Pathophysiology and Imaging Diagnosis of Demyelinating Disorders

The spectrum of “demyelinating disorders” is broad and it includes various disorders with central nervous system (CNS) demyelination[...

The Effect of Disease Modifying Therapies on Deep Gray Matter: A Longitudinal Comparative Study

Summary Cerebral gray matter (GM) atrophy is an important factor in determining disability in Multiple Sclerosis4,9. Disease modifying therapies reduce the GM atrophy to some degree, both in the cortical and deep gray matter (dGM). A previous study has shown that fingolimod (FTY720), asphingosine 1 phosphate immunomodulator can significantly reduced GM and thalamic volume loss in patients with relapsing-remitting Multiple Sclerosis(RRMS)1. In addition to its effect on reducing dGM volume loss, fingolimod is also believed to have protective effect on focal and diffuse dGM damage2,8. The effect of natalizumab on GM atrophy, however, is controversial5. Although compared with fingolimod, natalizumab- treated patients had a smaller number of areas of cortical GM atrophy, particularly in temporo-occipital regions, natalizumab-treated patients experienced accelerated GM atrophy in cerebellum. The effect of natalizumab on dGM atrophy is still unclear. glatirameracetate, another disease modifying agent, has shown a reduction of the accumulation of cortical lesions and slowing of the GM atrophy progression3. Although the effectiveness offingolimod, glatiramer acetate and natalizumab on maintaining GM volume has been studied separately, data about comparative longitudinal effect of these therapies are limited7, 10.Using clinical and MRI data on a 3T MRI that were collected over at least three years, we aim to provide acomprehensivecomparison of the effectofflingolimod, glatiramer acetate and natalizumab on the dGM. The primary hypothesis of the study is that all three disease modifying therapies, fingolimod, glatirameracetate and natalizumab will reduce the dGM atrophy to a certain degree in RRMS patients over the study period. The secondary hypothesis is that fingolimod-treated patientsmay show less dGM volume loss compared with glatirameracetate and natalizumab-treated MS patients. Methods All participants, including patients starting on fingolimod (n=55), onnatalizumab (n=28) or glatiramer acetate (n=30) underwent MRI scans at baseline (Y0), one year after the initiation of the drug (Y1), two years after the initiation of the drug (Y2) and three years after the initiation of the drug (Y3). Changes in dGM volume, including thalamus, caudate, putamen, pallidum, hippocampus, amygdala, accumbens, and brain stem, were recorded. Changes in dGM were then analyzed from the following three perspectives. Correlations between Clinical Measures and dGM Volume The dGMvolumeof all three drug-groups at Y0 was compiled. The correlation between patients’ eight dGMstructures with their Y0 clinical data, including age, Expanded Disability Status Scale (EDSS), Disease Duration (DD), Functional Systems Scores(FSS), number of relapses, Timed 25-Foot Walk (T25W), 9-Hole Peg Test (9HPTD and 9HPTND), Paced Auditory Serial Additiona Test (PASAT-3), and Symbol Digit Modalities Test (SDMT) were analyzed. Comparison of Longitudinal Changes in dGM Volumewithin Each Drug Group The changes in dGM volume between two time points, for example, Y0 and Y1 were analyzed using Wilcoxon Sighed Ranks test. Repeated Measures ANOVA test was used to compare three time points, for example, Y0, Y1, and Y2. For drug groups that have data from all three years, for example, fingolimod and natalizumab, both p value of the Test of Within-Subjects and p value of Pairwise Comparisons were recorded. Glatiramer acetate has data from Y0 and Y1, a Wilcoxon signed-rank test was done and p-value was recorded. Comparison of Different Drug effect on dGM Volume The volume change in each dGM structure from two time points, i.e. Y0 to Y1, Y1 to Y2, Y2 to Y3, Y0 to Y2 and Y0 to Y3 in each drug group were calculated. One Way ANOVA test was run to compare the volume changes over the same time period within three drug-groups. Results EDSS is negatively correlated with the volume of thalamus (p\u3c0.001), caudate (p=0.048), putamen (p=0.026), and accumbens (p=0.015). DD is negatively correlated with the volume of thalamus (p=0.012), caudate (p=0.028), putamen (p=0.030) and hippocampus (p=0.026). FSS is negatively correlated with the volume of thalamus (p=0.015). T25FW is negatively correlated with the volume of thalamus (p\u3c0.001), caudate (p=0.003), putamen (p\u3c0.001), pallidum (p\u3c0.007), accumbens (p=0.006) and brain stem (p=0.006). 