Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis.

OBJECTIVES: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS). METHODS: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated. RESULTS: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy. DISCUSSION: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.

Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial.

BACKGROUND AND OBJECTIVES: Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy in PMS. In this post hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype and (3) associations between OCT and MRI measures of neurodegeneration. METHODS: In the multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (PPMS) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations. RESULTS: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, p = 0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r = 0.27, r = 0.26, and r = 0.20, respectively; p < 0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%. DISCUSSION: Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ibudilast reduces composite ganglion cell + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Effects of Myopia on Rates of Change in Optical Coherence Tomography Measured Retinal Layer Thicknesses in People with Multiple Sclerosis and Healthy Controls.

PURPOSE: To quantify the associations of myopia with longitudinal changes in retinal layer thicknesses in people with multiple sclerosis (PwMS) and healthy controls (HC). METHODS: A cohort of PwMS and HC with recorded refractive error (RE) prospectively scanned on Cirrus HD-OCT at the Johns Hopkins MS Center was assessed for inclusion. Exclusion criteria included OCT follow-up < 6 months, ocular comorbidities, incidental OCT pathologies, and inadequate scan quality. Eyes were classified as having high myopia (HM) (RE≤ -6 diopters), low myopia (LM) (RE> -6 and ≤ -3 diopters), or no myopia (NM) (RE> -3 and ≤ +2.75). Linear mixed-effects regression models were used in analyses. RESULTS: A total of 213 PwMS (eyes: 67 HM, 98 LM, 207 NM) and 80 HC (eyes: 26 HM, 37 LM, 93 NM) were included. Baseline average ganglion cell/inner plexiform (GCIPL) and peri-papillary retinal nerve fiber layer (pRNFL) thicknesses were lower in MS HM compared with MS NM (diff: -3.2 µm, 95% CI: -5.5 to -0.8, p = 0.008 and -5.3 µm, 95% CI: -9.0 to -1.7, p = 0.004, respectively), and similarly in HC HM, as compared with HC NM. Baseline superior, inferior, and nasal pRNFL thicknesses were lower in HM compared with NM, while temporal pRNFL thickness was higher, both in MS and HC (MS: 7.1 µm, 95% CI: 2.7-11.6, p = 0.002; HC: 4.7 µm, 95% CI: -0.3 to 9.7, p = 0.07). No longitudinal differences in rates of GCIPL change were noted between HM and LM vs. NM, either in MS or HC. CONCLUSION: Cross-sectional differences in average GCIPL and pRNFL thicknesses are commonly seen in people with HM as compared to reference normative values from people with NM and can lead to false attribution of pathology if RE is not taken into account. However, our study suggests that longitudinal changes in average GCIPL thickness in PwMS with myopia are similar in magnitude to PwMS with NM, and therefore are appropriate for monitoring disease-related pathology.

