Brandt et al. – Frequent retinal ganglion cell damage after acute optic neuritis.

Mult Scler Relat Disord. 2018 May;22:141-147. doi: 10.1016/j.msard.2018.04.006.

by Alexander U. Brandt, Svenja Specovius, Timm Oberwahrenbrock, Hanna G. Zimmermann, Friedemann Paul,
Fiona Costello.

BACKGROUND: To identify the extent of ganglion cell damage after first-time optic neuritis (ON) using the inter-ocular difference between affected and fellow eyes, and whether this approach is able to detect more patients suffering from ganglion cell damage than using absolute values.
METHODS: Thirty-four patients with first-time unilateral ON were followed for a median 413 days. Patients underwent optical coherence tomography testing to determine ganglion cell plus inner plexiform layer thickness (GCIP). Ganglion cell loss was quantified as GCIP difference between ON-affected and fellow eyes (inter-GCIP) and was compared against measurements from 93 healthy controls (HC). Visual function was assessed with high contrast visual acuity; and standard automated perimetry-derived measures of mean deviation and foveal threshold.
RESULTS: At clinical presentation after median 19 days from symptom onset, 47.1% of patients showed early GCIP thinning in the ON-affected eye based on inter-GCIP. At the last visit acute ON was associated with 16.1 ± 10.0 µm GCIP thinning compared to fellow eyes (p = 3.669e-06). Based on inter-GCIP, 84.9% of ON patients sustained GCIP thinning in their affected eye at the last visit, whereas using absolute values only 71.0% of patients suffered from GCIP thinning (p = 0.002076). Only 32.3% of these patients had abnormal visual function. The best predictor of GCIP thinning as a measure of ON severity at the last visit was worse visual field mean deviation at clinical presentation.
CONCLUSION: Inter-ocular GCIP identifies significantly more eyes suffering damage from ON than absolute GCIP, visual fields or visual acuity loss. Effective interventional options are needed to prevent ganglion cell loss.

Chien et al. – MRI-Based Methods for Spinal Cord Atrophy Evaluation: A Comparison of Cervical Cord Cross-Sectional Area, Cervical Cord Volume, and Full Spinal Cord Volume in Patients with Aquaporin-4 Antibody Seropositive Neuromyelitis Optica Spectrum Disorders

AJNR Am J Neuroradiol. 2018 May 10. doi: 10.3174/ajnr.A5665

by Claudia Chien, Alexander U. Brandt, Felix Schmidt, Judith Bellmann-Strobl, Klemens Ruprecht, Friedemann Paul, Michael Scheel

BACKGROUND AND PURPOSE: Measures for spinal cord atrophy have become increasingly important as imaging biomarkers in the assessment of neuroinflammatory diseases, especially in neuromyelitis optica spectrum disorders. The most commonly used method, mean upper cervical cord area, is relatively easy to measure and can be performed on brain MRIs that capture cervical myelon. Measures of spinal cord volume (eg, cervical cord volume or total cord volume) require longer scanning and more complex analysis but are potentially better suited as spinal cord atrophy measures. This study investigated spinal cord atrophy measures in a cohort of healthy subjects and patients with aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders and evaluated the discriminatory performance of mean upper cervical cord cross-sectional area compared with cervical cord volume and total cord volume.
MATERIALS AND METHODS: Mean upper cervical cord area, cervical cord volume, and total cord volume were measured using 3T MRIs from healthy subjects (n = 19) and patients with neuromyelitis optica spectrum disorders (n = 30). Group comparison and receiver operating characteristic analyses between healthy controls and patients with neuromyelitis optica spectrum disorders were performed.
RESULTS: Mean upper cervical cord area, cervical cord volume, and total cord volume measures showed similar and highly significant group differences between healthy control subjects and patients with neuromyelitis optica spectrum disorders (P < .01 for all). All 3 measures showed similar receiver operating characteristic-area under the curve values (mean upper cervical cord area = 0.70, cervical cord volume = 0.75, total cord volume = 0.77) with no significant difference between them. No associations among mean upper cervical cord  cross-sectional area, cervical cord volume, or total cord volume with disability measures were found.
CONCLUSIONS: All 3 measures showed similar discriminatory power between healthy control and neuromyelitis optica spectrum disorders groups. Mean upper cervical cord area is easier to obtain compared with cervical cord volume and total cord volume and can be regarded as an efficient representative measure of spinal cord atrophy in the neuromyelitis optica spectrum disorders context.

