New paper – CuBe: parametric modeling of 3D foveal shape using cubic Bézier

In this paper from our group, Sunil Yadav and colleagues have developed and validated a 3D fovea morphometry, which clearly outperforms previous approaches in the diseases of interest, mainly autoimmune neuroinflammatory disorders.

Sunil Kumar Yadav, Seyedamirhosein Motamedi, Timm Oberwahrenbrock, Frederike Cosima Oertel, Konrad Polthier, Friedemann Paul, Ella Maria Kadas, and Alexander U. Brandt


Optical coherence tomography (OCT) allows three-dimensional (3D) imaging of the retina, and is commonly used for assessing pathological changes of fovea and macula in many diseases. Many neuroinflammatory conditions are known to cause modifications to the fovea shape. In this paper, we propose a method for parametric modeling of the foveal shape. Our method exploits invariant features of the macula from OCT data and applies a cubic Bézier polynomial along with a least square optimization to produce a best fit parametric model of the fovea. Additionally, we provide several parameters of the foveal shape based on the proposed 3D parametric modeling. Our quantitative and visual results show that the proposed model is not only able to reconstruct important features from the foveal shape, but also produces less error compared to the state-of-the-art methods. Finally, we apply the model in a comparison of healthy control eyes and eyes from patients with neuroinflammatory central nervous system disorders and optic neuritis, and show that several derived model parameters show significant differences between the two groups.


Read more at Biomedical Optics Express, Vol. 8, Issue 9, pp. 4181-4199 (2017).

Single-subject independent component analysis-based intensity normalization in non-quantitative multi-modal structural MRI Authors

New publication in Hum Brain Mapp. 2017 Apr 22. doi: 10.1002/hbm.23615.

Papazoglou S, Würfel J, Paul F, Brandt AU, Scheel M.

Non-quantitative MRI is prone to intersubject intensity variation rendering signal intensity level based analyses limited. Here, we propose a method that fuses non-quantitative routine T1-weighted (T1w), T2w, and T2w fluid-saturated inversion recovery sequences using independent component analysis and validate it on age and sex matched healthy controls. The proposed method leads to consistent and independent components with a significantly reduced coefficient-of-variation across subjects, suggesting potential to serve as automatic intensity normalization and thus to enhance the power of intensity based statistical analyses. To exemplify this, we show that voxelwise statistical testing on single-subject independent components reveals in particular a widespread sex difference in white matter, which was previously shown using, for example, diffusion tensor imaging but unobservable in the native MRI contrasts. In conclusion, our study shows that single-subject independent component analysis can be applied to routine sequences, thereby enhancing comparability in-between subjects. Unlike quantitative MRI, which requires specific sequences during acquisition, our method is applicable to existing MRI data.

Read more on the publisher’s website.

Contribution of blood vessels to retinal nerve fiber layer thickness in NMOSD

New publication in Neurol Neuroimmunol Neuroinflamm. 2017 Apr 18;4(3):e338. doi: 10.1212/NXI.0000000000000338. eCollection 2017 May.

Oertel FC, Zimmermann H, Mikolajczak J, Weinhold M, Kadas EM, Oberwahrenbrock T, Pache F, Bellmann-Strobl J, Ruprecht K, Paul F, Brandt AU.

Neuromyelitis optica spectrum disorders (NMOSDs) are relapsing inflammatory demyelinating disorders with optic neuritis (ON) as the hallmark. ON causes neuroaxonal damage to the optic nerve and retina, regularly leading to severely impaired visual acuity (VA).

Peripapillary retinal nerve fiber layer (pRNFL) thickness measured by optical coherence tomography (OCT) has been increasingly recognized as a marker for neuroaxonal damage and correlate of visual dysfunction. As such, pRNFL is implemented as an outcome in clinical trials of ON-associated disorders. Blood vessels (BVs) running within the pRNFL contribute approximately 13% to an average RNFL thickness2 and could present an important confounder when tracking small pRNFL changes or in diseases with severe thinning such as NMOSD. Against this background, the objective of this study was to investigate the influence of retinal BVs on pRNFL measurements in an NMOSD cohort.

Read more on PubMed Central.

Microstructural visual system changes in AQP4-antibody-seropositive NMOSD

New publication in Neurol Neuroimmunol Neuroinflamm. 2017 Feb 22;4(3):e334. doi: 10.1212/NXI.0000000000000334. eCollection 2017 May.

Oertel FC, Kuchling J, Zimmermann H, Chien C, Schmidt F, Knier B, Bellmann-Strobl J, Korn T, Scheel M, Klistorner A, Ruprecht K, Paul F, Brandt AU.

OBJECTIVE: To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.

METHODS: Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab-seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab-seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.

RESULTS: FT was reduced in both patients with NMOSD-LETM (p = 3.52e-14) and NMOSD-ON (p = 1.24e-16) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM (p = 0.046) and NMOSD-ON (p = 1.50e-5) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.

CONCLUSIONS: Patients with AQP4-ab-seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.

Read more on PubMed Central.

Longitudinal Intravital Imaging of the Retina Reveals Long-term Dynamics of Immune Infiltration and Its Effects on the Glial Network in Experimental Autoimmune Uveoretinitis, without Evident Signs of Neuronal Dysfunction in the Ganglion Cell Layer

Bremer et al.

