Perplexing Initial Presentations of MOGAD in Two Children: Intracranial Hypertension and New-Onset Seizure.

We report two distinct challenging initial presentations of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Case 1 describes a 12-year-old boy who developed headaches refractory to pain medication followed by cranial neuropathies and intracranial hypertension, confirmed by lumbar puncture with an opening pressure >36 cm H2O. Case 2 describes a 3-year-old boy who developed new-onset seizures refractory to antiseizure medications, a presentation of FLAIR-hyperintense lesions in MOG-antibody associated encephalitis with seizures (FLAMES). On repeat magnetic resonance imaging, both patients were found to have cortical T2 hyperintensities, leptomeningeal contrast enhancement, and bilateral optic nerve enhancement. In the cerebrospinal fluid, both patients had CSF pleocytosis with neutrophilic predominance. The patients were treated with intravenous immunoglobulins, plasma exchange, and high-dose corticosteroids. The first patient achieved disease remission, whereas the second patient required the addition of rituximab for management of seizures. The two cases highlight the pleomorphic clinical phenotypes of MOGAD.

The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation.

Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis.

Sex effects across the lifespan in women with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating central nervous system disorder that is more common in women, with onset often during reproductive years. The female:male sex ratio of MS rose in several regions over the last century, suggesting a possible sex by environmental interaction increasing MS risk in women. Since many with MS are in their childbearing years, family planning, including contraceptive and disease-modifying therapy (DMT) counselling, are important aspects of MS care in women. While some DMTs are likely harmful to the developing fetus, others can be used shortly before or until pregnancy is confirmed. Overall, pregnancy decreases risk of MS relapses, whereas relapse risk may increase postpartum, although pregnancy does not appear to be harmful for long-term prognosis of MS. However, ovarian aging may contribute to disability progression in women with MS. Here, we review sex effects across the lifespan in women with MS, including the effect of sex on MS susceptibility, effects of pregnancy on MS disease activity, and management strategies around pregnancy, including risks associated with DMT use before and during pregnancy, and while breastfeeding. We also review reproductive aging and sexual dysfunction in women with MS.

Pattern Recognition of the Multiple Sclerosis Syndrome.

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. These antibody-mediated inflammatory diseases of the CNS share a clinical presentation to MS. A number of practical learning points emerge in this review, which is geared toward the pattern recognition of optic neuritis, transverse myelitis, brainstem/cerebellar and hemispheric tumefactive demyelinating lesion (TDL)-associated MS, aquaporin-4-antibody and myelin oligodendrocyte glycoprotein (MOG)-antibody NMOSD, overlap syndrome, and some yet-to-be-defined/classified demyelinating disease, all unspecifically labeled under MSsyndrome. The goal of this review is to increase clinicians' awareness of the clinical nuances of the autoimmune conditions for MS and NMSOD, and to highlight highly suggestive patterns of clinical, paraclinical or imaging presentations in order to improve differentiation. With overlay in clinical manifestations between MS and NMOSD, magnetic resonance imaging (MRI) of the brain, orbits and spinal cord, serology, and most importantly, high index of suspicion based on pattern recognition, will help lead to the final diagnosis.

Acute onset of fingolimod-associated macular edema.

PURPOSE: Fingolimod is among the first oral disease-modifying agents for the treatment of relapsing-remitting multiple sclerosis (MS). Despite its favorable safety profile, fingolimod may cause macular edema, a significant adverse event, which occurs within the first 4 months of therapy. Macular edema usually resolves upon discontinuation of fingolimod; however, the time required for resolution of this condition is unknown. OBSERVATIONS: A 42-year-old white male with a history of relapsing-remitting MS presented with blurring of vision in his left eye 24 h after the first dose of fingolimod. Dilated fundus examination of the left eye revealed an increased retinal thickness and mild optic disc pallor. Spectral domain optical coherence tomography (SD-OCT) confirmed the diagnosis of cystoid macular edema. Topical nonsteroidal anti-inflammatory drug (NSAID) was initiated immediately after the diagnosis, and fingolimod therapy was discontinued shortly thereafter. Seven weeks after the initial presentation, intermediate uveitis was noted in the inferior periphery of the left eye, and SD-OCT revealed worsening of macular edema. Acetazolamide therapy was added to the topical NSAID to control the edema. Three weeks after initiation of acetazolamide, macular thickness reduced significantly. The patient then stopped all medications, and 3 weeks later macular edema rebounded. Systemic steroid was employed to control both the intermediate uveitis and macular edema. CONCLUSIONS AND IMPORTANCE: We report a case of acute and very rapid onset of fingolimod-associated macular edema (FAME). Acetazolamide may have a beneficial effect on macular edema secondary to fingolimod. It is unclear if intermediate uveitis is associated with the rapid development of FAME.

