Erdheim-Chester Disease Masquerading as CLIPPERS.

OBJECTIVES: To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). METHODS: Case series. RESULTS: Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. DISCUSSION: ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.

18 F-FDG Brain PET/MRI in Granulomatous Primary Angiitis of the Central Nervous System.

ABSTRACT: An 18-year-old man presented with encephalopathy, headache, tremor, and left hemiparesis. 18 F-FDG brain PET/MRI revealed pronounced hypometabolism in the right cerebral hemisphere corresponding to extensive T2/FLAIR signal abnormality, with accompanying miliary enhancement and microhemorrhages in this region. The differential diagnosis favored an autoimmune or inflammatory origin, rather than an infectious or neoplastic etiology. Brain biopsy demonstrated nonnecrotizing granulomatous inflammation affecting the vessel walls, without evidence of glial neoplasm, lymphoma, or infection. Treatment with corticosteroids was subsequently initiated, with favorable clinical response.

Frequency, characteristics, predictors and treatment of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have a monophasic or relapsing disease course. To date, factors that may predict a relapsing disease course remain largely unknown and only limited data exist regarding the efficacy of different utilized immunotherapy regimens at preventing or reducing relapses. OBJECTIVES: To assess the characteristics, predictors, and immunotherapy of relapsing MOGAD. METHODS: This multicenter retrospective analysis included all MOGAD cases at the University of Florida, Baylor College of Medicine and the University of California San Diego with minimum follow-up time of 6 months. Cox proportional hazards regression analyses, corrected for age and sex, were performed to evaluate hazard ratios (HR) of predictors of a relapsing disease course and to compare relapse hazards for utilized immunotherapies. RESULTS: The majority of included participants (51/79 [64.6 %]) had a relapsing course, and of these individuals, 68.6 % (35/51) experienced their first relapse within the first year. However, 10/51 (19.6 %) participants experienced their first relapse ≥5 years (5-15 years) after the initial presentation. Predictors of a relapsing course were CSF pleocytosis (>150 cells/mm3; HR 3.3 [1.18 - 9.24]; p = 0.023), a pediatric disease onset at age < 9 years (HR 2.69 [1.07-6.75]; p = 0.035), and an initial presentation with the clinical syndrome of meningoencephalitis (HR 3.42 [1.28 - 9.17]; p = 0.015),. In participants with a relapsing course, 13/24 (54.2 %) patients remained relapse-free on rituximab, 4/8 (50 %) on mycophenolate mofetil, and 11/14 (78.6 %) on scheduled immunoglobulins. Patients treated with immunoglobulins had significantly fewer relapses compared to patients treated with other immunotherapies (HR: 0.1 [0.2 - 0.63]; p = 0.014). CONCLUSIONS: In our cohort, the majority of MOGAD patients relapsed. The initial relapse occurred most frequently within the first year, but first relapses also took place over a decade after the initial presentation. Prepubertal onset, severe CSF pleocytosis, and the clinical syndrome of meningoencephalitis may be predictors of a relapsing course. Of the currently available off-label steroid-sparing treatments, scheduled immunoglobulins may be the most effective in relapse prevention.

18 F-FDG Brain PET/MRI in Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids.

ABSTRACT: An 89-year-old man presented with progressive gait disturbance, diplopia, and ataxia. Initial brain MRI demonstrated T2/FLAIR hyperintense signal abnormality in the pons extending along the middle cerebellar peduncles into the cerebellum, with associated punctate, patchy, and linear enhancement on postcontrast imaging. Initially, this was attributed to brainstem encephalitis; however, sarcoidosis, histiocytosis, and paraneoplastic/autoimmune encephalitis remained on the differential. One month after initial MRI, 18 F-FDG brain PET/MRI was performed and showed marked pontine hypermetabolism corresponding to the signal abnormality and enhancement on structural imaging. Collectively, these findings are characteristic of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.

Teaching NeuroImage: Unilateral Primary Angiitis of the CNS.

A 48-year-old woman was referred with an 18-year history of focal-onset seizures. She also reported years-long slowly progressive right-sided weakness that was corroborated on examination. Repeated brain MRIs over 15 years showed multifocal left hemispheric T2 fluid-attenuated inversion recovery-hyperintense lesions with patchy enhancement and microhemorrhages, no diffusion restriction, and a left cerebellar infarct (Figure 1, A-F). Only 2 nonspecific white matter lesions were seen contralaterally, indicating largely unihemispheric disease. Differential diagnosis included unilateral primary angiitis of the CNS (PACNS), Rasmussen encephalitis, and myelin oligodendrocyte glycoprotein antibody-associated disease.1 Serum and CSF testing for autoimmune, infectious, and malignant etiologies and whole-body fluorodeoxyglucose-PET, whole-exome genetic sequencing, and MR vessel-wall imaging were nondiagnostic. Brain biopsy revealed vasculitis (Figure 2, A-F), and the patient was diagnosed with unilateral PACNS. Treatment with mycophenolate mofetil has been initiated. Unilateral PACNS is a rare unihemispheric disease characterized by an indolent course and seizures, recognition of which is critical to accurate diagnosis.1,2.