Zimmermann et al. – Association of Retinal Ganglion Cell Layer Thickness With Future Disease Activity in Patients With Clinically Isolated Syndrome.

JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.1011.

by Zimmermann HG & Knier B, Oberwahrenbrock T, Behrens J, Pfuhl C, Aly L, Kaminski M, Hoshi MM, Specovius S, Giess RM, Scheel M, Mühlau M, Bellmann-Strobl J, Ruprecht K, Hemmer B, Korn T, Paul F, Brandt AU.

Importance: Clinically isolated syndrome (CIS) describes a first clinical incident suggestive of multiple sclerosis (MS). Identifying patients with CIS who have a high risk of future disease activity and subsequent MS diagnosis is crucial for patient monitoring and the initiation of disease-modifying therapy.
Objective: To investigate the association of retinal optical coherence tomography (OCT) results with future disease activity in patients with CIS.
Design, Setting, and Participants: This prospective, longitudinal cohort study took place between January 2011 and May 2017 at 2 German tertiary referral centers. A total of 179 patients with CIS were screened (80 in Berlin and 99 in Munich). Patients underwent neurological examination, magnetic resonance imaging (MRI), and OCT. Only eyes with no previous optic neuritis were considered for OCT analysis.
Main Outcomes and Measures: The primary outcome was not meeting the no evidence of disease activity (NEDA-3) criteria; secondary outcomes were MS diagnosis (by the 2010 McDonald criteria) and worsening of disability. The primary measure was OCT-derived ganglion cell and inner plexiform layer thickness; the secondary measures included peripapillary retinal nerve fiber layer thickness, inner nuclear layer thickness, and MRI-derived T2-weighted lesions.
Results: A total of 97 of the 179 screened patients (54.2%) were enrolled in the study at a median of 93 (interquartile range [IQR], 62-161) days after a first demyelinating event. The median follow-up duration (Kaplan-Meier survival time) was 729 (IQR, 664-903) days. Of 97 patients with CIS (mean age 33.6 [7.9] years; 61 [62.9%] female), 58 (59%) did not meet NEDA-3 criteria during the follow-up period. A Kaplan-Meier analysis showed a significant probability difference in not meeting NEDA-3 criteria by ganglion cell and inner plexiform later thickness (thinnest vs thickest tertile: hazard ratio [HR], 3.33 [95% CI, 1.70-6.55; P < .001; log-rank P = .001). A follow-up diagnosis of MS was more likely for patients with low ganglion cell and inner plexiform layer thickness (thinnest vs thickest tertile: HR, 4.05 [95% CI, 1.93-8.50]; P < .001). Low peripapillary retinal nerve fiber layer thickness likewise indicated risk of not meeting NEDA-3 criteria (thinnest vs thickest tertile: HR, 2.46 [95% CI, 1.29-4.66]; P = .01; log-rank P = .02). Inner nuclear layer thickness and T2-weighted lesion count were not associated with not meeting NEDA-3 criteria.
Conclusions and Relevance: Retinal ganglion cell and inner plexiform layer thickness might prove a valuable imaging marker for anticipating future disease activity and diagnosis of MS in patients with CIS, which can potentially support patient monitoring and initiation of disease-modifying therapy.

Oberwahrenbrock et al. – Multicenter reliability of semiautomatic retinal layer segmentation using OCT

Neurol Neuroimmunol Neuroinflamm. 2018 Mar 13;5(3):e449. doi: 10.1212/NXI.0000000000000449.

by Oberwahrenbrock T, Traber GL, Lukas S, Gabilondo I, Nolan R, Songster C, Balk L, Petzold A, Paul F, Villoslada P, Brandt AU, Green AJ, Schippling S

