Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.

BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS). OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments. METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010. RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity. CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.

Choroid plexus volume as a marker of retinal atrophy in relapsing remitting multiple sclerosis.

OBJECTIVE: To evaluate choroid plexus (CP) volume as a biomarker for predicting clinical disability and retinal layer atrophy in relapsing remitting multiple sclerosis (RRMS). METHODS: Ninety-five RRMS patients and 26 healthy controls (HCs) underwent 3 T whole brain MRI, expanded disability status scale (EDSS) and optical coherence tomography (OCT). Fully automated intra-retinal segmentation was performed to obtain the volumes of the retinal nerve fiber layer (RNFL), combined ganglion cell layer -inner plexiform layer (GCIPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL), retinal pigment epithelium (RPE), total macular volume (TMV) and papillomacular bundle (PMB). Automated segmentation of the CP within the lateral ventricles was performed and the choroid plexus volume (CPV) was normalized by total intracranial volume (TIV). Linear regression analysis and generalized estimating equation (GEE) models were applied to evaluate relationships between nCPV and EDSS, T2 lesion volume, disease duration, and retinal layer volumes, followed by Bonferroni correction analysis for multiple comparisons. RESULTS: RRMS patients had larger tChPV compared to HCs (p < 0.001). After Bonferroni correction, there was a significant positive correlation between tChPV and EDSS (r2 = 0.25, p = 0.0002), disease duration (r2 = 0.30, p = 0.01), and T2 lesion volume (r2 = 0.39, p = 0.0000). A robust negative correlation was found between tChPV and RNFL (p < 0.001), GCIPL (p = 0.003), TMV (p = 0.0185), PMB (p < 0.0001), G (p = 0.04), T(p = 0.0001). CONCLUSIONS: Our findings support the association of tChPV with disability and altered retinal integrity in RRMS.

Role of white matter in cognitive impairment among relapsing remitting multiple sclerosis patients.

BACKGROUND: Multiple Sclerosis (MS) associated cognitive impairment is believed to be mostly connected with damage to gray matter. The contribution of white matter is still poorly understood. We aim to examine the relationship between cognition and white matter tracts among relapsing remitting MS (RRMS) patients. METHODS: Thirty RRMS patients were selected undergo the (3-seconds-interstimulus-interval paced auditory serial addition test) PASAT-3, the (symbol digit modalities test (SDMT) and full-brain MRI scans on a SIEMENS 3 Tesla Verio scanner. Diffusion Tensor Imaging (DTI) parameters, such as fractional anisotropy (FA) and mean diffusivity (MD) were examined in 37 white matter (WM) tracts. WM tracts were selected from the association pathways, projection pathways, commissural pathways by applying Human Connectome project (HCP)842 tractography atlas after DTI data reconstruction and registration to HCP1065 diffusion template in DSI Studio (version March 2021) In SPSS v26, Spearman's rank correlation analysis was used to examine the connection between DTI WM tracts and cognitive scores. The power of the study was increased by using false discovery rate (FDR) software. RESULTS: The mean scores on the PASAT-3 and SDMT were 31.5 ± 12.8 and 46.9 ± 16.7 respectively. Better cognitive performance was correlated to higher FA values, while lower cognitive function was correlated to higher MD values. There was a positive correlation between FA values in the right medial lemniscus and superior cerebellar peduncle and SDMT scores (p 0.05). Additionally, there was a trend for significance between the FA values in the left corticothalamic tract and SDMT scores. MD values in the superior cerebellar peduncle, left arcuate Fasciculus and left extreme capsule were negatively correlated with SDMT scores (p<0.05). PASAT-3 scores were negatively correlated with MD values in the right cerebellum, however, there was no significant correlation between PASAT-3 and FA values. CONCLUSIONS: White matter tracts, particularly the superior cerebellar peduncle, contribute to the cognitive impairment in RRMS. Larger sample sizes for longitudinal research are necessary.

Autoimmune and paraneoplastic neurological disorders: A review of relevant neuroimaging findings.