Identifying specific myelopathy etiologies in the evaluation of suspected myelitis: A retrospective analysis.

BACKGROUND: Myelopathies require prompt etiologic diagnosis. We aimed to identify a specific myelopathy diagnosis in cases of suspected myelitis to highlight clinicoradiologic differences. METHODS: In this retrospective, single-centre cohort of subjects with suspected myelitis referred to London Multiple Sclerosis (MS) Clinic between 2006 and 2021, we identified those with MS and reviewed the remaining charts for etiologic diagnosis based on clinical, serologic, and imaging details. RESULTS: Of 333 included subjects, 318/333 (95.5%) received an etiologic diagnosis. Most (274/333, 82%) had MS or clinically isolated syndrome. Spinal cord infarction (n = 10) was the commonest non-inflammatory myelitis mimic characterized by hyperacute decline (n = 10/10, 100%), antecedent claudication (n = 2/10, 20%), axial owl/snake eye (n = 7/9, 77%) and sagittal pencillike (n = 8/9, 89%) MRI patterns, vertebral artery occlusion/stenosis (n = 4/10, 40%), and concurrent acute cerebral infarct (n = 3/9, 33%). Longitudinal lesions were frequent in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD) (n = 7/7, 100%) and myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) (n = 6/7, 86%), accompanied by bright spotty (n = 5/7, 71%) and central-grey-restricted (n = 4/7, 57%) T2-lesions on axial sequences, respectively. Leptomeningeal (n = 4/4, 100%), dorsal subpial (n = 4/4, 100%) enhancement, and positive body PET/CT (n = 4/4, 100%) aided the diagnosis of sarcoidosis. Spondylotic myelopathies had chronic sensorimotor presentations (n = 4/6, 67%) with relative bladder sparing (n = 5/6, 83%), localizable to sites of disc herniation (n = 6/6, 100%). Metabolic myelopathies showed dorsal column or inverted 'V' sign (n = 2/3, 67%) MRI T2-abnormality with B12 deficiency. CONCLUSIONS: Although no single feature reliably confirms or refutes a specific myelopathy diagnosis, this study highlights patterns that narrow the differential diagnosis of myelitis and facilitate early recognition of mimics.

Prolonged Corticosteroids Without Maintenance Immunotherapy for Treatment of Anti-LGI1 Encephalitis: Analysis of Outcomes and Relapse Rate.

OBJECTIVES: To analyze outcomes and relapse rate of patients with anti-LGI1 encephalitis referred to the London Health Sciences Centre Autoimmune Neurology Clinic, where prolonged (≥3 months) corticosteroids without steroid-sparing maintenance immunotherapy are the typical treatment approach. METHODS: Retrospective chart review. RESULTS: Eighteen patients with anti-LGI1 encephalitis were identified. The median age at symptom onset was 65 years (interquartile range [IQR]: 62-70 years), and 13 (72%) were men. All patients received corticosteroids, with a median treatment duration of 6.3 months (IQR: 3.8-9.6 months). Other first-line immunotherapies used included IV immunoglobulin (n = 11, 61%) and plasma exchange (n = 2, 11%). Three patients referred for refractory disease received rituximab as second-line immunotherapy. No other steroid-sparing maintenance immunotherapies for anti-LGI1 encephalitis were prescribed. At last follow-up, 16/18 (89%) achieved seizure freedom, and 16/18 (89%) had a favorable modified Rankin Scale score. Among 9 patients who had ≥2 years of follow-up from symptom onset, there was disease relapse in 3 (33%), 2 of whom had been referred for refractory disease. DISCUSSION: Among our patients with anti-LGI1 encephalitis who typically received prolonged corticosteroids without steroid-sparing maintenance immunotherapy, outcomes were generally favorable, and relapses were uncommon outside of refractory disease. Further investigation is needed to clarify the optimal corticosteroid regimen and role of steroid-sparing maintenance immunotherapy in anti-LGI1 encephalitis.

Importance of Identifying Cognitive Impairment in Multiple Sclerosis.