Visual Pathway Involvement in NMDA Receptor Encephalitis: A Clinical, Optical Coherence Tomography, and 18-Fluorodeoxyglucose PET/CT Approach.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis patients have been reported to exhibit visual dysfunction without retinal thinning. The objective of our study was to examine the involvement of the visual pathway structure and function in anti-NMDAR encephalitis by assessing postrecovery visual function and retinal structure, and acute-phase occipital cortex function. METHODS: In this cross-sectional study, patients diagnosed with anti-NMDAR encephalitis per consensus criteria underwent postrecovery visual acuity (VA) testing and optical coherence tomography (OCT) with automated retinal layer segmentation. Clinical data and acute-phase brain 18F-fluorodeoxyglucose (FDG) PET/CT (performed within 90 days of symptom onset, assessed qualitatively and semi-quantitatively) were retrospectively analyzed. VA and OCT measures were compared between anti-NMDAR and age, sex, and race-matched healthy controls (HC). When available, FDG-PET/CT metabolism patterns were analyzed for correlations with VA, and OCT measures. RESULTS: A total of 16 anti-NMDAR (32 eyes) and 32 HC (64 eyes) were included in the study. Anti-NMDAR exhibited lower low-contrast VA (2.5% contrast: -4.4 letters [95% CI; -8.5 to -0.3]; P = 0.04, 1.25% contrast: -6.8 letters [95%CI; -12 to -1.7]; P = 0.01) compared with HC, but no differences were found on OCT-derived retinal layer thicknesses. Acute-phase FDG-PET/CT medial occipital cortex metabolism did not correlate with follow-up low-contrast VA or ganglion cell/inner plexiform layer thickness (GCIPL) (n = 7, 2.5% contrast: r = -0.31; P = 0.50, 1.25% contrast: r = -0.34; P = 0.45, GCIPL: r = -0.04; P = 0.94). CONCLUSIONS: Although the visual system seems to be involved in anti-NMDAR encephalitis, no retinal structural or occipital cortex functional abnormalities seem to be responsible for the visual dysfunction. When detected acutely, occipital lobe hypometabolism in anti-NMDAR encephalitis does not seem to associate with subsequent retrograde trans-synaptic degenerative phenomena, potentially reflecting reversible neuronal/synaptic dysfunction in the acute phase of the illness rather than neuronal degeneration.

Use of retinal optical coherence tomography to differentiate suspected neuromyelitis optica spectrum disorder from multiple sclerosis: A cross-sectional study.

BACKGROUND: Retinal optical coherence tomography (OCT) can differentiate definite NMOSD (dNMOSD) from multiple sclerosis (MS), but has not been evaluated in patients with a high clinical suspicion of NMOSD and not fulfilling the current consensus diagnostic criteria, referred in this paper as "potential" NMOSD (pNMOSD). AIM: To compare the retinal OCT measurements between patients with pNMOSD, dNMOSD, MS, and reference healthy controls (HC). MATERIAL AND METHODS: In this cross-sectional study, clinical and demographic characteristics, as well as OCT measurements of peripapillary retinal nerve fiber layer (pRNFL), inner nuclear layer (INL), macular retinal nerve fiber layer (mRNFL), outer nuclear layer (ONL) ganglion cell/inner plexiform layer (GCIPL), and macular volume (MV) were compared between groups. Mixed-effects regression models adjusting for within-patient inter-eye correlations, controlling for age, gender, disease duration and history of optic neuritis per eye were explored. Subgroup analyses were performed on eyes with previous optic neuritis. RESULTS: 234 eyes (20 pNMOSD, 33 dNMOSD, 138 MS, and 43 HC) were included. Controlling for age, gender, disease duration, and history of optic neuritis per eye, pNMOSD eyes showed decreased GCIPL, pRNFL, mRNFL and MV thicknesses, similar to eyes with dNMOSD, but significantly thinner than MS and HC subjects' eyes. Similar results were obtained for the pRNFL, mRNFL, GCIPL, INL and MV thickness in the subgroup analysis exploring only eyes with history of optic neuritis (12 pNMOSD, 15 dNMOSD, and 27 MS). CONCLUSION: Retinal OCT measurements in patients with pNMOSD were similar to dNMOSD, but significantly lower than patients with MS and healthy controls. This suggests that retinal OCT measures could be helpful markers supportive of NMOSD diagnosis and should be explored in larger studies as a valuable addition to the current consensus diagnostic criteria.

Correlation of Pattern Reversal and Flash Visual Evoked Potential Latencies With Optical Coherence Tomography Measures in Patients With Optic Neuropathy and Patients With Multiple Sclerosis Without Optic Neuropathy.

