Case Reports of Acute Transverse Myelitis Associated With mRNA Vaccine for COVID-19.

Acute transverse myelitis (ATM) has been reported as rare complication of vaccination. Herein, we report 2 cases of ATM after the administration of an mRNA vaccine for coronavirus disease 2019 (COVID-19). The first one is an 81-year-old man who received the BNT162b2 vaccine. He presented with bilateral hand weakness. Spine magnetic resonance imaging (MRI) showed high signal intensity from the C1 to C3 vertebrae. The second is a 23-year-old woman who received the BNT162b2 vaccine and experienced tingling in her legs. Spine MRI showed a high signal intensity lesion at the conus medullaris. These patients were treated with intravenous methylprednisolone and their symptoms improved slightly. Careful follow-up is needed to identify adverse events after the administration of mRNA vaccines for COVID-19.

Neurological misdiagnoses of lymphoma.

BACKGROUND: Lymphoma of the nervous system is rare and usually involves the brain, spinal cord, or peripheral nerves. Hence, it has varied clinical presentations, and correct diagnosis is often challenging. Incorrect diagnosis delays the appropriate treatment and affects prognosis. We report 5 patients with delayed diagnosis of lymphoma involving the central and/or peripheral nervous system, initially evaluated for other neurological diagnoses. We also discuss the challenge of diagnosis and appropriate testing. METHODS: Retrospective review of 2011-2019 records of patients with confirmed nervous system lymphoma diagnosed in a tertiary care medical center. RESULTS: We present 5 adult patients initially evaluated for inflammatory myelopathy, inflammatory lumbosacral plexopathy, atypical parkinsonism, and demyelinating disease of the CNS. Final diagnosis of the nervous system lymphoma was delayed by 4 to 18 months and was based on tissue biopsy in 4, and on CSF and bone marrow examination in 1 patient. CONCLUSIONS: Lymphoma may imitate various central and peripheral nervous system disorders. We suggest several red flags that indicate the need to consider lymphoma, including subacute but progressive symptomatic evolution, painful neurological deficit, unclear clinical diagnosis, and transient steroid responsiveness. Correct diagnosis often requires a combination of diagnostic tests, while pathology testing is crucial for early diagnosis and is strongly recommended in the appropriate clinical setting.

Serum FAM19A5 in neuromyelitis optica spectrum disorders: Can it be a new biomarker representing clinical status?

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) targets astrocytes and elevates the levels of astrocyte-injury markers during attacks. FAM19A5, involved in reactive gliosis, is secreted by reactive astrocytes following central nervous system (CNS) damage. OBJECTIVE: To investigate the significance of serum FAM19A5 in patients with NMOSD. METHODS: We collected clinical data and sera of 199 patients from 11 hospitals over 21 months. FAM19A5 levels were compared among three groups: NMOSD with positive anti-aquaporin-4 antibody (NMOSD-AQP4), other CNS demyelinating disease, and healthy controls. RESULTS: The median serum FAM19A5 level was higher in the NMOSD-AQP4 (4.90 ng/mL (3.95, 5.79)) than in the other CNS demyelinating (2.35 ng/mL (1.83, 4.07), p < 0.001) or healthy control (1.02 ng/mL (0.92, 1.14), p < 0.001) groups. There were significant differences in the median serum FAM19A5 levels between the attack and remission periods (5.89 ng/mL (5.18, 6.98); 4.40 ng/mL (2.72, 5.13), p < 0.001) in the NMOSD-AQP4 group. Sampling during an attack (p < 0.001) and number of past attacks (p = 0.010) were independently associated with increased serum FAM19A5. CONCLUSION: Serum FAM19A5 was higher in patients with NMOSD-AQP4 and correlated with clinical characteristics. Thus, serum FAM19A5 may be a novel clinical biomarker for NMOSD-AQP4.

Mast cell inflammasome activity in the meninges regulates EAE disease severity.