This article aims to highlight the impact of cognitive impairment on outcomes and quality of life for people with multiple sclerosis (MS) and to review current evidence for the efficacy of disease-modifying therapies (DMTs) and other interventions. In addition, we provide clinical practice insights regarding screening and management of cognitive impairment in people with MS. Evidence suggests that cognitive deterioration often accompanies magnetic resonance imaging changes. Neocortical volume and deep grey matter atrophy correlate with cognitive impairment. Similarly, cognitive decline is predictive of a higher lesion burden. Cognitive impairment is an important clinical measure of disability and negatively impacts quality of life. Phase 3 studies suggest that DMTs such as natalizumab, ozanimod and fingolimod may provide long-lasting, clinically meaningful effects on cognition in people with MS. Further data are needed to support the use of adjunct cognitive behavioural and exercise interventions for people with MS who have cognitive impairment. More data are needed to define appropriate management strategies for cognitive impairment in people with MS. Baseline and periodic screening for cognitive impairment and inclusion of cognitive impairment as a clinical trial endpoint will help to inform efforts to manage this important aspect of MS.

Predictors of overlapping autoimmune disease in Neuromyelitis Optica Spectrum disorder (NMOSD): A retrospective analysis in two inner-city hospitals.

BACKGROUND: The coexistence of Neuromyelitis Optica spectrum disorder (NMOSD) with other autoimmune diseases (AD-NMOSD) presents worse clinical outcomes and healthcare costs than NMOSD alone (NMOSD-only). NMOSD and other autoimmune diseases also have a higher prevalence and morbidity in Black. We aim to compare clinical features and treatment responses in NMOSD patients with and without overlapping autoimmunity in a predominantly Black cohort. We further identify predictors associated with each clinical subtype. METHODS: AD-NMOSD (n = 14) and NMOSD-only (n = 27) patients were identified retrospectively. Demographic, clinical, laboratory, imaging, and response to treatment data were examined. RESULTS: Our cohort was predominately Black (82.9%). The prevalence of grouped-comorbidities, history of infections, sensory symptoms, Expanded Disability Status Scale (EDSS) before treatment, double-stranded DNA, antinuclear, ribonucleoprotein, and antiphospholipid antibodies, spinal-cord edema, white matter occipital lesions, and the levels of C-reactive protein, urine protein/creatinine, white blood cell count in cerebrospinal fluid (CSF), were higher in AD-NMOSD patients (p < 0.05 and/or Cramer's V > 30, Cohen's d > 50), whereas the age of males, visual symptoms, serum albumin, platelet count, and optic nerve enhancement were lower. EDSS after treatment improved in both groups being more evident in NMOSD-only patients (p = 0.003, SE = 0.58 vs p = 0.075, SE = 0.51). Other variables had a close to moderate SE, and others did not differ between NMOSD subtypes. A higher frequency of grouped-comorbidities, lower serum albumin, and platelet count were independently associated with a higher risk for AD-NMOSD. CONCLUSIONS: Some clinical features between AD-NMOSD and NMOSD-only patients were similar, while others differed. Comorbidities, serum albumin, and platelet count may be independent predictors of AD-NMOSD.

Testing for Antibodies Against Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in the Diagnosis of Patients With Suspected Autoimmune Myelopathy.

Autoimmune myelopathies are immune-mediated disorders of the spinal cord that can cause significant neurologic disability. Discoveries of antibodies targeting aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) have facilitated the diagnosis of autoimmune myelopathies that were previously considered to be atypical presentations of multiple sclerosis (MS) or idiopathic, and represent major advancements in the field of autoimmune neurology. The detection of these antibodies can substantially impact patient diagnosis and management, and increasing awareness of this has led to a dramatic increase in testing for these antibodies among patients with suspected autoimmune myelopathy. In this review we discuss test methodologies used to detect these antibodies, the role of serum vs. cerebrospinal fluid testing, and the value of antibody titers when interpreting results, with the aim of helping laboratorians and clinicians navigate this testing when ordered as part of the diagnostic evaluation for suspected autoimmune myelopathy.

Pearls & Oy-sters: Gait Instability, Jaw Dystonia, and Horizontal Diplopia in a Woman With Anti-Ri Antibodies and Breast Cancer.