INTRODUCTION: Paraneoplastic neurologic syndromes (PNS) and autoimmune encephalitis (AIE) are immune-mediated disorders. PNS is linked to cancer, while AIE may not Their clinical manifestations and imaging patterns need further elucidation. OBJECTIVE/AIMS: To investigate the clinical profiles, antibody associations, neuroimaging patterns, treatments, and outcomes of PNS and AIE. METHODS: A systematic review of 379 articles published between 2014 and 2023 was conducted. Of the 55 studies screened, 333 patients were diagnosed with either PNS or AIE and tested positive for novel antibodies. Data on demographics, symptoms, imaging, antibodies, cancer associations, treatment, and outcomes were extracted. RESULTS: The study included 333 patients (mean age 54 years, 67% males) with PNS and AIE positive for various novel antibodies. 84% had central nervous system issues like cognitive impairment (53%), rhombencephalitis (17%), and cerebellar disorders (24%). Neuroimaging revealed distinct patterns with high-risk antibodies associated with brainstem lesions in 98%, cerebellar in 91%, hippocampal in 98%, basal ganglia in 75%, and spinal cord in 91%, while low/intermediate-risk antibodies were associated with medial temporal lobe lesions in 71% and other cortical/subcortical lesions in 55%. High-risk antibodies were associated with younger males, deep brain lesions, and increased mortality of 61%, while low/intermediate-risk antibodies were associated with females, cortical/subcortical lesions, and better outcomes with 39% mortality. Associated cancers included seminomas (23%), lung (19%), ovarian (2%), and breast (2%). Treatments included IVIG, chemotherapy, and plasmapheresis. Overall mortality was 25% in this cohort. CONCLUSION: PNS and AIE have distinct clinical and radiological patterns based on antibody profiles. High-risk antibodies are associated with increased mortality while low/intermediate-risk antibodies are associated with improved outcomes. Appropriate imaging and antibody testing are critical for accurate diagnosis.

Disease modifying therapy and pregnancy outcomes in multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVES: To report pregnancy outcomes among multiple sclerosis (MS) patients treated with disease-modifying therapies (DMTs). METHODS: We performed a retrospective chart review of articles published from June 1996 to May 2023. Additional information was acquired from the drug registries of individual pharmaceutical companies. A comparison was also made with pregnancy data of the general population using the World Health Organization database. Summary analysis was achieved using R statistical software (v3.6), and the overall prevalence of outcomes was estimated using a random effects model. RESULTS: A meta-analysis of 44 studies was conducted. Dimethyl fumarate had the highest prevalence of premature births at 0.6667% (SD:0.5236-0.7845). The highest rates of stillbirths and infant deaths (perinatal and neonatal) were observed with interferons at 0.004% (SD:0.001-0.010) and 0.009% (SD:0.005-0.0015), respectively. Cladribine had the majority of ectopic pregnancies (0.0234%, SD:0.0041-1217), while natalizumab had the highest prevalence of spontaneous abortions (0.1177%, SD:0.0931-0.1477) and live birth defects (0.0755%, SD:0.0643-0.0943).None of the outcomes were significantly different from those of the general population (p > 0.05), except ectopic pregnancy and spontaneous abortion (p < 0.001), where the odds were 0.665 (0.061-0.886) and 0.537(0.003-0.786), respectively. The pooled prevalence of MS relapses was 221% for a single episode (SD:0.001-0.714), 0.075% for more than one episode (SD:0.006-0.167), and 0.141% for at least one episode requiring steroids (SD:0.073-0.206) none of these reached clinical significance. CONCLUSION: Existing research suggests that DMT use in MS patients during pregnancy is generally considered safe. This study supports their utilization on a case-by-case basis. However, further primary research on this topic with clinical trials is warranted.

Impact of Disease Modifying Therapy on MS-Related Fatigue: A Narrative Review.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system by causing inflammation, demyelination and neurodegeneration. Fatigue is the most prevalent and one of the most disabling symptoms among people with MS (pwMS). Due to its complexity and subjective character, fatigue is still little understood despite its frequent occurrence and severe impact. The potential causes, effects, and treatments of fatigue associated with MS have been extensively studied in recent years. Though the benefits of such a variety of contributions are obvious, there have not been many attempts to evaluate the effect of disease modifying therapies (DMTs) on MS-related fatigue. In this review, we summarize clinical trials and research studies, and we discuss the effect of different DMTs on MS-related fatigue.

Progressive multifocal leukoencephalopathy in anti-CD20 and other monoclonal antibody (mAb) therapies used in multiple sclerosis: A review.