A hallmark of autoimmune retinal inflammation is the infiltration of the retina with cells of the innate and adaptive immune system, leading to detachment of the retinal layers and even to complete loss of the retinal photoreceptor layer. As the only optical system in the organism, the eye enables non-invasive longitudinal imaging studies of these local autoimmune processes and of their effects on the target tissue. Moreover, as a window to the central nervous system (CNS), the eye also reflects general neuroinflammatory processes taking place at various sites within the CNS. Histological studies in murine neuroinflammatory models, such as experimental autoimmune uveoretinitis (EAU) and experimental autoimmune encephalomyelitis, indicate that immune infiltration is initialized by effector CD4+ T cells, with the innate compartment (neutrophils, macrophages, and monocytes) contributing crucially to tissue degeneration that occurs at later phases of the disease. However, how the immune attack is orchestrated by various immune cell subsets in the retina and how the latter interact with the target tissue under in vivo conditions is still poorly understood. Our study addresses this gap with a novel approach for intravital two-photon microscopy, which enabled us to repeatedly track CD4+ T cells and LysM phagocytes during the entire course of EAU and to identify a specific radial infiltration pattern of these cells within the inflamed retina, starting from the optic nerve head. In contrast, highly motile CX3CR+1 cells display an opposite radial motility pattern, toward the optic nerve head. These inflammatory processes induce modifications of the microglial network toward an activated morphology, especially around the optic nerve head and main retinal blood vessels, but do not affect the neurons within the ganglion cell layer. Thanks to the new technology, non-invasive correlation of clinical scores of CNS-related pathologies with immune infiltrate behavior and subsequent tissue dysfunction is now possible. Hence, the new approach paves the way for deeper insights into the pathology of neuroinflammatory processes on a cellular basis, over the entire disease course.

Bremer et al. Front. Immunol., 23 December 2016

Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients

Pache & Zimmermann et al. from our lab just published a study investigating afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. MOG-antibodies have recently been identified in a subgroup of patients with neuromyelitis optica and in patients with recurrent optic neuritis.

The paper has been published in Journal of Neuroinflammation 2016 13:282.

The study is part of a series of 4 papers describing different aspects of MOG-IgG in NMO and related disorders.

Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin
Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome
Part 3: Brainstem involvement – frequency, presentation and outcome
Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients

Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder

Neurol Neuroimmunol Neuroinflamm December 2016 vol. 3 no. 6 e286

In this just published study we investigated depressive symptoms and their current treatment in patients with neuromyelitis optica spectrum disorders in a collaboration with colleagues from Johns Hopkins University in Baltimore, MD, USA.


Objective: To investigate depression frequency, severity, current treatment, and interactions with somatic symptoms among patients with neuromyelitis optica spectrum disorder (NMOSD).

Methods: In this dual-center observational study, we included 71 patients diagnosed with NMOSD according to the International Panel for NMO Diagnosis 2015 criteria. The Beck Depression Inventory (BDI) was classified into severe, moderate, or minimal/no depressive state category. We used the Fatigue Severity Scale to evaluate fatigue. Scores from the Brief Pain Inventory and the PainDETECT Questionnaire were normalized to estimate neuropathic pain. Psychotropic, pain, and immunosuppressant medications were tabulated by established classes.

Results: Twenty-eight percent of patients with NMOSD (n = 20) had BDI scores indicative of moderate or severe depression; 48% of patients (n = 34) endorsed significant levels of neuropathic pain. Severity of depression was moderately associated with neuropathic pain (r = 0.341, p < 0.004) but this relationship was confounded by levels of fatigue. Furthermore, only 40% of patients with moderate or severe depressive symptoms received antidepressant medical treatment. Fifty percent of those treated reported persistent moderate to severe depressive symptoms under treatment.

Conclusions: Moderate and severe depression in patients with NMOSD is associated with neuropathic pain and fatigue and is insufficiently treated. These results are consistent across 2 research centers and continents. Future research needs to address how depression can be effectively managed and treated in NMOSD.

Afferent Visual Pathway Affection in Patients with PMP22 Deletion-Related Hereditary Neuropathy with Liability to Pressure Palsies.

PLoS ONE 0.1 371/journ al.pone.0164 617


Background: The PMP22 gene encodes a protein integral to peripheral myelin. Its deletion leads to hereditary neuropathy with liability to pressure palsies (HNPP). PMP22 is not expressed in the adult central nervous system, but previous studies suggest a role in CNS myelin development. The objective of this study was to identify potential structural and functional alterations in the afferent visual system in HNPP patients.

Methods: Twenty HNPP patients and 18 matched healthy controls (HC) were recruited in a cross-sectional study. Participants underwent neurological examination including visual acuity, visual evoked potential (VEP) examination, optical coherence tomography (OCT), and magnetic resonance imaging with calculation of brain atrophy, regarding grey and white matter, and voxel based morphometry (VBM), in addition answered the National Eye Institute’s 39-item Visual Functioning Questionnaire (NEI-VFQ). Thirteen patients and 6 HC were additionally examined with magnetic resonance spectroscopy (MRS).

Results: All patients had normal visual acuity, but reported reduced peripheral vision in comparison to HC in the NEI-VFQ (p = 0.036). VEP latency was prolonged in patients (P100 = 103.7±5.7 ms) in comparison to healthy subjects (P100 = 99.7±4.2 ms, p = 0.007). In OCT, peripapillary retinal nerve fiber layer thickness RNFL was decreased in the nasal sector (90.0±15.5 vs. 101.8±16.5, p = 0.013), and lower nasal sector RNFL correlated with prolonged VEP latency (Rho = -0.405, p = 0.012). MRS revealed reduced tNAA (731.4±45.4 vs. 814.9±62.1, p = 0.017) and tCr (373.8±22.2 vs. 418.7±31.1, p = 0.002) in the visual cortex in patients vs. HC. Whole brain volume, grey and white matter volume, VBM and metabolites in a MRS sensory cortex control voxel did not differ significantly between patients and HC.

Conclusion: PMP22 deletion leads to functional, metabolic and macro-structural alterations in the afferent visual system of HNPP patients. Our data suggest a functional relevance of these changes for peripheral vision, which warrants further investigation and confirmation.