9HPT D is negatively correlated with the volume of thalamus (p=0.014) and the volume of pallidum (p=0.023). 9HPT ND is negatively correlated with the volume of thalamus (p=0.019), putamen (p=0.02) and pallidum(p=0.005). PASAT is positively correlated with the volume of thalamus (p=0.013), caudate (p=0.009) and pallidum (p=0.009) but negatively correlated with the volume of putamen (p=0.038)(Table 1). Patients onfingolimod showed significant decrease in the volume of pallidum from Y0 to Y1 (p=0.008) and Y0 to Y2 (p=0.043), and thalamic volume from Y0 to Y2 (p=0.005). Patients who tooknatalizumab showed significant decrease in volume of thalamus from Y0 to Y1 (p=0.032) (Table 2). Over the same time period, patients from different drug groups did not show significant difference in the change in dGMvolume. Conclusion Patients who have smaller thalamus, putamen, caudate and accumbens tend to score higher EDSS score, indicating that the above structures are associated with more severe neurological impairment in MS. Patients who have lower thalamus, caudate, putamen, pallidum, accumbens and brain stem volume take longer to complete T25FW test, which shows deteriorated walking ability. Similar trend can be found in the upper extremity function in MS patients. Those with lower thalamic, putamen and pallidum volume perform worse in the 9HPT test. Higher cognitive function is correlated with higher thalamic, caudate, putamen and pallidum volume. Lastly, lowerthalamic, caudate, putamen and hippocampal volume is related to longer disease duration. The majority of the patients in the study did not show significant reduction in dGM volume, which proves that all three disease modifying agents slowed down the dGM atrophy over the course of 3 years.Compared to natalizumab and copaxone, fingolimod patients showed more significant loss in the volume of pallidum. References 1. Gaetano L, Häring DA, Radue EW, et al. Fingolimod effect on gray matter, thalamus, and white matter in patients with multiple sclerosis. Neurology. 2018;90(15):e1324-e1332. doi:10.1212/WNL.0000000000005292 2. Bajrami A, Pitteri M, Castellaro M, et al. The effect of fingolimod on focal and diffuse grey matter damage in active MS patients. J Neurol. 2018;265(9):2154-2161. doi:10.1007/s00415-018-8952-2 3. Crescenzo F, Marastoni D, Zuco C, et al. Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis. MultSclerRelatDisord. 2019;27:305-311. doi:10.1016/j.msard.2018.11.009 4. Koskimäki F, Bernard J, Yong J, et al. Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment. PLoS One. 2018;13(12):e0209326. Published 2018 Dec 21. doi:10.1371/journal.pone.0209326 5. Favaretto, A., Lazzarotto, A., Margoni, M. et al. Effects of disease modifying therapies on brain and grey matter atrophy in relapsing remitting multiple sclerosis. MultScler Demyelinating Disord 3, 1 (2018).https://doi.org/10.1186/s40893-017-0033-3 6. Pawate S, Wang L, Song Y, Sriram S. Analysis of T2 intensity by magnetic resonance imaging of deep gray matter nuclei in multiple sclerosis patients: effect of immunomodulatory therapies. J Neuroimaging. 2012 Apr;22(2):137-44. doi: 10.1111/j.1552-6569.2011.00622.x.Epub 2011 Jun 24. PMID: 21707826. 7. Preziosa P, Rocca MA, Pagani E, Storelli L, Rodegher M, Moiola L, Filippi M. Two-year regional grey and white matter volume changes with natalizumab and fingolimod. J NeurolNeurosurg Psychiatry. 2020 May;91(5):493-502. doi: 10.1136/jnnp-2019-322439. Epub 2020 Feb 28. PMID: 32111638. 8. Bernitsas E, Kopinsky H, Lichtman-Mikol S, Razmjou S, Santiago-Martinez C, Yarraguntla K, Bao F. Multimodal MRI Response to Fingolimod in Multiple Sclerosis: A Nonrandomized, Single Arm, Observational Study. J Neuroimaging. 2021 Mar;31(2):379-387. doi: 10.1111/jon.12824. Epub 2020 Dec 26. PMID: 33368776. 9. Bross M, Hackett M, Bernitsas MM, Bao F, Santiago-MartinezC,BernitsasE.Cortical surface thickness, subcortical volumes and disability between races in relapsing-remitting multiple sclerosis. MultSclRelatDisord 2021, in press 10. Sotirchos ES, Gonzalez-Caldito N, Dewey BE, Fitzgerald KC, Glaister J, Filippatou A, Ogbuokiri E, Feldman S, Kwakyi O, Risher H, Crainiceanu C, Pham DL, Van Zijl PC, Mowry EM, Reich DS, Prince JL, Calabresi PA, Saidha S. Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis. MultScler. 2020 Mar;26(3):312-321. doi: 10.1177/1352458519826364. Epub 2019 Feb 11. PMID: 30741108; PMCID: PMC6689465

