Joseph Kuchling

Microstructural visual system changes in AQP4-antibody–seropositive NMOSD

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.

Normal volumes and microstructural integrity of deep gray matter structures in AQP4+ NMOSD

Objective: To assess volumes and microstructural integrity of deep gray matter structures in a homogeneous cohort of patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: This was a cross-sectional study including 36 aquaporin-4 antibody-positive (AQP4 Ab-positive) Caucasian patients with NMOSD and healthy controls matched for age, sex, and education. Volumetry of deep gray matter structures (DGM; thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) was performed using 2 independent automated methods. Microstructural integrity was assessed based on diffusion tensor imaging. Results: Both volumetric analysis methods consistently revealed similar volumes of DGM structures in patients and controls without significant group differences. Moreover, no differences in DGM microstructural integrity were observed between groups. Conclusions: Deep gray matter structures are not affected in AQP4 Ab-positive Caucasian patients with NMOSD. NMOSD imaging studies should be interpreted with respect to Ab status, educational background, and ethnicity of included patients.

Identical lesion morphology in primary progressive and relapsing–remitting MS –an ultrahigh field MRI study

Potential differences between primary progressive (PP) and relapsing–remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.

Magnetic Resonance Phase Alterations in Multiple Sclerosis Patients with Short and Long Disease Duration

Objective The analysis of the MR phase provides additional information on the tissue microstructure. In multiple sclerosis (MS) lesions phase alterations may reflect different stages of inflammatory activity. Here we investigated lesion morphology in MS patients with short and long disease duration on T2* weighted, phase, magnitude and susceptibility weighted imaging (SWI) at 7 Tesla (T). Methods 17 MS or clinically isolated syndrome patients with short (<60 months) and 11 with long (>60 months) disease duration underwent 7T MRI. Lesions were subsequently analyzed side-by-side with regard to morphology and visibility on T2* weighted, SWI, magnitude and SWI-filtered phase images. Results 126 of 192 T2* weighted lesions (65.6%) were characterized by a phase alteration pattern, and hence could be differentiated on phase images. In detail, a significantly reduced proportion of lesions showing phase alterations was detectable in patients with longer disease duration (mean±SD 51±37%, range 0–100%) compared to patients with short disease duration (mean±SD 90±19.5%, range 50–100%, p = 0.003). Conclusion This cross-sectional study identified different patterns of phase changes in lesions of MS patients with short and long standing disease. Longitudinal studies are warranted to prove that MR phase imaging is useful in determining the activity and the developmental stage of individual MS plaques.

GAD Antibody-Associated Late-Onset Cerebellar Ataxia in Two Female Siblings

Background: Anti-glutamic acid decarboxylase antibody (GAD-ab)-associated cerebellar ataxia is a rare neurological disorder characterized by cerebellar symptoms concomitant with high GAD-ab levels in serum and cerebrospinal fluid (CSF). Case Report: We report on 2 female siblings (aged 74 and 76 years) presenting with gradual progression of rotational vertigo, gait ataxia and vertical diplopia, continuously progressing for 6 months and 6 years, respectively. Autoimmune laboratory examinations showed remarkably increased serum and CSF GAD-ab levels. Their medical histories revealed late-onset type 1 diabetes mellitus (T1DM) and other concomitant autoimmune disorders (Graves disease, Hashimotos thyroiditis). Cerebral MRI and laboratory examinations were unremarkable. The diagnosis of GAD-ab-associated cerebellar ataxia with particular brainstem involvement was established in both women. After the exclusion of an underlying malignancy, immunosuppressive therapy has been initiated in both patients, which resulted in stabilization in one and in clinical improvement in the other patient. Discussion: The unique association of autoantibody-mediated cerebellar ataxia and late-onset T1DM in 2 siblings with similar clinical and paraclinical phenotypes strengthens the concept that hereditary factors might play a relevant role also in autoimmune diseases so far considered to be sporadic. Moreover, the occurrence of continuous vertical diplopia broadens the clinical spectrum of GAD-ab-associated neurological syndromes.

Patients with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density

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.

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

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.

Anatomical Wiring and Functional Networking Changes in the Visual System Following Optic Neuritis

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.