Progressive multifocal leukoencephalopathy (PML) is a subacute CNS inflammatory disease seen primarily among immunocompromised patients. It is caused by the JC virus (JCV), a polyomavirus that otherwise induces an insidious, latent infection in the general population. This reactivated disease is characterized by cognitive and behavioral changes, language disturbances, motor weakness, or visual deficits. Median survival in patients with AIDS is approximately 2-4 months, and mortality is high (around 4% in untreated AIDS). Recent scientific developments indicate that PML can also be associated with the increased utilization of monoclonal antibody (mAb) immunotherapy. In fact, PML has been witnessed with several mAbs, including natalizumab in multiple sclerosis, rituximab for lymphoma or lupus, efalizumab for psoriasis, and ofatumumab in leukemia; this leads us to the risk reassessment of PML due to treatment-induced immunosuppression. The range of clinical presentations of JCV-related disease has transformed over time and can pose significant challenges to the current diagnostic criteria. Most cases with PML suffer from persistent and irreversible neurological conditions, and some with chronic, low-level viral replication in the CNS. With the expanded use of mAbs for various autoimmune and lymphoproliferative disorders, we are now seeing this infection in non-HIV patients on drugs such as natalizumab, rituximab, and other recently approved therapies. This article aims to review the relationship between the incidence of PML and all four mAbs used in the treatment of MS. Currently, at least 18 FDA-approved medications carry label warnings for PML;to this date, no treatment has been convincingly effective.

Neuromyelitis Optica in a Young Woman With Tuberous Sclerosis: Is There an Association?

Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder that presents with multi-organ involvement, including but not limited to hamartomas in the brain, eyes, heart, lung, liver, kidney, and skin. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory, autoimmune, demyelinating, central nervous system disorder, targeting the optic nerves and spinal cord. We report a 30-year-old woman with TSC who developed tingling in the legs that gradually involved her abdomen. Additional symptoms included severe vomiting that lasted for a week and spasms in her legs. One month later, she was hospitalized due to difficulty ambulating and tingling in her hands. Magnetic resonance imaging (MRI) of her spine showed longitudinally extensive upper cervical and lower thoracic cord signal changes. MRI scan of her brain showed few non-specific T2 signal changes along with cortical and subcortical tubers. Aquaporin (AQP4) IgG antibody was found to be positive in both serum and cerebrospinal fluid. Accordingly, she was diagnosed with NMOSD, treated with a 5-day course of intravenous steroids, followed by 5 sessions of plasma exchange. After her initial improvement, she was started on rituximab as maintenance therapy. Two years later, she is clinically stable, and her follow-up MRI showed marked improvement.

Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis and myelitis in COVID-19: a case report and a review of the literature.

Background: Our case explored the spectrum of autoimmune and infectious neurological complications of Coronavirus Disease 2019. In addition, we also reviewed and discussed clinical features, neuroimaging, CSF findings, and outcomes in patients with COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD) CNS inflammatory disorder. Case presentation: Here we presented a case of post-Coronavirus Disease 2019 infection Myelin Oligodendrocyte Glycoprotein Antibody Disorder in a 41-year-old male who presented with gait instability, urinary retention, and confusion. Workup done in hospital showed transverse myelitis in cervical spine region and left optic neuritis. Laboratory findings showed Myelin Oligodendrocyte Glycoprotein-IgG antibodies were positive in serum (1:100), suggestive of post-COVID Myelin Oligodendrocyte Glycoprotein Antibody Disorder. Conclusion: To our knowledge, this is the first comprehensive case report and the literature review that includes the clinical features, neuroimaging, CSF findings, and outcomes in COVID-19-associated Myelin Oligodendrocyte Glycoprotein Antibody Disorder.

COVID-19 Vaccination and Neurological Manifestations: A Review of Case Reports and Case Series.

BACKGROUND: With 10 vaccines approved by the WHO and nearly 48% of people fully vaccinated worldwide, we have observed several individual case studies of neurological manifestations post-COVID-19 vaccination. Through this systematic review, we aim to discern these CNS and PNS manifestations following the COVID-19 vaccine to help produce methods to mitigate them. METHODS: We conducted a thorough literature search of Google Scholar and PubMed from 1 December 2020 until 10 October 2021 and included all the case studies of COVID-19 vaccine-associated neurological side effects. The literature search and data analysis were performed by two independent reviewers according to prespecified inclusion and exclusion criteria using PRISMA. RESULTS: The most common CNS manifestation was CVST (14.47%), found in females (64%) younger than 50 years (71%) after the first AstraZeneca dose (93%). Others included CNS demyelinating disorders (TM, ADEM, MS, NMOSD) (9.30%), encephalopathy/encephalitis (3.10%), and others (4.13%). The most common PNS manifestation was GBS (14.67%) found in males (71%) older than 50 years (79%), followed by Bell's palsy (5.24%) and others (2.10%). Most occurred with the AstraZeneca (28.55%), Pfizer-BioNTech (9.18%), and Moderna (8.16%) vaccines. Nine (64%) out of the 14 patients with CVST died. However, most cases overall (42 out of 51) were non-fatal (82%). CONCLUSION: Several CNS and PNS adverse events have occurred post-COVID-19 vaccination, including CVST, GBS, and TM. High vigilance with early identification and treatment leads to better outcomes. Further studies with non-vaccinated controls might help in understanding the pathophysiologic mechanisms of these neurological manifestations following COVID-19 vaccination.