Inflammasomes are multiprotein complexes that assemble in response to microbial and other danger signals and regulate the secretion of biologically active IL-1ß and IL-18. Although they are important in protective immunity against bacterial, viral and parasitic infections, aberrant inflammasome activity promotes chronic inflammation associated with autoimmune disease. Inflammasomes have been described in many immune cells, but the majority of studies have focused on their activity in macrophages. Here we discuss an important role for mast cell-inflammasome activity in EAE, the rodent model of multiple sclerosis, a CNS demyelinating disease. We review our evidence that mast cells in the meninges, tissues that surround the brain and spinal cord, interact with infiltrating myelin-specific T cells in early disease. This interaction elicits IL-1ß expression by mast cells, which in turn, promotes GM-CSF expression by T cells. In view of the essential role that GM-CSF plays in T cell encephalitogenicity, we propose this mast cell-T cell crosstalk in the meninges is critical for EAE disease development.

MS arising during Tocilizumab therapy for rheumatoid arthritis.

BACKGROUND: Interleukin-6 (IL6) blockage is a treatment strategy used in many inflammatory conditions. Trials in Neuromyelitis Optica Spectrum Disorder (NMOSD) are ongoing. Secondary auto-immunity affecting the central nervous system (CNS) is well described with some biologic agents, mainly tumor necrosis factor (TNF)-alpha inhibitors. These treatments can also aggravate patients with known multiple sclerosis (MS). OBJECTIVES: To describe a case of a patient who developed MS using another biologic, IL6 receptor antibody Tocilizumab. RESULTS: A 48-year-old woman developed MS while on treatment with Tocilizumab for Rheumatoid Arthritis (RA). This is the first published report of this association. It has obvious implications for NMOSD patients receiving anti-IL6 therapy. Development of new white matter lesions suggestive of MS in a patient treated with anti-IL6 therapy might represent an important complication of therapy. CONCLUSION: This case illustrates that Tocilizumab might cause secondary auto-immunity in CNS. It is important to be aware of this potential complication as anti-IL6 therapy might become an option for the treatment NMOSD.

A Rare and Challenging Presentation of Acute Hemorrhagic Leukoencephalitis With Tumefactive Demyelinating Lesions in a 41-Year-Old Male.

Acute hemorrhagic leukoencephalitis (AHLE) is a rare and severe inflammatory condition of the central nervous system (CNS), characterized by hemorrhagic lesions in the brain's white matter. Here, we present a case of AHLE with concurrent tumefactive demyelinating disease, highlighting the diagnostic and management challenges associated with this complex presentation. Tumefactive multiple sclerosis (MS) is a rare variant of MS characterized by large, space-occupying lesions in the CNS. Concurrently, hemorrhagic leukoencephalitis (HLE) represents a severe inflammatory disorder characterized by hemorrhagic lesions within the CNS white matter. The diagnosis of tumefactive MS with associated HLE posed significant diagnostic challenges due to overlapping clinical and radiological features. Management involved high-dose corticosteroid therapy and supportive care measures, with longitudinal follow-up to assess treatment response and prevent complications. The patient exhibited a favorable clinical response to treatment, with gradual improvement in symptoms and resolution of radiological abnormalities. The coexistence of tumefactive MS with HLE is exceptionally rare and presents diagnostic and therapeutic challenges. We report a 41-year-old male presenting with acute neurological symptoms, including severe headache, confusion, left-sided body weakness, slurred speech, and blurred vision. Neurological examination revealed dysarthric speech, right homonymous hemianopia, left upper motor neuron facial palsy, and motor deficits. MRI demonstrated multifocal areas of T2 hyperintensity with associated hemorrhage, suggestive of tumefactive MS with associated HLE. Diagnostic workup included neurological examination, MRI imaging, cerebrospinal fluid analysis, and serological testing. Management involved high-dose corticosteroid therapy and supportive care measures. The patient exhibited a favorable clinical response to treatment, with gradual improvement in symptoms and resolution of radiological abnormalities. Longitudinal follow-up confirmed sustained improvement. In conclusion, the coexistence of tumefactive MS with HLE poses diagnostic challenges due to overlapping features. This case underscores the importance of considering rare and atypical presentations of CNS demyelinating disease and the potential complications, including associated HLE. Comprehensive evaluation, multidisciplinary collaboration, and individualized management are essential for optimizing outcomes in patients with complex CNS inflammatory disorders.