Objective: To evaluate the inter-rater reliability of semiautomated segmentation of spectral domain optical coherence tomography (OCT) macular volume scans.
Methods: Macular OCT volume scans of left eyes from 17 subjects (8 patients with MS and 9 healthy controls) were automatically segmented by Heidelberg Eye Explorer (v1.9.3.0) beta-software (Spectralis Viewing Module v6.0.0.7), followed by manual correction by 5 experienced operators from 5 different academic centers. The mean thicknesses within a 6-mm area around the fovea were computed for the retinal nerve fiber layer, ganglion cell layer (GCL), inner plexiform layer (IPL), inner nuclear layer, outer plexiform layer (OPL), and outer nuclear layer (ONL). Intraclass correlation coefficients (ICCs) were calculated for mean layer thickness values. Spatial distribution of ICC values for the segmented volume scans was investigated using heat maps.
Results: Agreement between raters was good (ICC > 0.84) for all retinal layers, particularly inner retinal layers showed excellent agreement across raters (ICC >0.96). Spatial distribution of ICC showed highest values in the perimacular area, whereas the ICCs were poorer for the foveola and the more peripheral macular area. The automated segmentation of the OPL and ONL required the most correction and showed the least agreement, whereas differences were less prominent for the remaining layers.
Conclusions: Automated segmentation with manual correction of macular OCT scans is highly reliable when performed by experienced raters and can thus be applied in multicenter settings. Reliability can be improved by restricting analysis to the perimacular area and compound segmentation of GCL and IPL.

Finke et al. – Association of Visual Impairment in Neuromyelitis Optica Spectrum Disorder With Visual Network Reorganization.

JAMA Neurol. 2018 Mar 1;75(3):296-303

by Finke C, Zimmermann H, Pache F, Oertel FC, Chavarro VS, Kramarenko Y, Bellmann-Strobl J, Ruprecht K, Brandt AU, Paul F

Importance: Severe visual impairment is one of the major symptoms in neuromyelitis optica spectrum disorder (NMOSD), but functional network reorganization induced by the diminished sensory input has not been investigated thus far.
Objective: To examine adaptive visual network connectivity changes in NMOSD.
Design, Setting, and Participants: In this cross-sectional study, data were collected from May 1, 2013, through February 31, 2016, from 31 patients with aquaporin-4 antibody-positive NMOSD and 31 age- and sex-matched healthy control individuals at the Department of Neurology and NeuroCure Clinical Research Center at Charité-Universitätsmedizin Berlin, Berlin, Germany.
Main Outcomes and Measures: Visual function (high-contrast visual acuity and contrast sensitivity), optical coherence tomography (peripapillary retinal nerve fiber layer and ganglion cell layer thickness), and resting-state functional magnetic resonance imaging (functional connectivity of large-scale brain networks).
Results: Thirty-one patients with NMOSD (mean [SD] age, 48.2 [13.9] years; 28 women and 3 men) and 31 healthy controls (mean [SD] age, 47.2 [15.3] years; 28 women and 3 men) participated in the study. Patients had a selective and pronounced increase of functional connectivity in the primary and secondary visual networks. Increased primary visual network connectivity correlated with reduced high-contrast visual acuity (r = -0.39, P = .006), reduced low-contrast sensitivity (r = -0.33, P = .03), and more severe retinal damage measured by optical coherence tomography (r = -0.4, P = .01). Furthermore, visual functional connectivity was significantly higher in patients with a history of optic neuritis compared with patients without optic neuritis (mean [SD] regression coefficients, 50.0 [4.3] vs 34.6 [5.6]; P = .04).
Conclusions and Relevance: Impaired visual function and retinal damage are associated with selective reorganization of the visual network in NMOSD. These findings advance the understanding of visual system dysfunction in NMOSD and, more generally, provide insight into pathophysiologic responses of the visual system to impaired visual input.

Backner et al. – Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis.