CNS and PNS manifestation in immune checkpoint inhibitors: A systematic review.

INTRODUCTION: Immunomodulatory therapies, including the use of immune checkpoint inhibitors (ICIs), have made a profound impact on treatment of advanced cancers in recent decades. Neurologic immune-related adverse events (irAEs) related to use of these agents are rare but potentially fatal sequelae. This systematic reviewed aimed to describe onset, clinical features, treatment, and outcome of neurological irAEs following ICI usage. METHODS: A systematic literature search was conducted to identify all case reports (n = 168) and case series (n = 29) describing neurological irAEs (n = 255 patients). Patient demographics, clinical features, and clinical courses were extracted and used to assess statistical relationships between reported variables. RESULTS: Of reports describing neurological irAEs related to ICI use, the majority of cases were in men (66%) and patients above the age of fifty (85%). Disorders of the peripheral nervous system (PNS, 83%) were more common than central nervous system involvement. Neuromuscular disorders were the most common type of neurological irAE (e.g. myasthenia gravis, 36%), followed by peripheral neuropathies (16%), followed by all CNS disorders combined (15%). Most cases presented within the first 5 doses of ICI treatment. Most patients improved clinically, but 24% of cases were fatal. Mortality was highest in patients with neuromuscular irAEs, such as myasthenia gravis and myositis. CONCLUSION: This systematic literature review describes the largest collection of neurological irAEs to date including both CNS and PNS manifestations of ICIs. The information described herein can be used to better inform monitoring and treatment of patients undergoing treatment with ICIs.

COVID-19 and neuroinflammation: a literature review of relevant neuroimaging and CSF markers in central nervous system inflammatory disorders from SARS-COV2.

BACKGROUND: The literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19). METHODS: We screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; "SARS-CoV-2 and neurological complication", "SARS-CoV-2 and CNS Complication" looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021. RESULTS: Our literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities. CONCLUSION: To our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.

Paraneoplastic neurological syndromes: clinical presentations and management.

We provide an overview of the varied presentations of paraneoplastic neurological syndromes. We also review the onconeural antibodies and their particular oncological and neurological associations. Recognition of these syndromes and their oncological associations is crucial, as early diagnosis and management has been associated with better patient outcomes. Specific management strategies and prognosis vary widely depending on the underlying etiology. An understanding of the relevant clinical details, imaging findings, and other diagnostic information can help tailor treatment approaches. We provide an outline of the diagnostic evaluation and treatment of various paraneoplastic neurological disorders, presenting with central and/or peripheral nervous system involvement. We briefly discuss neurologic immune checkpoint inhibitor-related adverse events, which can occasionally present with paraneoplastic neurological syndrome phenotypes.

Relevance and Clinical Significance of Magnetic Resonance Imaging of Neurological Manifestations in COVID-19: A Systematic Review of Case Reports and Case Series.

We performed a systematic literature review of neuroimaging, predominantly focusing on magnetic resonance imaging (MRI) findings associated with neurological manifestations of coronavirus disease-2019 (COVID-19). We screened articles from PubMed, Google Scholar and Scopus, looking for reports that would potentially have neuroimaging findings in patients with COVID-19. Data analysis was performed with patient-based data based on the availability of clinical characteristics and outcomes for each individual patient from the studies. Chi square and Wilcoxon rank-sum tests were used to report COVID-19 severity and outcomes based on neurological imaging indicators and pathophysiology. A total of 171 patients with COVID-19 having neurological complications, from 134 studies, were identified in our review. The most common neuroimaging finding was ischemic stroke (62, 36.2%) cases, followed by CNS inflammatory disorder (44, 25.7%), and hemorrhagic stroke (41, 24.0%). Around 51% of all the fatal COVID-19 cases had an ischemic stroke. Among patients with ischemic stroke, the mean age of those who suffered from COVID-19 infection was 57.5 years (SD = 15.4) whereas it was 50.7 years (SD = 15.1) among those without stroke/other diagnosis. Fatality was more common in patients with ischemic stroke compared to those with other diagnosis (40% vs. 22%, p = 0.011). The most frequently published neuroimaging findings in patients with COVID-19 were ischemic stroke, CNS inflammatory disorder, and hemorrhagic disorder. In those studies, ischemic stroke was associated with fatality, and was more frequently seen in older patients. Based on our findings, early usage of MRI in COVID-19 patients may be recommended.