Tumefactive demyelinating lesions during etanercept treatment requiring decompressive hemicraniectomy.

Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders. Etanercept, a TNF-α antagonist (anti-TNF-α) acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. This paper aims to report an unusual case showing tumefactive central nervous system (CNS) inflammatory demyelination in a patient in the course of TNF -α antagonist therapy, requiring decompressive hemicraniectomy. This report is based on magnetic resonance imaging (MRI) findings and histology. A biopsy confirmed the inflammatory demyelinating nature of the lesions. The clinical presentation is unusual due to the severity of the disease process, requiring decompressive hemicraniotomy with a clinically favorable outcome.

Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment.

Neuromyelitis optica is an autoimmune disease characterized by acute episodes of transverse myelitis and optic neuritis. Several small, open-label studies suggest rituximab, a monoclonal antibody against CD20, prevents relapses in neuromyelitis optica; however, there is little consensus on timing or duration of treatment. Here we report four patients with severe relapsing neuromyelitis optica who were stabilized on rituximab and, after discontinuing treatment, continued to experience prolonged remission of their disease. Remission ranged from 4.5 to 10.5 years total, including 3 to 9 years off all therapies. The patients had sustained clinical responses despite normal B-lymphocyte levels and, in at least 2 patients, continued seropositivity for aquaporin-4 antibodies. These cases suggest that rituximab may induce prolonged remission in certain neuromyelitis optica patients, and they highlight the need for further elucidation of rituximab's mechanism in neuromyelitis optica.

Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain.

Theiler's murine encephalomyelitis virus (TMEV) can induce demyelination or myocarditis in susceptible mouse strains. A deficiency of NKT cells exacerbated TMEV-induced demyelinating disease (TMEV-IDD) in SJL/J and BALB/c mice. In C57BL/6 background, however, NKT-cell-deficient Jα18 KO mice remained as resistant to TMEV-IDD as wild-type mice. Echocardiography and histology showed that Jα18 KO mice developed more severe myocarditis (greater T cell infiltration and fibrosis) than wild-type mice, suggesting a protective role of NKT cells in myocarditis in C57BL/6 mice. Jα18 KO mice had higher cardiac viral RNA and anti-viral antibody titers, but had lower lymphoproliferation and IL-4 and IL-10 production.

Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis.

Inflammation in the meninges, tissues surrounding the brain and spinal cord that enclose the cerebrospinal fluid, closely parallels clinical exacerbations in relapsing-remitting experimental autoimmune encephalomyelitis (EAE). In preclinical disease, an influx of innate immune cells precedes loss of blood brain barrier (BBB) integrity and large-scale inflammation in the central nervous system (CNS). T cell infiltration into the meninges is observed in acute disease as well as during relapse, when neither BBB permeability nor significant increases in peripherally-derived immune cell numbers in the CNS are observed. These findings support the idea that the meninges are a gateway for immune cell access into the CNS, a finding that has important therapeutic implications.

Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain.