PURPOSE: The object of the study is to relate the pattern reversal visual evoked potential (PRVEP) and flash VEP (f-VEP) latencies with retinal neurons and their fibers. METHODS: We studied 104 eyes. Forty-two eyes from patients with optic neuritis (ON), 28 eyes from patients with multiple sclerosis without involvement of the optic nerves (MS-non-ON), and 34 eyes of normal controls. RESULTS: Pattern reversal visual evoked potential latency is more delayed in patients with ON than in patients with multiple sclerosis nonON. Flash visual evoked potential (f-VEP) latency was delayed in both categories. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell/inner plexiform layer (GCIPL) thickness was lower in patients with ON and multiple sclerosis non-ON. In patients with ON, f-VEP latencies correlated negatively with pRNFL thickness but not GCIPL thickness. In patients with ON, PRVEP latencies did not correlate with pRNFL thickness but correlate negatively with GCIPL thickness. CONCLUSIONS: Patients with ON have delayed VEPs and thinner optical coherence tomography values. Flash visual evoked potentials correlate with pRNFL, indicating axonal pathology. PRVEP correlate with GCIPL, indicating ganglion cell pathology. Abnormal PRVEP with preserved normal f-VEP indicate isolated myelin damage. Abnormalities in both PRVEP and f-VEP indicate myelin and axonal damage in the optic nerve. Combining the results of PRVEP, f-VEP, pRNFL, and GCIPL, one can define the location, type, and extent of the lesion in the macula and optic nerve.

Central vein sign: A putative diagnostic marker for multiple sclerosis.

The presence of a "central vein sign" (CVS) has been introduced as a biomarker for the diagnosis of multiple sclerosis (MS) and shown to have the ability to accurately differentiate MS from other white matter diseases (MS mimics). Following the development of susceptibility-based magnetic resonance venography that allowed the in vivo detection of CVS, a standard CVS definition was established by introducing the "40% rule" that assesses the number of MS lesions with CVS as a fraction of the total number of lesions to differentiate MS lesions from other types of lesions. The "50% rule," the "three-lesion criteria," and the "six-lesion criteria" were later introduced and defined. Each of these rules had high levels of sensitivity, specificity, and accuracy in differentiating MS from other diseases, which has been recognized by the Magnetic Resonance Imaging in MS (MAGNIMS) group and the Consortium of MS Centers task force. The North American Imaging in Multiple Sclerosis Cooperative even provided statements and recommendations aiming to refine, standardize and evaluate the CVS in MS. Herein, we review the existing literature on CVS and evaluate its added value in the diagnosis of MS and usefulness in differentiating it from other vasculopathies. We also review the histopathology of CVS and identify available automated CVS assessment methods as well as define the role of vascular comorbidities in the diagnosis of MS.

Rituximab Treatment for Chronic Idiopathic Axonal Polyneuropathy.

ABSTRACT: Chronic idiopathic axonal polyneuropathy is a disorder of unknown etiology resulting in progressive weakness and sensory disturbances predominantly in the hands and feet. Nerve conduction studies and electromyography confirm axonal damage in the nerves of the upper and lower extremities. The pathology is symmetrical with a distal predilection. Patients usually do not respond to the classical treatment with steroids, intravenous immunoglobulin, plasmapheresis, or immunosuppressant drugs. We describe 2 cases of chronic idiopathic axonal polyneuropathy who received intravenous rituximab as a last resort because of the severity of their symptoms. Both patients showed dramatic improvement in their weakness, muscle atrophy, numbness, and paresthesias only few weeks after the induction dose. Their daily functional activities improved to self-independence.

Spinal cord infarction in a young adult: What is the culprit?

Context: Non-traumatic spinal cord infarction in the young adult is usually associated with a single or multiple genetic mutations. There are certain gene mutations that are more commonly associated with spinal cord infarctions. Homozygous or heterozygous mutations, and single mutations or polymorphism, do not seem to determine the probability of spinal cord infarction.Findings: We add another case of spinal cord infarction in a young adult to the few reported in the literature, and discuss the value of genetic studies and genetic counseling.Conclusion: Non-traumatic spinal cord infarction is usually caused by a genetic mutation. Early recognition of this entity and definition of the mutation will limit unnecessary and invasive procedures and allows early rehabilitation, preventive measures for complications and genetic counseling.