Eaneff et al. – Patient perspectives on neuromyelitis optica spectrum disorders: Data from the PatientsLikeMe online community

Mult Scler Relat Disord. 2017 Oct;17:116-122

by Eaneff S, Wang V, Hanger M, Levy M, Mealy MA, Brandt AU, Eek D, Ratchford JN, Nyberg F, Goodall J, Wicks P

BACKGROUND: Few studies have evaluated patient perspectives on neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD).
OBJECTIVE: Describe patient-reported clinical and treatment experience in NMOSD and compare disease characteristics of NMOSD with those of multiple sclerosis (MS).
METHODS: This retrospective, observational study included 522 members with NMO or NMOSD (hereafter collectively referred to as NMOSD) from PatientsLikeMe (PLM), an online patient community. Data describing member demographics, symptoms, and treatments were collected, analysed descriptively, and compared with data from PLM members with MS.
RESULTS: Fatigue, pain, and stiffness/spasticity were each rated as moderate to severe by more than half of NMOSD members, and 59% reported that their health limited the type of work or other activities they could perform all or most of the time. Overall, symptom severity and disability levels were comparable between NMOSD and MS members; however, NMOSD members were more likely than MS members to attribute disability to vision-related symptoms and were less likely to report moderate to severe cognitive and emotional symptoms, including brain fog, depressed or anxious mood, and emotional lability.
CONCLUSION: This analysis underscores the challenges of living with fatigue, pain, stiffness/spasticity, and visual difficulties, prevalent NMOSD symptoms among members of the PLM community.

Yadav et al. – CuBe: parametric modeling of 3D foveal shape using cubic Bézier

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

by 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.

Rakhymzhan et al. – Synergistic Strategy for Multicolor Two-photon Microscopy: Application to the Analysis of Germinal Center Reactions In Vivo

Sci Rep. 2017 Aug 2;7(1):7101

by Rakhymzhan A, Leben R, Zimmermann H, Günther R, Mex P, Reismann D, Ulbricht C, Acs A, Brandt AU,  Lindquist RL, Winkler TH, Hauser AE, Niesner RA

(DIAL in cooperation with DRFZ AG Niesner)

Simultaneous detection of multiple cellular and molecular players in their native
environment, one of the keys to a full understanding of immune processes, remains
challenging for in vivo microscopy. Here, we present a synergistic strategy for
spectrally multiplexed in vivo imaging composed of (i) triple two-photon
excitation using spatiotemporal synchronization of two femtosecond lasers, (ii) a
broad set of fluorophores with emission ranging from blue to near infrared, (iii)
an effective spectral unmixing algorithm. Using our approach, we simultaneously
excite and detect seven fluorophores expressed in distinct cellular and tissue
compartments, plus second harmonics generation from collagen fibers in lymph
nodes. This enables us to visualize the dynamic interplay of all the central
cellular players during germinal center reactions. While current in vivo imaging
typically enables recording the dynamics of 4 tissue components at a time, our
strategy allows a more comprehensive analysis of cellular dynamics involving 8
single-labeled compartments. It enables to investigate the orchestration of
multiple cellular subsets determining tissue function, thus, opening the way for
a mechanistic understanding of complex pathophysiologic processes in vivo. In the
future, the design of transgenic mice combining a larger spectrum of fluorescent
proteins will reveal the full potential of our method.

Kuchling et al. – Diffusion tensor imaging for multilevel assessment of the visual pathway: possibilities for personalized outcome prediction in autoimmune disorders of the central nervous system.

EPMA J. 2017 Jul 25;8(3):279-294

by Kuchling J, Brandt AU, Paul F, Scheel M.

The afferent visual pathway represents the most frequently affected white matter pathway in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Diffusion tensor imaging (DTI) can reveal microstructural or non-overt brain tissue damage and quantify pathological processes. DTI facilitates the reconstruction of major white matter fiber tracts allowing for the assessment of structure-function and damage-dysfunction relationships. In this review, we outline DTI studies investigating the afferent visual pathway in idiopathic optic neuritis (ON), NMOSD, and MS. Since MS damage patterns are believed to depend on multiple factors, i.e., ON (anterior visual pathway damage), inflammatory lesions (posterior visual pathway damage), and global diffuse inflammatory and neurodegenerative processes, comprehensive knowledge on different contributing factors using DTI in vivo may advance our understanding of MS disease pathology. Combination of DTI measures and visual outcome parameters yields the potential to improve routine clinical diagnostic procedures and may further the accuracy of individual prognosis with regard to visual function and personalized disease outcome. However, due to the inherent limitations of DTI acquisition and post-processing techniques and the so far heterogeneous and equivocal data of previous studies, evaluation of the true potential of DTI as a possible biomarker for afferent visual pathway dysfunction is still substantially limited. Further research efforts with larger longitudinal studies and standardized DTI acquisition and post-processing validation criteria are needed to overcome current DTI limitations. DTI evaluation at different levels of the visual pathway has the potential to provide markers for individual damage evaluation in the future. As an imaging biomarker, DTI may support individual outcome prediction during personalized treatment algorithms in MS and other neuroinflammatory diseases, hereby leveraging the concept of predictive, preventive, and personalized medicine in the field of clinical neuroimmunology.

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.