JAMA Neurol. 2018 Mar 1;75(3):287-295

by Backner Y, Kuchling J, Massarwa S, Oberwahrenbrock T, Finke C, Bellmann-Strobl J, Ruprecht K, Brandt AU, Zimmermann H, Raz N, Paul F, Levin N

Importance: Clinical outcome in multiple sclerosis was suggested to be driven by not only remyelination but also adaptive reorganization. This mechanism needs to be further understood.
Objective: To explore anatomical and functional visual networks in patients with optic neuritis (ON) to assess the relative weight of each connectivity modality to expedite visual recovery.
Design, Setting, and Participants: Between March 11, 2011, and May 26, 2014, 39 patients with either clinically isolated syndrome (CIS) ON (n = 18) or other CIS (non-ON) (n = 21) were recruited 1 to 28 months following an initial clinical event. These patients enrolled in an ongoing prospective cohort study (107 participants at the time of this present study) about the disease course of CIS and multiple sclerosis. Inclusion criteria were an age of 18 to 65 years, the suggestive clinical and paraclinical diagnosis of CIS or multiple sclerosis after relevant differential diagnoses have been ruled out, the existence of complete imaging data, and no ocular comorbidities. Anatomical connectivity was evaluated by diffusion tensor imaging, and functional connectivity was evaluated by resting-state functional magnetic resonance imaging. The visual pathways, including optic tracts, optic radiations, and splenial fibers, were delineated, and the resting-state visual networks were detected. Data analysis took place from September 1, 2015, to December 1, 2015.
Main Outcomes and Measures: Connectivity changes were quantified and compared to determine the association of ON with the visual network.
Results: This study included 18 patients with CIS ON, 11 (61%) of whom were women with a mean (SD) age of 32.83 (8.53) years, and 21 patients with CIS non-ON (11 [52%] of whom were women with a mean [SD] age of 30.86 [7.54] years). With the use of diffusion tensor imaging, reduced diffusivity (mean [SD] fractional anisotropy, 0.35 [0.03] vs 0.38 [0.03]; P < .01) was evident along the optic tracts of patients with ON, suggesting the extension of axonal injury from the damaged optic nerve. Neither the optic radiations nor the splenial fibers showed evidence of loss of integrity. Yet, in the presence of an intact postgeniculate anatomical network, the functional connectivity within the visual network was higher in the ON cohort. Functional connectivity observed in cortical motion-related areas was inversely correlated with the visual evoked potential-measured conduction velocity (r = -0.59; P < .05).
Conclusions and Relevance: In this cohort, local optic nerve demyelinating damage does not affect distant wiring, but even in the presence of an intact anatomical network, functional modification may occur. These functional network changes may be part of the recovery process, but further research is needed to elucidate this process.

Brandt et al. – Self-perception and determinants of color vision in Parkinson’s disease

J Neural Transm (Vienna). 2018 Feb;125(2):145-152

by Brandt AU, Zimmermann HG, Oberwahrenbrock T, Isensee J, Müller T, Paul F

Visual dysfunction is common in patients with Parkinson’s disease (PD). The objective of this study was to investigate the perceived impact of visual dysfunction and especially color vision loss on PD patients, and to identify retinal and disease factors associated with color vision. Thirty PD patients and thirty-four healthy controls were included. Participants performed the Farnsworth-Munsell Hue-100 test (FMT). Patients answered the National Eye Institute Visual Function Questionnaire (NEI-VFQ), Unified Parkinson’s Disease Rating Scale (UPDRS) assessment, and underwent optical coherence tomography with measurement of retinal nerve fiber layer, ganglion cell layer + inner plexiform layer (GCIPL), and outer nuclear and photoreceptor layer. Dopaminergic treatment was assessed as levodopa equivalent dose (LED). Vision domains significantly worse in PD patients compared to normative data were General Vision, Near Activities, Distance Activities, Vision-Specific Dependency, Driving, and Peripheral Vision. Worse NEI-VFQ total scores were associated with worse UPDRS, higher LED, and higher age, but not with FMT, visual acuity, or OCT measures. Only two patients (7%) reported problems with color vision. In contrast, patients performed significantly worse in the FMT than healthy controls and 17 (56.7%) patients were outside the 95th percentile of normative data. In multiple regression analyses, lower LED and higher age were associated with worse color vision in the FMT. PD patients are not aware of color vision deficits. Given the impact of color vision loss on everyday tasks in other conditions, future research should investigate the impact of vision deficits on disease burden in PD.

