Albrecht et al. Optical coherence tomography for the diagnosis and monitoring of idiopathic intracranial hypertension

J Neurol. 2017 Jul;264(7):1370-1380

by Albrecht P, Blasberg C, Ringelstein M, Müller AK, Finis D, Guthoff R, Kadas EM, Lagreze W, Aktas O, Hartung HP, Paul F, Brandt AU, Methner A

(in cooperation with Universitätsklinikum Düsseldorf AG Albrecht)

The objectives of the study were to investigate the value of optical coherence tomography in detecting papilledema in patients with idiopathic intracranial hypertension (IIH), a disease which is difficult to monitor and which can lead to permanent visual deficits; to analyze retinal changes over time. In this non-interventional case-control study, spectral-domain optical coherence tomography (SD-OCT) was used to analyze the retinal and optic nerve head (ONH) morphology of 21 patients with IIH and 27 age- and sex-matched healthy controls over time. We analyzed the ONH volume using a custom-made algorithm and employed semi-automated segmentation of macular volume scans to assess the macular retinal nerve fiber layer (RNFL) and ganglion cell layer and inner plexiform layer complex as well as the total macular volume. In IIH patients, the ONH volume was increased and correlated with cerebrospinal fluid (CSF) pressure. The ONH volume decreased after the initiation of treatment with acetazolamide. The macular RNFL volume decreased by 5% in 3.5 months, and a stepwise multivariate regression analysis identified CSF pressure as the main influence on macular RNFL volume at diagnosis. The only factor predicting macular RNFL volume loss over time was ONH volume. SD-OCT can non-invasively monitor changes in retinal and ONH morphology in patients with IIH. Increased ONH volume leads to retinal atrophy in the form of macular RNFL volume loss, presumably due to mechanic jamming of the optic nerve at the disc and subsequent axonal loss.

Schlemm et al. – Gadopentetate but not gadobutrol accumulates in the dentate nucleus of multiple sclerosis patients

Mult Scler. 2017 Jun;23(7):963-972

by Schlemm L, Chien C, Bellmann-Strobl J, Dörr J, Wuerfel J, Brandt AU, Paul F, Scheel M

BACKGROUND: Previous studies have postulated an association between dentate nucleus T1 hyperintensity and multiple sclerosis (MS)-related progressive neurodegeneration. Therefore, MS patients have been excluded from most studies investigating brain deposition of gadolinium-based contrast agents (GBCAs).
OBJECTIVE: To study the hypothesis that dentate nucleus T1 hyperintensity in MS patients is associated with GBCA administration.
METHODS: In a cohort of 97 MS patients, the dentate-to-pons signal intensity ratio (DPSIR) was calculated for 265 consecutive T1-weighted magnetic resonance (MR) scans (including sessions with and without the administration of GBCA). Patients exclusively received either gadopentetate dimeglumine (Gd-DTPA, linear) or gadobutrol (Gd-BT-DO3A, macrocyclic).
RESULTS: In patients receiving Gd-DTPA, DPSIR increased significantly between the first and the last scan (+0.009, p < 0.001), and following magnetic resonance imaging (MRI) with Gd-DTPA administration as compared to following an MRI without Gd-DTPA administration (+0.005 vs -0.001; p = 0.022). Additionally, there was a positive linear relationship between the number of Gd-DTPA administrations and the increase in DPSIR ( p = 0.017). No DPSIR increase was observed after Gd-BT-DO3A administration.
CONCLUSION: Dentate nucleus T1 hyperintensity in MS patients is associated with Gd-DTPA (but not Gd-BT-DO3A) administration, suggesting an alternative explanation for the association of T1 hyperintensity with disease duration and severity.

Papazoglou et al. – Single-subject independent component analysis-based intensity normalization in non-quantitative multi-modal structural MRI Authors

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

by 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.

Oertel & Zimmermann et al. – Contribution of blood vessels to retinal nerve fiber layer thickness in NMOSD

Neurol Neuroimmunol Neuroinflamm. 2017 Apr 18;4(3):e338

by 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.

