Meier analysis. CSF, serum, and plasma NfL discriminated patients with ALS from healthy controls with high sensitivity (97%, 89%, 90%, respectively) and specificity (95%, 75%, 71%, respectively). CSF NfL was highly correlated with serum levels (r = 0.78, p < 0.0001). Blood NfL levels were approximately 4 times as high in patients with ALS compared with controls in both cohorts, and maintained a relatively constant expression during follow-up. Blood NfL levels at recruitment were strong, independent predictors of survival. The highest tertile of blood NfL at baseline had a mortality hazard ratio of 3.91 (95% confidence interval 1.98-7.94, p < 0.001). Blood-derived NfL level is an easily accessible biomarker with prognostic value in ALS. The individually relatively stable levels longitudinally offer potential for NfL as a pharmacodynamic biomarker in future therapeutic trials. This report provides Class III evidence that the NfL electrochemiluminescence immunoassay accurately distinguishes patients with sporadic ALS from healthy controls. © 2015 American Academy of Neurology.
    Neurology 05/2015; 84(22). DOI:10.1212/WNL.0000000000001642 · 8.30 Impact Factor
  • Neuro-Ophthalmology 04/2015; 39(2):101-102. DOI:10.3109/01658107.2015.1004589 · 0.18 Impact Factor
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    Axel Petzold
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    ABSTRACT: This review on the role of glial fibrillary acidic protein (GFAP) as a biomarker for astroglial pathology in neurological diseases provides background to protein synthesis, assembly, function and degeneration. Qualitative and quantitative analytical techniques for the investigation of human tissue and biological fluid samples are discussed including partial lack of parallelism and multiplexing capabilities. Pathological implications are discussed in view of immunocytochemical, cell-culture and genetic findings. Particular emphasis is given to neurodegeneration related to autoimmune astrocytopathies and to genetic gain of function mutations. The current literature on body fluid levels of GFAP in human disease is summarised and illustrated by disease specific meta–analyses. In addition to the role of GFAP as a diagnostic biomarker for chronic neurodegenerative conditions, there are important data on the prognostic value for acute neurodegeneration. The published evidence permits to classify the dominant GFAP signatures in biological fluids. This classification may serve as a template for supporting diagnostic criteria of autoimmune astrocytopathies, monitoring disease progression in toxic gain of function mutations, clinical treatment trials (secondary outcome and toxicity biomarker) and provide prognostic information in neurocritical care if used within well defined time–frames.
    Brain Research 12/2014; 55. DOI:10.1016/j.brainres.2014.12.027 · 2.83 Impact Factor
  • Axel Petzold
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    ABSTRACT: Retinal spectral domain optical coherence tomography (OCT) has emerged as a clinical and research tool in multiple sclerosis (MS) and optic neuritis (ON). This chapter summarizes a short OCT protocol as included in international consensus guidelines. The protocol was written for hands-on style such that both clinicians and OCT technicians can make use of it. The protocol is suitable for imaging of the optic nerve head and macular regions as a baseline for follow-up investigations, individual layer segmentation, and diagnostic assessment.
    Methods in molecular biology (Clifton, N.J.) 12/2014; DOI:10.1007/7651_2014_153 · 1.29 Impact Factor
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    ABSTRACT: Objectives To test for structural and functional contribution of mitochondrial dysfunction to neurodegeneration in multiple sclerosis (MS). A visual pathway model void of MS lesions was chosen in order to exclude neurodegeneration secondary to lesion related axonotmesis.MethodsA single-centre cohort study (230 MS patients, 63 controls). Spectral domain optical coherence tomography of the retina, 3T magnetic resonance imaging of the brain, spectrophotometric assessment of serum lactate levels. Postmortem immunohistochemistry.ResultsThe visual pathway was void of MS lesions in 31 patients and 31 age-matched controls. Serum lactate was higher in MS compared to controls (P = 0.029). High serum lactate was structurally related to atrophy of the retinal nerve fiber layer at the optic disc (P = 0.041), macula (P = 0.025), and the macular ganglion cell complex (P = 0.041). High serum lactate was functionally related to poor color vision (P < 0.01), Expanded Disability Status Scale score (R = 0.37, P = 0.041), Guy's Neurological disability score (R = 0.38, P = 0.037), MS walking scale (R = 0.50, P = 0.009), upper limb motor function (R = 0.53, P = 0.002). Immunohistochemistry demonstrated increased astrocytic expression of a key lactate generating enzyme in MS lesions as well as profound vascular expression of monocarboxylate transporter-1, which is involved in lactate transport.InterpretationThis study provides structural, functional, and translational evidence for visual pathway neurodegeneration in MS related to mitochondrial dysfunction.
