Neuromyelitis optica: Clinical course and potential prognostic indicators.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune neurological disorder associated with antibodies to aquaporin-4 (AQP4). NMOSD has been thought to follow a progressive disease course, with step-wise accumulation of disability over time, even in patients undergoing immunosuppressive/immunomodulatory therapy. The influence of factors such as AQP4 seropositivity, AQP4 serum titer levels, and administration of plasmapheresis on NMOSD prognosis is, as yet, unclear. METHODS: We performed a retrospective chart review of 53 persons with NMOSD at Duke University Hospital-collecting data on longitudinal disease course, imaging, demographics, and serum AQP4 titers (measured using the ELISA or FACS method). Most patients in our cohort were treated with high-dose corticosteroids and, following diagnosis, received maintenance immunosuppressive/immunomodulatory therapies. Longitudinal data on EDSS scores were used to calculate the slope of disability over time for each participant. We additionally investigated the correlation between initial AQP4 seropositivity, initial AQP4 serum titer levels, and treatment with plasmapheresis on disability progression for each participant. RESULTS: Contrary to current views on NMOSD disease course, the majority of our participants showed either no change (31.9%) or improvement (27.1%) in disability over time. Our results additionally revealed no significant association between clinical prognosis and initial AQP4 seropositivity (p = 0.830), initial AQP4 serum titer levels (p = 0.338), or administration of plasmapheresis (p = 0.1149). CONCLUSIONS: Our study presents a contemporary view of the clinical course of NMOSD and shows a more favorable view of its disease course than prior studies (performed before high-efficacy disease modifying therapies became widely-used for this patient population). Most patients in this study received treatment with high-dose corticosteroids following NMOSD flares, as well as a variety of maintenance immunosuppressive therapies. The results of this study cannot shed light on the disease course of untreated NMOSD. Our findings additionally challenge the theory that AQP4 seropositivity or serum titer levels at time of diagnosis may be used to effectively predict NMOSD prognosis. While we were unable to find evidence supporting a favorable effect of plasmapheresis administration on disease outcomes, further research is needed to determine the role plasmapheresis ought to play in the treatment of NMOSD.

A possible case of serum sickness after ocrelizumab infusion.

A 41-year-old female diagnosed with multiple sclerosis began ocrelizumab treatment. She received her first treatment course without significant complication. After receiving the first maintenance dose 6 months later, she developed weakness, myalgias, gastrointestinal symptoms, headache, and intermittent fever persisting for 4 weeks. A working diagnosis of serum sickness was determined after excluding other probable entities. She received 3 days of 1 g methylprednisolone intravenously and five plasma exchanges, experiencing gradual improvement. Serum sickness has occurred with monoclonal antibodies including rituximab. This case of possible ocrelizumab-associated serum sickness suggests that clinicians should remain vigilant about this possibility with this medication.

Early complement genes are associated with visual system degeneration in multiple sclerosis.

Multiple sclerosis is a heterogeneous disease with an unpredictable course and a wide range of severity; some individuals rapidly progress to a disabled state whereas others experience only mild symptoms. Though genetic studies have identified variants that are associated with an increased risk of developing multiple sclerosis, no variants have been consistently associated with multiple sclerosis severity. In part, the lack of findings is related to inherent limitations of clinical rating scales; these scales are insensitive to early degenerative changes that underlie disease progression. Optical coherence tomography imaging of the retina and low-contrast letter acuity correlate with and predict clinical and imaging-based outcomes in multiple sclerosis. Therefore, they may serve as sensitive phenotypes to discover genetic predictors of disease course. We conducted a set of genome-wide association studies of longitudinal structural and functional visual pathway phenotypes in multiple sclerosis. First, we assessed genetic predictors of ganglion cell/inner plexiform layer atrophy in a discovery cohort of 374 patients with multiple sclerosis using mixed-effects models adjusting for age, sex, disease duration, optic neuritis and genetic ancestry and using a combination of single-variant and network-based analyses. For candidate variants identified in discovery, we conducted a similar set of analyses of ganglion cell/inner plexiform layer thinning in a replication cohort (n = 376). Second, we assessed genetic predictors of sustained loss of 5-letters in low-contrast letter acuity in discovery (n = 582) using multivariable-adjusted Cox proportional hazards models. We then evaluated candidate variants/pathways in a replication cohort. (n = 253). Results of both studies revealed novel subnetworks highly enriched for connected genes in early complement activation linked to measures of disease severity. Within these networks, C3 was the gene most strongly associated with ganglion cell/inner plexiform layer atrophy (P = 0.004) and C1QA and CR1 were top results in analysis of sustained low-contrast letter acuity loss. Namely, variant rs158772, linked to C1QA, and rs61822967, linked to CR1, were associated with 71% and 40% increases in risk of sustained LCLA loss, respectively, in meta-analysis pooling discovery and replication cohorts (rs158772: hazard ratio: 1.71; 95% confidence interval 1.30-2.25; P = 1.3 × 10-4; rs61822967: hazard ratio: 1.40; 95% confidence interval: 1.16-1.68; P = 4.1 × 10-4). In conclusion, early complement pathway gene variants were consistently associated with structural and functional measures of multiple sclerosis severity. These results from unbiased analyses are strongly supported by several prior reports that mechanistically implicated early complement factors in neurodegeneration.