Mikolajczak et al. – Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density

Mult Scler. 2017 Dec;23(14):1847-1853

by Mikolajczak J, Zimmermann H, Kheirkhah A, Kadas EM, Oberwahrenbrock T, Muller R, Ren A, Kuchling J, Dietze H, Prüss H, Paul F, Hamrah P, Brandt AU

BACKGROUND: Many studies in multiple sclerosis (MS) have investigated the retina. Little, however, is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response to environmental stimuli.
OBJECTIVE: This study aims to investigate the effect of MS on corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM).
METHODS: We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with cornea module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography.
RESULTS: We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity but not with previous clinical trigeminal symptoms, retinal neuro-axonal damage, visual acuity or disease duration.
CONCLUSION: Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.

Oertel et al. – Optical coherence tomography in neuromyelitis optica spectrum disorders: potential advantages for individualized monitoring of progression and therapy.

EPMA J. 2017 Dec 22;9(1):21-33

by Oertel FC, Zimmermann H, Paul F, Brandt AU

Neuromyelitis optica spectrum disorders (NMOSD) are mostly relapsing inflammatory disorders of the central nervous system (CNS). Optic neuritis (ON) is the first NMOSD-related clinical event in 55% of the patients, which causes damage to the optic nerve and leads to visual impairment. Retinal optical coherence tomography (OCT) has emerged as a promising method for diagnosis of NMOSD and potential individual monitoring of disease course and severity. OCT not only detects damage to the afferent visual system caused by ON but potentially also NMOSD-specific intraretinal pathology, i.e. astrocytopathy. This article summarizes retinal involvement in NMOSD and reviews OCT methods that could be used now and in the future, for differential diagnosis, for monitoring of disease course, and in clinical trials.

Grobelny et al. – Maximum walking speed in multiple sclerosis assessed with visual perceptive computing

PLoS One. 2017 Dec 15;12(12):e0189281

by Grobelny A, Behrens JR, Mertens S, Otte K, Mansow-Model S, Krüger T, Gusho E, Bellmann-Strobl J, Paul F, Brandt AU, Schmitz-Hübsch T

BACKGROUND: Gait is often impaired in people with multiple sclerosis (PwMS), but detailed assessment of gait impairment in research and care remains challenging. In a previous pilot study we reported the feasibility of visual perceptive computing (VPC) for gait assessment in PwMS using the Short Maximum Speed Walk (SMSW), which assesses gait on recording distances confined to less than 4 meters.
OBJECTIVE: To investigate the equivalence of SMSW to rater-based timed 25ft. walk (T25FW) in a large cohort of PwMS, and to investigate the association of SMSW-derived gait parameters with clinical disability, as well as subjective and objective gait impairment, in order to validate the SMSW as a quick and objective measure of clinical relevance possibly superior to T25FW.
METHODS: 95 PwMS and 60 healthy controls (HC) performed the SMSW using a VPC system with Microsoft Kinect. All participants received two immediate retests to establish test-retest-reliability. Both PwMS and HC performed the T25FW. PwMS were rated according to the Expanded Disability Status Scale (EDSS) and answered the 12-item Multiple Sclerosis Walking Scale (MSWS-12) as a measure of self-perceived walking impairment.
RESULTS: PwMS showed reduced average speed (p<0.001) and higher mediolateral deviation (p = 0.002) during SMSW than HC. Average speed was the most reliable SMSW parameter in PwMS and HC (intra-class correlation coefficient (ICC) in PwMS = 0.985, and in HC = 0.977). Average speed declined with age in PwMS and HC (r in PwMS = -0.648, and in HC = -0.452, both p<0.001). Correlation of SMSW average speed and T25FW speed was high in both groups (r in PwMS = 0.783, and in HC = 0.747, both p<0.001) and mean difference (0.0013 m/s) between methods was below smallest detectable change. Average speed correlated well with both clinical disability based on EDSS (r = -0.586, p<0.001) and self-perceived walking impairment based on MSWS-12 (r = -0.546, p<0.001).
CONCLUSION: VPC-assessed walking parameters during SMSW can reliably detect gait disturbance in PwMS over very short distance. Specifically, maximum gait speed can be obtained with high accuracy in this simple test set-up. Cross-sectional associations with disability and self-perceived walking impairment support clinical relevance. Given its objectivity in a simple test set-up, SMSW is superior to T25FW.