Diffuse anaplastic leptomeningeal oligodendrogliomatosis mimicking neurosarcoidosis.

Diffuse leptomeningeal oligodendrogliomatosis is a rare, frequently fatal CNS malignancy that most often affects children.1 Although potentially treatable with chemotherapy and radiation, the radiologic findings are nonspecific and pathologic confirmation of the diagnosis is difficult. We describe an adult patient whose initial presentation mimicked neurosarcoidosis. Despite extensive imaging abnormalities, 3 biopsies were required before the diagnosis of diffuse leptomeningeal oligodendrogliomatosis was confirmed.

Elevation of matrix metalloproteinases (MMPs) in multiple sclerosis and impact of immunomodulators.

The matrix metalloproteinases (MMPs) are implicated in the pathology of multiple sclerosis (MS). This review summarizes the consequences of upregulation of MMP members in MS as well as in an animal model of the disease, experimental autoimmune encephalomyelitis (EAE). The pathogenic roles of MMPs are considered, especially in the transmigration of leukocytes into the CNS. We review the evidence that interferon-beta, an immunomodulator that is commonly used in MS, affects MMP expression in the disease. The potential of minocycline as a therapy in MS, based on its activity as an MMP inhibitor, is discussed. Besides affecting MMPs, minocycline may have other actions that help account for its possible utility in MS.

The association of depression with disease course in multiple sclerosis.

The relative frequency of depression in people with primary progressive multiple sclerosis (PPMS) (30 patients) compared with those with a history of relapse (106 patients) was determined. Three participants in the progressive group and 28 in the relapsing group had a lifetime history of major depression. The lifetime morbidity ratio for major depression in relapsing patients was 2.64 compared with that of PPMS.

Gamma knife radiosurgery in patients with advanced breast cancer undergoing bone marrow transplant.

OBJECT: Recent studies have suggested a high incidence of cognitive deficits in patients undergoing high-dose chemotherapy, which appears to be dose related. Whole-brain radiotherapy (WBRT) has previously been associated with cognitive impairment. The authors attempted to use gamma knife radiosurgery (GKS) to delay or avoid WBRT in patients with advanced breast cancer treated with high-dose chemotherapy and autologous bone marrow transplantation (HDC/ABMT) in whom brain metastases were diagnosed. METHODS: A retrospective review of our experience from 1996 to 2001 was performed to identify patients who underwent HDC/ABMT for advanced breast cancer and brain metastasis. They were able to conduct GKS as initial management to avoid or delay WBRT in 12 patients following HDC/ABMT. All patients were women. The median age was 48 years (range 30-58 years). The Karnofsky Performance Scale score was 70 (range 60-90). All lesions were treated with a median prescription dose of 17 Gy (range 15-18 Gy) prescribed to the 50% isodose. Median survival was 11.5 months. Five patients (42%) had no evidence of central nervous system disease progression and no further treatment was given. Four patients were retreated with GKS and three of them eventually received WBRT as well. Two patients were treated with WBRT as the primary salvage therapy. The median time to retreatment with WBRT was 8 months after the initial GKS. CONCLUSIONS: Gamma knife radiosurgery can be effectively used for the initial management of brain metastases to avoid or delay WBRT in patients treated previously with HDC, with acceptable survival and preserved cognitive function.