Multiple sclerosis and sarcoidosis: A case for coexistence.

BACKGROUND: Patients with biopsy-proven systemic sarcoidosis who develop a chronic CNS disorder are often presumed to have neurosarcoidosis (NS), however, the possibility of comorbid neurologic disease, such as MS, must be considered if presentation and course are not typical for NS. METHODS: Retrospective chart review across 4 academic MS centers was undertaken to identify patients with diagnosis of MS (2017 McDonald criteria) and biopsy-confirmed extraneural sarcoidosis. Data were abstracted from each chart using a case report form that systematically queried for demographic, clinical, and paraclinical characteristics relevant to NS and MS. RESULTS: Ten patients met our inclusion criteria (mean age 47.7 [±5.9] years; 80% female). Noncaseating granulomas consistent with sarcoidosis were found on biopsy in all cases (lung 7/10, mediastinum 2/10, liver 1/10, spleen 1/10, and skin 1/10). Diagnosis of MS was based on clinical history of MS-like relapses and MRI findings characteristic of demyelination and typical disease evolution during follow-up (average of 7 years). No patient developed features of NS that could be considered a "red flag" against the diagnosis of MS (such as meningeal enhancement, hydrocephalus, and pituitary involvement). All patients were treated with disease-modifying therapy for MS. CONCLUSIONS: We propose a rational diagnostic approach to patients with sarcoidosis who may have comorbid MS. When the clinical picture is equivocal, the presence of multiple "MS-typical lesions" and the absence of any "NS-typical lesions" on MRI favor diagnosis of MS. Close follow-up is required to ascertain whether clinical and radiologic disease evolution and response to MS therapies conform to the proposed diagnosis of MS.

Cross-sectional study of smoking exposure: no differential effect on OCT metrics in a cohort of MS patients.

BACKGROUND: Optical coherence tomography (OCT) provides quantitative measures of retinal layer thickness. Cigarette smoking is a risk factor for multiple sclerosis (MS) onset and disease severity: its effects on OCT metrics have not been assessed. OBJECTIVE: The objective of this study was to assess the effect of smoking history on retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform (GCIP) of MS patients by OCT. METHODS: 112 MS patients were recruited from the Brigham and Women's Hospital. Spectralis OCT scans were acquired to measure GCIP, peripapillary RNFL, and total macular volume. Multivariable linear mixed effects regression model assessed RNFL and GCIP change with fixed effects for smoking history while adjusting for optic neuritis eye status, age, disease duration, sex, baseline EDSS, and disease modifying therapies (DMTs). RESULTS: Smoking histories were available for 102 patients: 46 (45.10%) had a history of smoking cigarettes and 56 (54.90%) never smoked. No statistically significant differences were found between ever-smokers and never-smokers with respect to GCIP, RNFL, and macular volume. CONCLUSION: Our study shows no significant difference in retinal thickness between ever-smokers and never-smokers. If confirmed, this result suggests mechanistic differences between the retina and other central nervous system (CNS) compartments in response to smoking and should be noted when considering OCT as a surrogate measure of CNS activity.

Case Report: Two Cases of Nicolau Syndrome Associated with Glatiramer Acetate.

We report two cases of Nicolau syndrome (embolia cutis medicamentosa), a rare complication of injectable medications, both associated with the administration of 20 mg of subcutaneous glatiramer acetate. Both patients required surgical debridement and were subsequently treated conservatively without additional complications. Patient 1 opted to discontinue disease-modifying therapy. Patient 2 continued glatiramer acetate therapy without complications by using other injection sites. These cases highlight the need for prompt investigation of new unusual skin lesions in patients receiving injectable multiple sclerosis treatments (regardless of length of treatment and previous minor cosmetic concerns) and illustrate the clinical distinction between Nicolau syndrome and drug-induced skin necrosis.

