Brainstem and cerebellar involvement in MOG-IgG-associated disorder versus aquaporin-4-IgG and MS

ObjectiveTo determine the frequency and characteristics of brainstem or cerebellar involvement in myelin-oligodendrocyte-glycoprotein-antibody-associated-disorder (MOGAD) versus aquaporin-4-IgG-seropositive-neuromyelitis optica spectrum disorder (AQP4-IgG-NMOSD) and multiple sclerosis (MS).MethodsIn this observational study, we retrospectively identified 185 Mayo Clinic MOGAD patients with: (1) characteristic MOGAD phenotype, (2) MOG-IgG seropositivity by live cell-based assay and (3) MRI lesion(s) of brainstem, cerebellum or both. We compared the symptomatic attacks to AQP4-IgG-NMOSD (n=30) and MS (n=30).ResultsBrainstem or cerebellar involvement occurred in 62/185 (34%) MOGAD patients of which 39/62 (63%) were symptomatic. Ataxia (45%) and diplopia (26%) were common manifestations. The median age in years (range) in MOGAD of 24 (2–65) was younger than MS at 36 (16–65; p=0.046) and AQP4-IgG-NMOSD at 45 (6–72; p=0.006). Isolated attacks involving the brainstem, cerebellum or both were less frequent in MOGAD (9/39 (23%)) than MS (22/30 (73%); p<0.001) but not significantly different from AQP4-IgG-NMOSD (14/30 (47%); p=0.07). Diffuse middle cerebellar peduncle MRI-lesions favoured MOGAD (17/37 (46%)) over MS (3/30 (10%); p=0.001) and AQP4-IgG-NMOSD (3/30 (10%); p=0.001). Diffuse medulla, pons or midbrain MRI lesions occasionally occurred in MOGAD and AQP4-IgG-NMOSD but never in MS. Cerebrospinal fluid (CSF) oligoclonal bands were rare in MOGAD (5/30 (17%)) and AQP4-IgG-NMOSD (2/22 (9%); p=0.68) but common in MS (18/22 (82%); p<0.001). Disability at nadir or recovery did not differ between the groups.ConclusionInvolvement of the brainstem, cerebellum or both is common in MOGAD but usually occurs as a component of a multifocal central nervous system attack rather than in isolation. We identified clinical, CSF and MRI attributes that can help discriminate MOGAD from AQP4-IgG-NMOSD and MS.

Kappa Index versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders

Background: Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID). Methods: We enrolled patients who underwent a diagnostic spinal tap throughout two years. KFLC levels were determined using a Freelite assay (Binding Site) and the turbidimetric Optilite analyzer. Results: Of 540 included patients, 223 had a CNSID, and 84 had MS. The kappa index was more sensitive (0.89 versus 0.85) and less specific (0.84 versus 0.89), with the same AUC (0.87) as OCB for MS diagnosis (optimal cut-off: 6.2). Adding patients with a single CSF IgG band to the OCB-positive group slightly increased the AUC (0.88). Likewise, the kappa index (cut-off: 3.9) was more sensitive (0.67 versus 0.50) and less specific (0.81 versus 0.97), with the same AUC (0.74) as OCB, for a CNSID diagnosis. Conclusion: The kappa index and CSF OCB have comparable diagnostic accuracies for a MS or CNSID diagnosis and supply the clinician with useful, complementary information.

352. Seronegative Relapse of Brucellosis in the Central Nervous System

Background Brucellosis is the most common zoonotic infection in the world. High risk areas include the Mediterranean Basin, Eastern Europe and the Middle East. Clinical presentation is quite heterogenous. CNS involvement (neurobrucellosis) varies widely, from 0,5 to 25%. This reflects a high prevalence in endemic areas and the lack of established criteria for a diagnosis. We present a patient with a seronegative relapse of brucellosis, confined in the CNS, identified by Brucella IgG ELISA and 16S rRNA sequencing. Methods Case Report Results A 60-year-old man, farmer, with a history of systematic brucellosis two years before admission, presented with high fever, headache and agitation. A serum agglutination test and anti-Brucella IgG ELISA were negative at baseline. Spinal tap revealed lymphocytosis and low glucose. CSF culture was negative. The patient received ceftriaxone, ampicillin and acyclovir with an initial remission. A week later the patient’s symptoms relapsed. Administration of ceftriaxone and acyclovir was reinitiated with clinical improvement, however, lymphocytic meningitis persisted even after 15 days of treatment. Brain MRI demonstrated nonspecific white matter hyperintensities and severe meningitis as identified by contrast-enhanced 3D Flair MRI. CSF oligoclonal bands showed intrathecal immunoglobin synthesis. CSF agglutination tests and CSF IgG ELISA were positive for Brucella. Though CSF PCR for Brucella was negative, 16S rRNA sequencing revealed the presence of Brucella spp. Patient was treated with ceftriaxone and dexamethasone and despite an initial worsening of neurological symptoms of tremor, loss of balance, hearing loss and diplopia, a clinical remission was achieved after a month and a laboratory remission after eight months of treatment. Brain MRI: 3D Flair Sequence with Contrast Enhancement Table. CSF Parameters Conclusion Neurobrucellosis presents with a variety of clinical symptoms and it should always be considered in neurological patients in highly endemic areas. Establishing a diagnosis is challenging. In our patient, CSF oligoclonal bands and the agglutination test in the CSF helped in achieving a diagnosis, suggesting their possible role in the diagnostic criteria. Although still under debate, the use of corticosteroids in our patient as well as the prolonged use of ceftriaxone in the therapeutic regime were crucial. Disclosures All Authors: No reported disclosures