    12/2014; 2(2). DOI:10.1002/acn3.157
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    Ophthalmology 11/2014; 121(11):e63. DOI:10.1016/j.ophtha.2014.06.018 · 6.17 Impact Factor
  • American Journal of Ophthalmology 10/2014; 158(4):845. DOI:10.1016/j.ajo.2014.06.022 · 4.02 Impact Factor
  • Investigative Ophthalmology &amp Visual Science 08/2014; 55(8):4728. DOI:10.1167/iovs.14-14876 · 3.66 Impact Factor
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    ABSTRACT: Objective To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). Methods A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. Results Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. Conclusions Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression.
    Journal of Neurology Neurosurgery & Psychiatry 07/2014; 86(5). DOI:10.1136/jnnp-2014-307672 · 5.58 Impact Factor
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    ABSTRACT: Optic neuritis is an inflammatory optic neuropathy that affects many patients with multiple sclerosis (MS) at some point during their disease course. Differentiation of acute episodes of MS-associated optic neuritis from other autoimmune and inflammatory optic neuropathies is vital for treatment choice and further patient management, but is not always straightforward. Over the past decade, a number of new imaging, laboratory and electrophysiological techniques have entered the clinical arena. To date, however, no consensus guidelines have been devised to specify how and when these techniques can be most rationally applied for the diagnostic work-up of patients with acute optic neuritis. In this article, we review the literature and attempt to formulate a consensus for the investigation of patients with acute optic neuritis, both in standard care and in research with relevance to clinical treatment trials.
    Nature Reviews Neurology 07/2014; 10(8). DOI:10.1038/nrneurol.2014.108 · 14.10 Impact Factor
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    ABSTRACT: Background and Objectives Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system in young adults. Over time, the disease progresses and, with accumulating disability, symptoms such as spasticity may occur. Although several treatment options are available, some patients may not respond to first-line therapeutics. However, some of these patients may benefit from intrathecally administered triamcinolone-acetonide (TCA), a derivative of glucocorticosteroids (GCS). GCS may have neurotoxic effects, and cell apoptosis may occur. The aim of this study was to investigate the effects of TCA on biomarkers in the cerebrospinal fluid (CSF) suggestive of neurodegeneration. Methods In order to assess neurotoxic effects of TCA, neurofilament heavy-chain (NfH)SMI35, tau protein, and S-100B protein levels were determined before and during treatment with TCA in 54 patients with primary progressive MS, as well as relapsing MS (relapsing–remitting and secondary progressive MS). Results NfHSMI35 levels in the CSF of patients treated with TCA intrathecally did not increase significantly during the treatment cycle (p = 0.068). After application of TCA, tau protein levels were increased significantly at day 4 (p = 0.03) and at day 8 (p ≤ 0.001). S-100B protein levels decreased significantly (p ≤ 0.05) during treatment with TCA. Conclusion NfHSMI35 levels did not change significantly; however, tau protein levels did increase significantly within the reference range. Taking these findings together, the long-term effects of TCA on NfHSMI35 and tau protein levels need to be investigated further to understand whether levels of both biomarkers will change over repeated TCA applications. Interestingly, S-100B protein levels decreased significantly during the first applications, which may have represented reduced astrocytic activity during TCA treatment.
    Molecular Diagnosis & Therapy 07/2014; 18(6). DOI:10.1007/s40291-014-0114-3 · 2.59 Impact Factor
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    ABSTRACT: There is evidence for physiological variation of retinal thicknesses as determined by optical coherence tomography (OCT). We tested if such changes could be explained by hydration and would exceed what may be expected from normal ageing. Subjects (n=26) of a previous study were re-assessed and were randomised to 3 groups of a hydration escalation trial (no hydration, 1× hydration, 2× hydration). Automated retinal layer segmentations were performed for the macular retinal nerve fibre layer (RNFL), ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer (INL), outer plexiform layer (OPL) and outer nuclear layer (ONL). The averaged volumes were calculated for the central foveola, 3mm and 6mm circles of the ETDRS grid. Following oral hydration there were no significant differences of retinal layer thicknesses between the three randomised groups in any of the ETDRS regions at any time-point. Ageing related changes were significant over an 18month period for the GCL. The negative outcome of this trial implies that, until the causes for the observed variation are resolved, investigators may need to accept, and include into trial power calculations, a small degree of variation (<1%) of quantitative SD-OCT imaging either due to human physiology or instrument/software related factors.