Comparison of probabilistic tractography and tract-based spatial statistics for assessing optic radiation damage in patients with autoimmune inflammatory disorders of the central nervous system

Background Diffusion Tensor Imaging (DTI) can evaluate microstructural tissue damage in the optic radiation (OR) of patients with clinically isolated syndrome (CIS), early relapsing-remitting multiple sclerosis and neuromyelitis optica spectrum disorders (NMOSD). Different post-processing techniques, e.g. tract-based spatial statistics (TBSS) and probabilistic tractography, exist to quantify this damage. Objective To evaluate the capacity of TBSS-based atlas region-of-interest (ROI) combination with 1) posterior thalamic radiation ROIs from the Johns Hopkins University atlas (JHU-TBSS), 2) Juelich Probabilistic ROIs (JUEL-TBSS) and tractography methods using 3) ConTrack (CON-PROB) and 4) constrained spherical deconvolution tractography (CSD-PROB) to detect OR damage in patients with a) NMOSD with prior ON (NMOSD-ON), b) CIS and early RRMS patients with ON (CIS/RRMS-ON) and c) CIS and early RRMS patients without prior ON (CIS/RRMS-NON) against healthy controls (HCs). Methods Twenty-three NMOSD-ON, 18 CIS/RRMS-ON, 21 CIS/RRMS-NON, and 26 HCs underwent 3 T MRI. DTI data analysis was carried out using JUEL-TBSS, JHU-TBSS, CON-PROB and CSD-PROB. Optical coherence tomography (OCT) and visual acuity testing was performed in the majority of patients and HCs. Results Absolute OR fractional anisotropy (FA) values differed between all methods but showed good correlation and agreement in Bland-Altman analysis. OR FA values between NMOSD and HC differed throughout the methodologies (p-values ranging from p < 0.0001 to 0.0043). ROC-analysis and effect size estimation revealed higher AUCs and R2 for CSD-PROB (AUC = 0.812; R2 = 0.282) and JHU-TBSS (AUC = 0.756; R2 = 0.262), compared to CON-PROB (AUC = 0.742; R2 = 0.179) and JUEL-TBSS (AUC = 0.719; R2 = 0.161). Differences between CIS/RRMS-NON and HC were only observable in CSD-PROB (AUC = 0.796; R2 = 0.094). No significant differences between CIS/RRMS-ON and HC were detected by any of the methods. Conclusions All DTI post-processing techniques facilitated the detection of OR damage in patient groups with severe microstructural OR degradation. The comparison of distinct disease groups by use of different methods may lead to different - either false-positive or false-negative - results. Since different DTI post-processing approaches seem to provide complementary information on OR damage, application of distinct methods may depend on the relevant research question.

MRI Markers and Functional Performance in Patients With CIS and MS: A Cross-Sectional Study

Introduction: Brain atrophy is a widely accepted marker of disease severity with association to clinical disability in multiple sclerosis (MS). It is unclear to which extent this association reflects common age effects on both atrophy and function. Objective: To explore how functional performance in gait, upper extremities and cognition is associated with brain atrophy in patients with Clinically Isolated Syndrome (CIS) and relapsing-remitting MS (RRMS), controlling for effects of age and sex. Methods: In 27 patients with CIS, 59 with RRMS (EDSS ≤3) and 63 healthy controls (HC), 3T MRI were analyzed for T2 lesion count (T2C), volume (T2V) and brain volumes [normalized brain volume (NBV), gray matter volume (NGMV), white matter volume (NWMV), thalamic volume (NThalV)]. Functional performance was measured with short maximum walking speed (SMSW speed), 9-hole peg test (9HPT) and symbol digit modalities test (SDMT). Linear regression models were created for functional variables with stepwise inclusion of age, sex and MR imaging markers. Results: CIS differed from HC only in T2C and T2V. RRMS differed from HC in NBV, NGMV and NThalV, T2C and T2V, but not in NWMV. A strong association with age was seen in HC, CIS and RRMS groups for NBV (r = −0.5 to −0.6) and NGMV (r = −0.6 to −0.8). Associations with age were seen in HC and RRMS but not CIS for NThalV (r = −0.3; r = −0.5), T2C (rs = 0.3; rs = 0.2) and T2V (rs = 0.3; rs = 0.3). No effect of age was seen on NWMV. Correlations of functional performance with age in RRMS were seen for SMSW speed, 9HPTand SDMT (r = −0.27 to −0.46). Regression analyses yielded significant models only in the RRMS group for 9HPT, SMSW speed and EDSS. These included NBV, NGMV, NThalV, NWMV, logT2V, age and sex as predictors. NThalV was the only MRI variable predicting a functional measure (9HPTr) with a higher standardized beta than age and sex (R2 = 0.36, p < 1e-04). Conclusion: Thalamic atrophy was a stronger predictor of hand function (9HPT) in RRMS, than age and sex. This underlines the clinical relevance of thalamic atrophy and the relevance of hand function as a clinical marker even in mildly disabled patients.