Modelling complex disorders presents considerable challenges, and multiple sclerosis (MS) is no exception to this rule. The aetiology of MS is unknown, and its pathophysiology is poorly understood. Moreover, the last two decades have witnessed a dramatic revision of the long-held view of MS as an inflammatory demyelinating white matter disease. Instead, it is now regarded as a global central nervous system (CNS) disorder with a neurodegenerative component. Currently, there is no animal model recapitulating MS immunopathogenesis. Available models are based on autoimmune-mediated demyelination, denoted experimental autoimmune encephalomyelitis (EAE) or virally or chemically induced demyelination. Of these, the EAE model has been the most commonly used. It has been extensively improved since its first description and now exists as a number of variants, including genetically modified and humanized versions. Nonetheless, EAE is a distinct disease, and each variant models only certain facets of MS. Whilst the search for more refined MS models must continue, it is important to further explore where mechanisms underlying EAE provide proof-of-principle for those driving MS pathogenesis. EAE variants generated with the myelin component myelin oligodendrocyte glycoprotein (MOG) have emerged as the preferred ones, because in this particular variant disease is associated with both T- and B-cell effector mechanisms, together with demyelination. MOG-induced EAE in the non-obese diabetic (NOD) mouse strain exhibits a chronic-relapsing EAE clinical profile and high disease incidence. We describe the generation of this variant, its contribution to the understanding of MS immune and pathogenetic mechanisms and potential for evaluation of candidate therapies.

Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis.

Multiple sclerosis (MS) has been proposed to be an immune-mediated disease in the central nervous system (CNS) that can be triggered by virus infections. In Theiler's murine encephalomyelitis virus (TMEV) infection, during the first week (acute stage), mice develop polioencephalomyelitis. After 3 weeks (chronic stage), mice develop immune-mediated demyelination with virus persistence, which has been used as a viral model for MS. Regulatory T cells (Tregs) can suppress inflammation, and have been suggested to be protective in immune-mediated diseases, including MS. However, in virus-induced inflammatory demyelination, although Tregs can suppress inflammation, preventing immune-mediated pathology, Tregs may also suppress antiviral immune responses, leading to more active viral replication and/or persistence. To determine the role and potential translational usage of Tregs in MS, we treated TMEV-infected mice with ex vivo generated induced Tregs (iTregs) on day 0 (early) or during the chronic stage (therapeutic). Early treatment worsened clinical signs during acute disease. The exacerbation of acute disease was associated with increased virus titers and decreased immune cell recruitment in the CNS. Therapeutic iTreg treatment reduced inflammatory demyelination during chronic disease. Immunologically, iTreg treatment increased interleukin-10 production from B cells, CD4(+) T cells and dendritic cells, which may contribute to the decreased CNS inflammation.

Crystal-storing histiocytosis: An unusual relapsing inflammatory CNS disorder.

The differential diagnosis of acute leukoencephalopathy often focuses on central nervous system idiopathic inflammatory demyelinating diseases (IIDDs) such as multiple sclerosis (MS). However, a spectrum of conditions mimic IIDDs, therefore it is critical to consider whether symptoms, signs, imaging and/or response to therapies are compatible with the diagnosis. We describe a 32-year-old previously healthy woman presenting with a 2 year history of steroid-responsive relapsing episodes lasting 2-10 days characterized by transient visual blurring, right-hemiparesis, and spells of aphasia. MRI demonstrated multifocal, relapsing, predominantly white matter enhancing brain lesions, a longitudinally extensive cord lesion, and abnormal visual evoked potentials. Notably, some lesions persistently enhanced whereas others demonstrated progressive T2W hypointensity. Brain biopsy revealed an atypical plasma cell infiltrate and crystal-storing histiocytosis, which by mass spectrometry confirmed the presence of macrophages containing intracellular kappa-light chain restricted crystals. Bone marrow was negative. The patient did well for several years on pulse dexamethasone, however subsequent scans demonstrated increasing enhancement. Repeat biopsy demonstrated a clonal plasma cell proliferation. She was treated with melphalan, and has remained stable. Although this patient initially met McDonald criteria, atypical imaging prompted further workup, and advanced proteomic technology helped secured an accurate diagnosis. Crystal-storing histiocytosis should be considered in the differential diagnosis of inflammatory CNS disorders.