    Journal of the Neurological Sciences 06/2014; 344(1-2). DOI:10.1016/j.jns.2014.06.031 · 2.26 Impact Factor
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    ABSTRACT: Objective To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain involvement in longstanding multiple sclerosis (MS). Methods In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. Results In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. Interpretation This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans–synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.
    Journal of Neurology Neurosurgery & Psychiatry 06/2014; 86(4). DOI:10.1136/jnnp-2014-308189 · 5.58 Impact Factor
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    ABSTRACT: Background Neurofilaments (Nf) are major structural proteins that occur exclusively in neurons. In spinal cord injury (SCI), the severity of disease is quantified by clinical measures that have limited sensitivity and reliability, and no blood-based biomarker has been established to further stratify the degree of injury. We aimed to examine a serum-based NfL immunoassay as predictor of the clinical outcome in SCI. Methods Longitudinal measurement of serum NfL was performed in patients with central cord syndrome (CCS, n=4), motor-incomplete SCI (iSCI, n=10), motor-complete SCI (cSCI, n=13) and healthy controls (HC, n=67), and correlated with clinical severity, neurological outcome, and neuroprotective effect of the drug minocycline. Results Baseline NfL levels were higher in iSCI (21 pg/mL) and cSCI (70 pg/mL) than in HC (5 pg/mL, p=0.006 and p<0.001) and CCS (6 pg/mL, p=0.025 and p=0.010). Levels increased over time (p<0.001) and remained higher in cSCI versus iSCI (p=0.011) and than in CCS (p<0.001). NfL levels correlated with American Spinal Injury Association (ASIA) motor score at baseline (r=−0.53, p=0.004) and after 24 h (r=−0.69, p<0.001) and 3–12-month motor outcome (baseline NfL: r=−0.43, p=0.026 and 24 h NfL: r=−0.72, p<0.001). Minocycline treatment showed decreased NfL levels in the subgroup of cSCI patients. Conclusions Serum NfL concentrations in SCI patients show a close correlation with acute severity and neurological outcome. Our data provide evidence that serum NfL is of prognostic value in SCI patients for the first time. Further, blood NfL levels may qualify as drug response markers in SCI.
    Journal of Neurology Neurosurgery & Psychiatry 06/2014; 86(3). DOI:10.1136/jnnp-2013-307454 · 5.58 Impact Factor
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    ABSTRACT: Background: Retinal optical coherence tomography (OCT) permits quantification of retinal layer atrophy relevant to assessment of neurodegeneration in multiple sclerosis (MS). Measurement artefacts may limit the use of OCT to MS research. Objective: An expert task force convened with the aim to provide guidance on the use of validated quality control (QC) criteria for the use of OCT in MS research and clinical trials. Methods: A prospective multi-centre (n = 13) study. Peripapillary ring scan QC rating of an OCT training set (n = 50) was followed by a test set (n = 50). Inter-rater agreement was calculated using kappa statistics. Results were discussed at a round table after the assessment had taken place. Results: The inter-rater QC agreement was substantial (kappa = 0.7). Disagreement was found highest for judging signal strength (kappa = 0.40). Future steps to resolve these issues were discussed. Conclusion: Substantial agreement for QC assessment was achieved with aid of the OSCAR-IB criteria. The task force has developed a website for free online training and QC certification. The criteria may prove useful for future research and trials in MS using OCT as a secondary outcome measure in a multi-centre setting.
    Multiple Sclerosis 06/2014; 21(2). DOI:10.1177/1352458514538110 · 4.86 Impact Factor
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    ABSTRACT: Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neuronegenerative component. Impaired mitochondrial functioning has been hypothesised to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n=613) were recruited, assessed for disability and clinically classified (relapling-remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n=281), at the MS Centre Amsterdam, The Netherlands (n=158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n=174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04±1.26mmol/l) than that of healthy controls (1.09±0.25mmol/l, p<0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing-remitting disease course. In addition, there was a linear correlation between serum lactate levels and the EDSS (R2=0.419; p<0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of "virtual hypoxia" in MS. and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS.