Oertel & Kuchling et al. – Microstructural visual system changes in AQP4-antibody-seropositive NMOSD

Neurol Neuroimmunol Neuroinflamm. 2017 Feb 22;4(3):e334

by 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.

Bremer et al. – 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

Front Immunol. 2016 Dec 23;7:642

by Bremer D, Pache F, Günther R, Hornow J, Andresen V, Leben R, Mothes R, Zimmermann H, Brandt AU, Paul F, Hauser AE, Radbruch H, Niesner R

(in cooperation with DRFZ AG Niesner)

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.

Pache & Zimmermann et al. – 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.

BACKGROUND: Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients.
METHODS: Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials.
RESULTS: Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity  was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year,  p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients.
CONCLUSIONS: Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.

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

Chavarro et al. – Insufficient treatment of severe depression in neuromyelitis optica spectrum disorder

Neurol Neuroimmunol Neuroinflamm. 2016 Oct 24;3(6):e286

by Chavarro VS & Mealy MA, Simpson A, Lacheta A, Pache F, Ruprecht K, Gold SM, Paul F, Brandt AU, Levy M

(in cooperation with Johns Hopkins Neuromyelitis Optica Clinic)

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.

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

PLoS One. 2016 Oct 17;11(10):e0164617.

by Brandt AU, Meinert-Bohn E, Rinnenthal JL, Zimmermann H, Mikolajczak J, Oberwahrenbrock T, Papazoglou S, Pfüller CF, Schinzel J, Tackenberg B, Paul F, Hahn K, Bellmann-Strobl J

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.

New NIC schedule for Winter Term 2016/2017

Dear all,

our new schedule for our Neuroimmunology Colloquium (NIC) for this year’s winter term is final and available on this website.

We have put together an exciting mix from local, national and international speakers to give you a current update on topics in the context of our neuroimmunological research.

Hope to see you every Monday at 2 pm Charité Mitte Campus – Universitätsmedizin Berlin Ferdinand Sauerbruch Hörsaal 4, Hufelandweg 6.

The NIC will be part of the official teaching curriculum at Charité. Additional CME certification is pending.

NIC Winter 2016/2017 Schedule as PDF

October 17th Alexander Brandt, MD

NeuroCure Clinical Research Center, Charitè – Universitätsmedizin Berlin

Imaging Autoimmunity in the Central Nervous System

October 24th Charles Guttmann, MD

Center for Neurological Imaging, Harvard Medical School, Boston USA

International Platform for MRI Data Sharing

November 7th Tanja Schmitz-Hübsch, MD

Department of Neurology, Charitè – Universitätsmedizin Berlin

Motor Function of the Upper Limb: KINECT in Multiple Sclerosis

November 14th Martina Minnerop, MD

Institute for Neuroscience and Medicine, Jülich Germany

MR Morphometry in Cerebellar Ataxia

November 21th Doktorand Lunch Series

Julian Pohlan, Niesner Lab

Laura Pastura, Paul Lab

Bimala Malla, Infante-Duarte Lab

November 28th Klemens Ruprecht, MD

Department of Neurology, Charitè – Universitätsmedizin Berlin

Autoimmune Diseases of the CNS: Differential Diagnosis

December 5th Helena Radbruch, MD

Department of Neuropathology, Charitè – Universitätsmedizin Berlin

Role of B Cells and Antibody Producing Cells in Chronic Neuroinflammation

December 12th Michael Hoffmann, MD

University Eye Clinic, Otto von Guericke University, Madgeburg Germany

Electrophysiology of Visual Dysfunction

January 9th Velina Chavarro

NeuroCure Clinical Research Center, Charitè – Universitätsmedizin Berlin

Cognitive Function in Demyelinating Diseases

January 16th Doktorand Lunch Series

Silvina Romero, Infante-Duarte Lab

Frederike Oertel, Paul Lab

Karolin Pollok, Radbruch Lab

January 23rd Volker Siffrin, MD

Max-Delbrück-Centrum for Molecular Medicine, Berlin

Introduction to Basic Science – Neuroimmunology

January 30th Friedemann Paul, MD

Department of Neurology, Charitè – Universitätsmedizin Berlin

Pitfalls of Translational Research in Neuroimmunology – from Animal Models to Clinical Studies