Retinal damage and vision loss in African American multiple sclerosis patients.

OBJECTIVE: To determine whether African American (AA) multiple sclerosis (MS) patients exhibit more retinal damage and visual impairment compared to Caucasian American (CA) MS patients. METHODS: A total of 687 MS patients (81 AAs) and 110 healthy control (HC) subjects (14 AAs) were recruited at 3 academic hospitals between 2008 and 2012. Using mixed effects regression models, we compared high- and low-contrast visual acuity (HCVA and LCVA) and high-definition spectral domain optical coherence tomography measures of retinal architecture between MS patients of self-identified AA and CA ancestry. RESULTS: In HCs, baseline peripapillary retinal nerve fiber layer (RNFL) thickness was 6.1µm greater in AAs (p = 0.047), whereas ganglion cell/inner plexiform layer (GCIP) thickness did not differ by race. In MS patients, baseline RNFL did not differ by race, and GCIP was 3.98µm thinner in AAs (p = 0.004). AAs had faster RNFL and GCIP thinning rates compared to CAs (p = 0.004 and p = 0.046, respectively). AA MS patients had lower baseline HCVA (p = 0.02) and worse LCVA per year of disease duration (p = 0.039). Among patients with an acute optic neuritis (AON) history, AAs had greater loss of HCVA than CA patients (p = 0.012). INTERPRETATION: This multicenter investigation provides objective evidence that AA MS patients exhibit accelerated retinal damage compared to CA MS patients. Self-identified AA ancestry is associated with worse MS-related visual disability, particularly in the context of an AON history, suggesting a more aggressive inflammatory disease course among AA MS patients or a subpopulation therein.

Predictors of recurrence following an initial episode of transverse myelitis.

OBJECTIVE: This study sought to identify factors that increased the risk of recurrence after an initial transverse myelitis (TM) presentation. METHODS: Retrospective cohort study of 192 patients initially presenting with TM of unknown etiology. Patients diagnosed with multiple sclerosis during the first myelitis episode were excluded. Demographic and laboratory data were analyzed for associations with recurrence. RESULTS: One hundred ten of 192 patients (57%) eventually developed recurrent symptoms: 69 (63%) neuromyelitis optica (NMO) or NMO spectrum disorder, 34 (31%) non-NMO recurrent TM, and 7 (6%) systemic autoimmune disease. Multiple independent risk factors for recurrence were identified: African American race (risk ratio 1.60, p < 0.001, 95% confidence interval 1.26-2.03; similarly noted hereafter), female sex (1.88, p = 0.007, 1.19-2.98), longitudinally extensive myelitis at onset (1.34, p = 0.036, 1.01-1.78), Sjogren syndrome antigen A (1.89, p = 0.003, 1.44-2.48), vitamin D insufficiency (4.00, p < 0.001, 1.60-10.0), antinuclear antibody titer ≥1:160 (1.69, p = 0.006, 1.23-2.32), and the presence of inflammatory markers (e.g., immunoglobulin G index) in the CSF (2.14, p < 0.001, 1.44-3.17). CONCLUSIONS: Sex, race, and serologic biomarkers warrant consideration when assessing risk of TM recurrence. Male sex and Caucasian American race were independently associated with risk of monophasic idiopathic TM. Recurrence risk in female and African American patients appears driven by a greater likelihood of developing NMO or NMO spectrum disorder.

Cerebrospinal fluid (1,3)-ß-D-glucan detection as an aid for diagnosis of iatrogenic fungal meningitis.

This case series highlights our experience with use of the Fungitell assay for quantifying (1,3)-ß-d-glucan in cerebrospinal fluid during the current U.S. outbreak of fungal meningitis related to contaminated methylprednisolone acetate. This test may prove a useful adjunct in diagnosis and management of exposed patients.

Treatment of Neuromyelitis Optica: Review and Recommendations.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease preferentially targeting the optic nerves and spinal cord. Once regarded as a variant of multiple sclerosis (MS), NMO is now recognized to be a different disease with unique pathology and immunopathogenesis that does not respond to traditional MS immunomodulators such as interferons. Preventive therapy in NMO has focused on a range of immunosuppressive medications, none of which have been validated in a rigorous randomized trial. However, multiple retrospective and a few recent prospective studies have provided evidence for the use of six medications for the prevention of NMO exacerbations: azathioprine, rituximab, mycophenolate mofetil, prednisone, methotrexate and mitoxantrone. This review provides a comprehensive analysis of each of these medications in NMO and concludes with a set of recommended consensus practices.