    Biochimica et Biophysica Acta 04/2014; 1842(7). DOI:10.1016/j.bbadis.2014.04.005 · 4.66 Impact Factor
  • Lisanne J Balk · Axel Petzold
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    ABSTRACT: SUMMARY Multiple sclerosis (MS) is a disorder characterized by inflammation and neuroaxonal degeneration. The latter is held responsible for the irreversible disability in patients with MS. The eye is a unique window into the brain. With the advent of optical coherence tomography, accurate quantification of retinal layer thickness has become feasible. Neuroaxonal degeneration affecting the retinal layers is structurally and functionally related to pathology in the visual pathways, which is most severe following MS optic neuritis. This is relevant to recognize because MS optic neuritis may mask the subtle thinning of retinal layers associated with global CNS atrophy, which is also related to more global loss of neurological function. Taken together, optical coherence tomography stands at the brink of becoming a validated imaging biomarker for monitoring neurodegeneration in MS and to provide end points for clinical trials.
    04/2014; 4(2):165-76. DOI:10.2217/nmt.14.10
  • J. Sellner · N. W. Davies · R. S. Howard · A. Petzold
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    ABSTRACT: Background and purposeThe neurological outcome of acute encephalitis can be devastating and early prognosis remains difficult. Biomarkers that quantify the extent of early brain injury are needed to improve the prognostic accuracy and aid patient management. Our objective was to assess whether cerebrospinal fluid (CSF) protein biomarkers of neuroaxonal and glial cell injury are elevated in distinct forms of acute encephalitis and predictive of poor outcome.Methods This was a prospective study of patients presenting with acute encephalitis to three teaching hospitals in London, UK. Levels of neurofilament heavy chain (NfH, SMI35) and S100B were quantified in CSF using enzyme-linked immunosorbent assay. The outcome was assessed by the Glasgow Outcome Scale (GOS).ResultsFifty-six patients with acute encephalitis were recruited and classified into the following diagnostic categories: infectious (n = 20), inflammatory (n = 14) and unknown etiology (n = 22). Pathological levels of NfH and S100B were observed in 24/56 (43%) and 54/56 (96%), respectively. Patients with infectious encephalitis had significantly higher NfH levels compared with the other two groups (P < 0.05). A poor outcome (GOS < 5) was associated with significantly higher CSF NfH levels within samples taken 2 weeks after symptom onset.Conclusions This study suggests that longitudinal CSF NfH levels are of superior prognostic value compared with CSF S100B levels. Prolonged release of NfH, a marker of neuroaxonal damage, was associated with poor outcome. Potentially there is a window of opportunity for future neuroprotective treatment strategies in encephalitis.
    European Journal of Neurology 03/2014; 21(6). DOI:10.1111/ene.12390 · 4.06 Impact Factor
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    ABSTRACT: The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies.This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept.The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.
    Multiple Sclerosis 02/2014; 20(12). DOI:10.1177/1352458514524999 · 4.86 Impact Factor

Publication Stats

5k Citations
958.71 Total Impact Points

Institutions

  • 2010–2014
    • VU University Amsterdam
      Amsterdamo, North Holland, Netherlands
    • VU University Medical Center
      • Department of Neurology
      Amsterdamo, North Holland, Netherlands
    • Leiden University Medical Centre
      Leyden, South Holland, Netherlands
    • Universität Ulm
      • Division of Neurophysiology
      Ulm, Baden-Württemberg, Germany
  • 2009–2014
    • UCL Eastman Dental Institute
      Londinium, England, United Kingdom
  • 2003–2014
    • University College London
      • • Institute of Neurology
      • • Sobell Department of Motor Neuroscience and Movement Disorders
      • • Department of Neuroinflammation
      Londinium, England, United Kingdom
    • University of London
      Londinium, England, United Kingdom
    • The National Institute of Neurology and Neurosurgery
      Tlalpam, The Federal District, Mexico
  • 2010–2013
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 2010–2012
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Department of Neurology
      Amsterdamo, North Holland, Netherlands
  • 2011
    • Universitätsspital Basel
      • Neurobiology Unit
      Bâle, Basel-City, Switzerland
  • 2000–2009
    • Moorfields Eye Hospital NHS Foundation Trust
      • Department of Medical Retina
      Londinium, England, United Kingdom
    • Technische Universität München
      München, Bavaria, Germany