A 40-year-old woman was admitted for six months of progressive gait disturbance, lower limb-predominant weakness, stiffness, falls, jaw dystonia, horizontal diplopia, and weight loss. Neurological examination revealed horizontal gaze paresis, limited jaw opening with palpable masseter hypertrophy, and spastic paraparesis with sustained clonus and upgoing plantar responses. MRI revealed T2-hyperintense signal abnormalities in dorsal pons, medulla and upper cervical cord central grey matter extending to C3, without gadolinium enhancement. Cerebrospinal fluid (CSF) showed mildly elevated protein and immunoglobulin (IgG) index with CSF-specific oligoclonal bands. Neural autoantibody testing was positive for anti-Ri in CSF and serum by mouse brain indirect immunofluorescence and immunoblot. Testing for aquaporin 4 (AQP4)-IgG and myelin oligodendrocyte glycoprotein (MOG)-IgG by cell-based assay were negative. The patient received methylprednisolone 1 gram for 5 days and intravenous immunoglobulin 2 grams/kilogram over 2 days with prednisone taper, and botulinum toxin injections for jaw dystonia. PET-CT revealed an enlarged left axillary lymph node with high FDG uptake. Left axillary lymph node biopsy confirmed high-grade, locally invasive breast adenocarcinoma. Neurologic stabilization was documented at two-week follow-up after hospital discharge before modified radical mastectomy. Our case demonstrates a clinical triad highly suggestive of anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS): gait instability, jaw dystonia, and horizontal gaze paresis. The more slowly progressive course and poor response to immunotherapy help distinguish it from AQP4-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) and MOG-IgG associated disease that share similar radiographic features. Early diagnosis, prompt immunotherapy and cancer treatment are paramount for disease stabilization.

Clinical Reasoning: A 57-Year-Old Man With Stepwise Progressive Paraparesis, Sensory Loss, Urinary Retention, and Constipation.

We present the case of a 57-year-old man with protein S deficiency and left leg deep vein thrombosis (DVT) 5 years earlier, who developed stepwise progressive bilateral lower limb weakness, numbness/paresthesia, gait imbalance, hesitancy of micturition, and constipation in the setting of recurrent left common femoral DVT treated with apixaban. Symptoms amplified with Valsalva, corticosteroids, and postlumbar puncture, with longitudinally extensive midthoracic T2-hyperintense lesion extending to the conus associated with hazy holocord enhancement on magnetic resonance imaging (MRI), raising suspicion for spinal dural arteriovenous fistula (sDAVF). Initial digital subtraction angiography (DSA) was negative for sDAVF. However, cerebral spinal fluid (CSF) was herpes simplex virus (HSV)-2 positive, and he was treated with antiviral therapy. Unfortunately, he continued to worsen despite treatment. Repeat neuroimaging 12 months after initial presentation demonstrated persistent lower thoracic/conus lesion in addition to cauda equina enhancement and subtle dorsal T2-hypointense flow voids. We raised red flags (e.g., lack of clinical prodrome, no herpetic rash, no CSF pleocytosis, and rostral extent of the lesion) that suggested the HSV2 nucleic acid detection was perhaps unrelated to the neurologic syndrome. Given the high index of suspicion for sDAVF, we repeated spinal vascular imaging. Spinal MRA demonstrated dilated right dorsal perimedullary veins from T10 to T11. Repeat DSA revealed a right T10 sDAVF. Microsurgical treatment rather than embolization of the fistula was successful without complication, with significant improvement in motor, sphincter, and to a lesser extent sensory function, with residual gait imbalance after inpatient rehabilitation 3 weeks postoperatively.

Fingolimod-related cryptococcal meningoencephalitis and immune reconstitution inflammatory syndrome in a patient with multiple sclerosis.

Fingolimod is an oral medication for multiple sclerosis that sequesters certain subsets of lymphocytes in lymph nodes, reducing egress into blood and their subsequent CNS migration. The initial multi-site randomized Phase III controlled trials found rates of infection similar to those in control groups. However, post-marketing surveillance has revealed an association with several opportunistic infections, including cryptococcosis. We report a case of fingolimod-related cryptococcal meningoencephalitis and IRIS after drug discontinuation and suggest a surveillance and risk mitigation strategy.

The concurrence of multiple sclerosis and glioblastoma.

INTRODUCTION: Glioblastoma rarely coincides with multiple sclerosis. Although registries have reported a higher proportion of brain tumors-most of which are glial-these events appear to be underreported. The relative contribution of JC virus (an oncogenic virus) and disease modifying therapies that may facilitate JC virus neurotropism and tumor-specific immune evasion remain unknown. CASE REPORT: We present the case of a 64-year-old woman who developed a primary glioblastoma eight years after diagnosis of multiple sclerosis while on dimethyl fumarate. CONCLUSION: Systematic reporting may help answer whether JC virus seropositivity and certain disease modifying therapies confer higher risk for glioblastoma in patients with multiple sclerosis.