From Postural Orthostatic Tachycardia Syndrome to Radiologically Isolated Syndrome

Background. Autonomic dysfunction is common in Multiple Sclerosis (MS) patients. Most spinal cord lesions entail some degree of autonomic nervous system dysfunction. MS patients may develop autonomic dysfunction later in their disease course. Methods. We report a patient with no prior history of MS presenting with orthostatic symptoms and diagnosed initially with postural orthostatic tachycardia syndrome (POTS). Four months later, she was diagnosed with radiologically isolated syndrome (RIS). The diagnosis was supported by imaging and CSF analysis. Conclusion. Our case sheds light on the need to consider autonomic dysfunction as an initial presentation of demyelinating pathology. Larger trials are needed to outline the possible association between POTS and RIS

From Animal Models to Clinical Trials: The Potential of Antimicrobials in Multiple Sclerosis Treatment

Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disease of the central nervous system (CNS). Microbes, including bacteria and certain viruses, particularly Epstein–Barr virus (EBV), have been linked to the pathogenesis of MS. While there is currently no cure for MS, antibiotics and antivirals have been studied as potential treatment options due to their immunomodulatory ability that results in the regulation of the immune process. The current issue addressed in this systematic review is the effect of antimicrobials, including antibiotics, antivirals, and antiparasitic agents in animals and humans. We performed a comprehensive search of PubMed, Google Scholar, and Scopus for articles on antimicrobials in experimental autoimmune encephalomyelitis animal models of MS, as well as in people with MS (pwMS). In animal models, antibiotics tested included beta-lactams, minocycline, rapamycin, macrolides, and doxycycline. Antivirals included acyclovir, valacyclovir, and ganciclovir. Hydroxychloroquine was the only antiparasitic that was tested. In pwMS, we identified a total of 24 studies, 17 of them relevant to antibiotics, 6 to antivirals, and 1 relevant to antiparasitic hydroxychloroquine. While the effect of antimicrobials in animal models was promising, only minocycline and hydroxychloroquine improved outcome measures in pwMS. No favorable effect of the antivirals in humans has been observed yet. The number and size of clinical trials testing antimicrobials have been limited. Large, multicenter, well-designed studies are needed to further evaluate the effect of antimicrobials in MS

Optical Coherence Tomography in Chronic Relapsing Inflammatory Optic Neuropathy, Neuromyelitis Optica and Multiple Sclerosis: A Comparative Study

Purpose: To examine the optical coherence tomography (OCT) features of the retina in patients with chronic relapsing inflammatory optic neuropathy (CRION) and compare them with those of neuromyelitis optica spectrum disorder (NMOSD), relapsing-remitting multiple sclerosis (RRMS) with and without optic neuritis (ON), and healthy controls (HC). Methods: In this retrospective cross-sectional study, we used spectral domain OCT to evaluate the retinal structure of 14 participants with CRION, 22 with NMOSD, 40 with RRMS with unilateral ON, and 20 HC. The peripapillary retinal nerve fiber layer (pRNFL), total macular volume (TMV), and papillomacular bundle (PMB) were measured, and intra-retinal segmentation was performed to obtain the retinal nerve fiber (RNFL), ganglion cell (GCL), inner plexiform (IPL), inner nuclear (INL), outer plexiform (OPL) and outer nuclear (ONL) layer volumes. Results: The global pRNFL [39.33(±1.8) µm] and all its quadrants are significantly thinner in CRION compared with all other groups (p < 0.05). CRION patients have decreased volumes of TMV, RNFL, GCL, and IPL compared with all other groups (p < 0.05). Conclusion: Severe thinning in pRNFL and thinning in intra-retinal segments of IPL, GCL, RNFL, and TMV could be helpful in differentiating CRION from NMOSD and RRMS

ENT-MS-12 questionnaire: a novel tool to investigate otolaryngology symptoms in patients with relapsing-remitting multiple sclerosis. Results from a pilot study