Neuromyelitis Optica and Systemic Lupus Erythematosus Association – the Chicken or the Egg Dilemma: a Case Report

We present a case report of a 32-year-old woman diagnosed with opticomyelitis of Devic (OMD) and systemic lupus erythematosus (SLE). The onset of neurological symptoms was with optic neuritis. Five months later the neurological deficit progressed within a few days to lower paraplegia and upper paraparesis, retention of urine and faeces, impaired somatic and deep sensation below the level of Th1 dermatome. The results from laboratory investigations confirmed anaemic syndrome, increased urea and creatinine, hypoproteinemia and severe proteinuria. The results from CSF investigations demonstrated hyperproteinorachia with extremely high Ig fractions. Serum and CSF oligoclonal bands and positive serum Aquaporin IgG 32 times higher than the upper referent limit were found. The association with SLE was confirmed by the increased levels of total ANA and anti-ds-DNA ANA. MRT visualized the spinal cord as non-homogenously hypointense on T1 and extremely hyperintense on FLAIR sequences through its whole length up to the bulbar-pontine region. The MRT findings and the serum Aquaporin IgG confirmed the diagnosis OMD. The patient was treated with intravenous immunomodulating agents.&nbsp; We consider the presented case of special interest because of the comorbidity of an aggressive autoimmune systemic and an organ-specific disease of the central nervous system.&nbsp;

Does CSF pleocytosis have a predictive value for disease course in MS?

ObjectiveMS is a demyelinating CNS disorder with a spectrum of clinical patterns regarding course and prognosis. Although several prognostic factors are considered in the initial evaluation of patients, biological markers defining the disease course and guiding treatments are currently lacking. It is unknown whether patients with CSF pleocytosis differ in regard to symptoms, disease course, and prognosis from those without. The aim of this study was to evaluate whether CSF pleocytosis during the initial presentation has an impact on the clinical course and progression of MS.MethodsWe retrospectively evaluated patients attending the MS Clinic at Rabin Medical Center between January 1999 and January 2016 who underwent lumbar puncture (LP) at disease presentation, considering CSF cell count, clinical diagnosis (clinically isolated syndrome [CIS] and relapsing-remitting MS [RRMS]), annualized relapse rate (ARR), paraclinical findings (imaging, CSF oligoclonal bands, and evoked potentials), and disease progression, expressed by the Expanded Disability Status Scale (EDSS).ResultsOne hundred fourteen patients (72 females) underwent LP at disease presentation (RRMS: n = 100, CIS: n = 14). Age at diagnosis was 32.4 ± 12.2 years, and the follow-up time was 9.4 ± 3.8 years. Forty-six patients showed a pleocytic CSF (≥5 cells per μL). Compared with patients with <4 cells per μL, patients with pleocytosis had a higher ARR (0.60 ± 0.09 vs 0.48 ± 0.04; p = 0.0267) and a steeper increase (slope) in the EDSS score throughout the follow-up period (correlation coefficient: r2 = 0.04; p = 0.0251).ConclusionsCSF pleocytosis may be considered a biological unfavorable predictive factor regarding disease course and progression in MS.

Ocular flutter as presenting manifestation of pediatric MOG antibody–associated demyelination: A case report

A 13-year-old girl presented with a 5-day history of oscillopsia. On examination, ocular flutter and mild cerebellar signs were found. Brain magnetic resonance imaging (MRI) revealed four periventricular and subcortical non-enhancing lesions. Cerebrospinal fluid (CSF) oligoclonal bands were negative. Neuroblastoma or other malignancies were not found. She responded well to a corticosteroid–intravenous immunoglobulin (IVIG) combination and remained symptom-free for 3 years until presenting again with isolated ocular flutter. Brain MRI at this time remained atypical for classic multiple sclerosis (MS) with a predominance of juxtacortical demyelinating lesions. CSF was positive for oligoclonal bands. Serum myelin oligodendrocyte glycoprotein (MOG) antibodies were present. Ocular flutter can be the presenting feature of MOG antibody–associated pediatric demyelination.

Rituximab, IVIg, and Tetracosactide (ACTH1–24) Combination Immunotherapy (“RITE-CI”) for Pediatric Opsoclonus-Myoclonus Syndrome: Immunomarkers and Clinical Observations

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 ± 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case–control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined “RITE-CI”) were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had ≥3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (−85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors.

Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years’ follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71–2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52–2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04–3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98–0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.