Optical coherence tomography of patients with Parkinson's disease and progressive supranuclear palsy.

OBJECTIVES: To determine if Parkinson's disease (PD) and progressive supranuclear palsy (PSP) differed on retinal measurements using optical coherence tomography (OCT). PATIENTS AND METHODS: In a prospective, controlled, cross-sectional cohort study, we recruited patients with PD or PSP for more than three years, as well as control subjects. We measured peripapillary retinal nerve fiber layer (RNFL) thickness and macular volume using spectral-domain OCT. The association between these OCT measures and the disease characteristics of duration and disability were examined using a linear mixed effect model. RESULTS: We analyzed eyes from n = 12 PD patients, n = 11 PSP patients, and n = 12 control subjects. RNFL thickness was reduced in eyes from patients with PSP, but there were no differences in macular volume between groups. RNFL thickness and macular volume were not significantly different between eyes from patients with PD and controls. Worse disability was associated with reduced macular volumes. CONCLUSION: PSP but not PD is associated with thinning of the peripapillary RNFL when symptoms have been present for more than three years.

SPARC expression by cerebral microvascular endothelial cells in vitro and its influence on blood-brain barrier properties.

BACKGROUND: SPARC (secreted protein acidic and rich in cysteine) is a nonstructural, cell-matrix modulating protein involved in angiogenesis and endothelial barrier function, yet its potential role in cerebrovascular development, inflammation, and repair in the central nervous system (CNS) remains undetermined. METHODS: This study examines SPARC expression in cultured human cerebral microvascular endothelial cells (hCMEC/D3)-an in vitro model of the blood-brain barrier (BBB)-as they transition between proliferative and barrier phenotypes and encounter pro-inflammatory stimuli. SPARC protein levels were quantified by Western blotting and immunocytochemistry and messenger RNA (mRNA) by RT-PCR. RESULTS: Constitutive SPARC expression by proliferating hCMEC/D3s is reduced as cells mature and establish a confluent monolayer. SPARC expression positively correlated with the proliferation marker Ki-67 suggesting a role for SPARC in cerebrovascular development. The pro-inflammatory molecules tumor necrosis factor-α (TNF-α) and endotoxin lipopolysaccharide (LPS) increased SPARC expression in cerebral endothelia. Interferon gamma (IFN-γ) abrogated SPARC induction observed with TNF-α alone. Barrier function assays show recombinant human (rh)-SPARC increased paracellular permeability and decreased transendothelial electrical resistance (TEER). This was paralleled by reduced zonula occludens-1 (ZO-1) and occludin expression in hCMEC/D3s exposed to rh-SPARC (1-10 µg/ml) compared with cells in media containing a physiological dose of SPARC. CONCLUSIONS: Together, these findings define a role for SPARC in influencing cerebral microvascular properties and function during development and inflammation at the BBB such that it may mediate processes of CNS inflammation and repair.

The Role of Therapeutic Hypothermia After Traumatic Spinal Cord Injury--A Systematic Review.

BACKGROUND: Traumatic spinal cord injury (SCI) is a devastating neurologic entity characterized by a primary insult followed by a secondary pathologic cascade that propagates further injury. Hypothermia has an established clinical role in preventing SCI after cardiac arrest and thoracoabdominal aortic aneurysm repair, yet its emergence as a potential neuroprotectant after spinal cord trauma remains experimental. There are currently no pharmacologic interventions available to prevent secondary mechanisms of injury after spinal cord trauma. METHODS: Systematic review of literature. RESULTS: Experimental studies demonstrated that hypothermia diminishes secondary pathomechanisms, such as ischemia, oxidative stress, apoptosis, inflammation, and edema. Early onset and longer durations of hypothermia as well as concomitant steroids or neural stem cell engraftment combined with hypothermia appear to improve functional and histologic outcomes in animal models of spinal cord trauma. Recent clinical studies provide evidence that localized and systemic hypothermia may be applied safely and efficaciously in patients with severe acute SCI. Randomized clinical trials are needed to better evaluate optimal cooling parameters and the effectiveness of hypothermia after traumatic SCI. CONCLUSION: Although variability exists in the literature, therapeutic hypothermia most likely confers neuroprotection after spinal cord trauma by diminishing the destructive secondary cascade. The available clinical data suggest that regional and systemic hypothermia is a relatively safe and feasible initial treatment modality for patients with acute SCI when combined with surgical decompression/stabilization with or without steroids. However, establishing a clinical role for therapeutic hypothermia after spinal cord trauma will invariably depend on future well-designed, multicentered, randomized, controlled clinical trial data.