Background: Multiple sclerosis (MS) is associated with otolaryngology-related manifestations including vestibular or auditory symptoms; facial motor or sensory disorders; voice or swallowing impairment; and snoring/sleep apnea. Because these symptoms are nonspecific, their significance in MS is seldom recognized by patients with MS and their physicians; yet, presence of these symptoms may be a harbinger of impending relapse or disease progression. We developed and investigated a survey instrument, the ENT-MS-12, to standardize reporting of otolaryngology symptoms in patients with MS, correlating its scoring with disability and lesions. Methods: The ENT-MS-12 was administered to 40 patients with relapsing-remitting MS in different phases of their disease. We collected data using the Expanded Disability Status Scale (EDSS) and analyzed patient brain MRIs to evaluate the state (active or non-active) of brain lesions based on gadolinium enhancement. Odds ratios for diverse otolaryngology symptoms across the EDSS scores and brain lesions were calculated. Results: Higher EDSS scores were associated with auditory and vestibular symptoms (Odd Ratio (OR): 3.06; p: 0.0003); voice and swallowing symptoms (OR: 6.8; p=0.007); and snoring/sleep apnea (OR: 5.1; p=0.03). Presence of active brain lesions was also associated with auditory and vestibular symptoms (OR: 6.7); voice and swallowing symptoms (OD: 5.7); and snoring/sleep apnea (OR: 5). Conclusions: The ENT-MS-12 survey instrument standardizes reporting of otolaryngology symptoms in patients with MS and documents association between symptoms and phase of disease in this series. Because ear, nose and throat (ENT)- related symptoms (i.e., sensory symptoms, such as numbness) are under-reported in MS, further investigation is warranted, as such data may improve clinical management of MS

Structural and Neuronal Integrity Measures of Fatigue Severity in Multiple Sclerosis

Fatigue is a common and disabling symptom in Multiple Sclerosis (MS). However, consistent neuroimaging correlates of its severity are not fully elucidated. In this article, we study the neuronal correlates of fatigue severity in MS. Forty-three Relapsing Remitting MS (RRMS) patients with MS-related fatigue (Fatigue Severity Scale (FSS) range: 1–7) and Expanded Disability Status Scale (EDSS) ≤ 4, were divided into high fatigue (HF, FSS ≥ 5.1) and low fatigue groups (LF, FSS ≤ 3). We measured T2 lesion load using a semi-automated technique. Cortical thickness, volume of sub-cortical nuclei, and brainstem structures were measured using Freesurfer. Cortical Diffusion Tensor Imaging (DTI) parameters were extracted using a cross modality technique. A correlation analysis was performed between FSS, volumetric, and DTI indices across all patients. HF patients showed significantly lower volume of thalamus, (p = 0.02), pallidum (p = 0.01), and superior cerebellar peduncle ((SCP), p = 0.002). The inverse correlation between the FSS score and the above volumes was significant in the total study population. In the right temporal cortex (RTC), the Radial Diffusivity ((RD), p = 0.01) and Fractional Anisotropy ((FA), p = 0.01) was significantly higher and lower, respectively, in the HF group. After Bonferroni correction, thalamic volume, FA-RTC, and RD-RTC remained statistically significant. Multivariate regression analysis identified FA-RTC as the best predictor of fatigue severity. Our data suggest an association between fatigue severity and volumetric changes of thalamus, pallidum, and SCP. Early neuronal injury in the RTC is implicated in the pathogenesis of MS-related fatigue

Characterizing Fatigue-Related White Matter Changes in MS: A Proton Magnetic Resonance Spectroscopy Study

Few cross-sectional studies have investigated the correlation between neurochemical changes and multiple sclerosis (MS) fatigue, but little is known on the fatigue-related white matter differences between time points. We aim to investigate the longitudinal neurometabolite profile of white matter in MS fatigue. Forty-eight relapsing remitting multiple sclerosis (RRMS) patients with an expanded disability status scale (EDSS) ≤ 4 underwent high field 1H-multivoxel magnetic resonance spectroscopy (MRS) at baseline and year 1. Fatigue severity was evaluated by the fatigue severity scale (FSS). Patients were divided into low (LF, FSS ≤ 3), moderate (MF, FSS = 3.1−5), and high fatigue (HF, FSS ≥ 5.1) groups. In a two-way analysis of variance (ANOVA), we observed a decline in the ratio of the sum of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) to the sum of creatine (Cr) and phosphocreatine (PCr) in the right anterior quadrant (RAQ) and left anterior quadrant (LAQ) of the MRS grid in the HF group at baseline and year 1. This decline was significant when compared with the LF group (p = 0.018 and 0.020). In a one-way ANOVA, the fatigue group effect was significant and the ratio difference in the right posterior quadrant (RPQ) and left posterior quadrant (LPQ) of the HF group was also significant (p = 0.012 and 0.04). Neurochemical changes in the bilateral frontal white matter and possibly parietooccipital areas were noted in the HF group at two different time points. Our findings may shed some light on the pathology of MS fatigue

Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases

Background: B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time. Objective: The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer. Methods: This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection related adverse events (AE), serious adverse events (SAE), and malignancies were observed. Results: There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period. Conclusions: This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases.</p

Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases

BACKGROUND: B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time. OBJECTIVE: The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer. METHODS: This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection related adverse events (AE), serious adverse events (SAE), and malignancies were observed. RESULTS: There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period. CONCLUSIONS: This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases