Rituximab and pregnancy: Late-onset neutropenia in a 2-month infant whose mother received rituximab 2 weeks prior to childbirth.

Late-onset neutropenia (LON) is a rare adverse event that has not been reported from in utero exposure. We describe a case of LON in an infant, whose mother had neuromyelitis optica and received rituximab in the third trimester due to re-emergence of CD19 B cells. The newborn was born without complications but 2 months later was found to have grade IV neutropenia. No etiology was identified. Neutropenia self-resolved within 1 week. This case emphasizes an unmet need for developing guidelines and protocols to manage in utero rituximab exposure.

Progressive Multiple Sclerosis Is Associated with Faster and Specific Retinal Layer Atrophy.

OBJECTIVE: Therapeutic development in progressive multiple sclerosis (PMS) has been hampered by a lack of reliable biomarkers to monitor neurodegeneration. Optical coherence tomography (OCT)-derived retinal measures have been proposed as promising biomarkers to fulfill this role. However, it is unclear whether retinal atrophy persists in PMS, exceeds normal aging, or can be distinguished from relapsing-remitting multiple sclerosis (RRMS). METHODS: 178 RRMS, 186 PMS, and 66 control participants were followed with serial OCT for a median follow-up of 3.7 years. RESULTS: The estimated proportion of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell + inner plexiform layer (GCIPL) thinning in multiple sclerosis (MS) attributable to normal aging increased from 42.7% and 16.7% respectively at age 25 years, to 83.7% and 81.1% at age 65 years. However, independent of age, PMS was associated with faster pRNFL (-0.34 ± 0.09%/yr, p < 0.001) and GCIPL (-0.27 ± 0.07%/yr, p < 0.001) thinning, as compared to RRMS. In both MS and controls, higher baseline age was associated with faster inner nuclear layer (INL) and outer nuclear layer (ONL) thinning. INL and ONL thinning were independently faster in PMS, as compared to controls (INL:-0.09 ± 0.04%/yr, p = 0.03; ONL:-0.12 ± 0.06%/yr, p = 0.04), and RRMS (INL:-0.10 ± 0.04%/yr, p = 0.01; ONL:-0.13 ± 0.05%/yr, p = 0.01), whereas they were similar in RRMS and controls. Unlike RRMS, disease-modifying therapies (DMTs) did not impact rates of retinal layer atrophy in PMS. INTERPRETATION: PMS is associated with faster retinal atrophy independent of age. INL and ONL measures may be novel biomarkers of neurodegeneration in PMS that appear to be unaffected by conventional DMTs. The effects of aging on rates of retinal layer atrophy should be considered in clinical trials incorporating OCT outcomes. ANN NEUROL 2020;87:885-896.

Effect of disease-modifying therapies on subcortical gray matter atrophy in multiple sclerosis.

BACKGROUND: The effects of disease-modifying therapies (DMTs) on region-specific brain atrophy in multiple sclerosis (MS) are unclear. OBJECTIVE: To determine the effects of higher versus lower efficacy DMTs on rates of brain substructure atrophy in MS. METHODS: A non-randomized, observational cohort of people with MS followed with annual brain magnetic resonance imaging (MRI) was evaluated retrospectively. Whole brain, subcortical gray matter (GM), cortical GM, and cerebral white matter (WM) volume fractions were obtained. DMTs were categorized as higher (DMT-H: natalizumab and rituximab) or lower (DMT-L: interferon-beta and glatiramer acetate) efficacy. Follow-up epochs were analyzed if participants had been on a DMT for ⩾6 months prior to baseline and had at least one follow-up MRI while on DMTs in the same category. RESULTS: A total of 86 DMT epochs (DMT-H: n = 32; DMT-L: n = 54) from 78 participants fulfilled the study inclusion criteria. Mean follow-up was 2.4 years. Annualized rates of thalamic (-0.15% vs -0.81%; p = 0.001) and putaminal (-0.27% vs -0.73%; p = 0.001) atrophy were slower during DMT-H compared to DMT-L epochs. These results remained significant in multivariate analyses including demographics, clinical characteristics, and T2 lesion volume. CONCLUSION: DMT-H treatment may be associated with slower rates of subcortical GM atrophy, especially of the thalamus and putamen. Thalamic and putaminal volumes are promising imaging biomarkers in MS.

Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures.

BACKGROUND: The retinal vasculature may be altered in multiple sclerosis (MS), potentially acting as a biomarker of disease processes. OBJECTIVE: To compare retinal vascular plexus densities in people with MS (PwMS) and healthy controls (HCs), and examine correlations with visual function and global disability. METHODS: In this cross-sectional study, 111 PwMS (201 eyes) and 50 HCs (97 eyes) underwent optical coherence tomography angiography (OCTA). Macular superficial vascular plexus (SVP) and deep vascular plexus (DVP) densities were quantified, and poor quality images were excluded according to an artifact-rating protocol. RESULTS: Mean SVP density was 24.1% (SD = 5.5) in MS eyes (26.0% (SD = 4.7) in non-optic neuritis (ON) eyes vs. 21.7% (SD = 5.5) in ON eyes, p < 0.001), as compared to 29.2% (SD = 3.3) in HC eyes (p < 0.001 for all MS eyes and multiple sclerosis optic neuritis (MSON) eyes vs. HC eyes, p = 0.03 for MS non-ON eyes vs. HC eyes). DVP density did not differ between groups. In PwMS, lower SVP density was associated with higher levels of disability (expanded disability status scale (EDSS): R2 = 0.26, p = 0.004; multiple sclerosis functional composite (MSFC): R2 = 0.27, p = 0.03) and lower letter acuity scores (100% contrast: R2 = 0.29; 2.5% contrast: R2 = 0.40; 1.25% contrast: R2 = 0.31; p < 0.001 for all). CONCLUSIONS: Retinal SVP density measured by OCTA is reduced across MS eyes, and correlates with visual function, EDSS, and MSFC scores.

Spinal cord and infratentorial lesions in radiologically isolated syndrome are associated with decreased retinal ganglion cell/inner plexiform layer thickness.

BACKGROUND: The role of retinal imaging with optical coherence tomography (OCT) in assessing individuals with radiologically isolated syndrome (RIS) remains largely unexplored. OBJECTIVE: To assess retinal layer thicknesses in RIS and examine their associations with clinical features suggestive of increased risk for conversion to multiple sclerosis (MS). METHODS: A total of 30 RIS subjects and 60 age- and sex-matched healthy controls (HC) underwent retinal imaging with spectral-domain OCT, followed by automated segmentation of retinal layers. RESULTS: Overall, retinal layer thicknesses did not differ between RIS and HC. However, RIS subjects with spinal cord (SC) lesions had lower ganglion cell + inner plexiform layer (GCIP) thickness compared to HC (-4.41 µm; p = 0.007) and RIS without SC lesions (-3.53 µm; p = 0.041). Similarly, RIS subjects with infratentorial (IT) brain lesions had lower GCIP thickness compared to HC (-4.07 µm; p < 0.001) and RIS without IT lesions (-3.49 µm; p = 0.029). Multivariate analyses revealed that the presence of SC or IT lesions were independently associated with lower GCIP thickness in RIS (p = 0.04 and p = 0.03, respectively). Other patient characteristics, including sex, abnormal cerebrospinal fluid, and presence of gadolinium-enhancing or juxtacortical lesions, were not associated with retinal layer thicknesses. CONCLUSION: The presence of SC or IT lesions in RIS may be associated with retinal neuro-axonal loss, supporting the presence of more disseminated disease.

Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders.

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune cytokine that belongs to the TNF superfamily of receptor ligands. The cytokine exists as either a transmembrane or a soluble molecule, and targets two distinct receptors, TNF-α receptor 1 (TNFR1) and TNF-α receptor 2 (TNFR2), which activate different signaling cascades and downstream genes. TNF-α cellular responses depend on its molecular form, targeted receptor, and concentration levels. TNF-α plays a multifaceted role in normal physiology that is highly relevant to human health and disease. In the central nervous system (CNS), this cytokine regulates homeostatic functions, such as neurogenesis, myelination, blood-brain barrier permeability and synaptic plasticity. However, it can also potentiate neuronal excitotoxicity and CNS inflammation. The pleiotropism of TNF-α and its various roles in the CNS, whether homeostatic or deleterious, only emphasizes the functional complexity of this cytokine. Anti-TNF-α therapy has demonstrated effectiveness in treating various autoimmune inflammatory diseases and has emerged as a significant treatment option for CNS autoimmune diseases. Nevertheless, it is crucial to recognize that the effects of this therapeutic target are diverse and complex. Contrary to initial expectations, anti-TNF-α therapy has been found to have detrimental effects in multiple sclerosis. This article focuses on describing the various roles, both physiological and pathological, of TNF-α in the CNS. Additionally, it discusses the specific disease processes that are dependent or regulated by TNF-α and the rationale of its use as a therapeutic target.

Neuroimaging Insights Into Early Stages of HIV-Progressive Multifocal Leukoencephalopathy: A Case Report.

This report aims to enhance the understanding of early longitudinal neuroimaging features of progressive multifocal leukoencephalopathy (PML) in human immunodeficiency virus (HIV). Neuroimaging has become crucial in the diagnosis and early recognition of PML. Recognition of magnetic resonance imaging (MRI) features in the early stages of PML is paramount to avoid misdiagnosis and facilitate the delivery of treatments aimed at reducing disease progression. A 49-year-old white man with HIV presented with 4-month progressive left-sided weakness. Neurological examination revealed mild cognitive impairment, left-sided hemiparesis, and somatosense impairment to all modalities. Brain MRI revealed a punctate pattern with innumerable T2-FLAIR (fluid attenuated inversion recovery) hyperintensities in the cortex, brainstem, cerebellum, subcortical, and periventricular areas. Susceptibility-weighted imaging (SWI) revealed hypointensities involving subcortical U-fibers and cortical architecture. A comprehensive diagnostic evaluation was inconclusive. John Cunningham virus (JCV) PCR in cerebrospinal fluid (CSF) was indeterminate. He was started on antiretroviral therapy. Repeat brain MRI performed 1.5 months later, in the setting of further neurological decline, demonstrated progression of the T2-hyperintensities into a large confluent white matter lesion in the right frontoparietal lobe. Despite an indeterminate JCV PCR, the appearance and characteristic progression of the lesions in successive imaging in the setting of severe immunosuppression, with extensive negative infectious workup, was indicative of PML. This clinical experience illustrates unique neuroimaging features of HIV-PML in early stages and its progression over time. It especially highlights the relevance of the SWI sequence in the diagnosis and features observed with disease evolution. Short-term imaging follow-up may assist with the recognition of MRI features consistent with the biology of the infection.

Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials.

Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for the treatment of disease activity and are effective in reducing relapses and new magnetic resonance imaging (MRI) lesions. However, disease activity generally subsides with time, and age-dependent changes in DMT efficacy are not well-established. We aimed to investigate whether age impacts the efficacy of DMTs in treating disease activity in patients with relapsing-remitting MS (RRMS). Methods: DMT efficacy related to age was assessed through a meta-analysis of clinical trials that evaluated the efficacy of DMTs in RRMS patients as measured by reductions in the annualized relapse rate (ARR), new T2 lesions, and gadolinium-enhanced lesions on MRI. Using the mean baseline patient age from each trial, a weighted linear regression was fitted to determine whether age was associated with treatment efficacy on a group level. Results: Group-level data from a total of 28,082 patients from 26 trials of 14 different DMTs were included in the meta-analysis. There were no statistically significant associations between age and reductions in ARR, new T2 lesions, and gadolinium-enhanced lesions of the treatment group compared with placebo. Conclusion: DMTs for RRMS show efficacy in treating disease activity independent of age as demonstrated by group-level data from DMT clinical trials. Nevertheless, clinical trials select for patients with baseline disease activity regardless of age, thereby not representing real-world patients with RRMS, where disease activity declines with age.

Analysis of Agreement of Retinal-Layer Thickness Measures Derived from the Segmentation of Horizontal and Vertical Spectralis OCT Macular Scans.

PURPOSE: Optical coherence tomography (OCT) is a reliable method used to quantify discrete layers of the retina. Spectralis OCT is a device used for this purpose. Spectralis OCT macular scan imaging acquisition can be obtained on either the horizontal or vertical plane. The vertical protocol has been proposed as favorable, due to postulated reduction in confound of Henle's fibers on segmentation-derived metrics. Yet, agreement of the segmentation measures of horizontal and vertical macular scans remains unexplored. Our aim was to determine this agreement. MATERIALS AND METHODS: Horizontal and vertical macular scans on Spectralis OCT were acquired in 20 healthy controls (HCs) and 20 multiple sclerosis (MS) patients. All scans were segmented using Heidelberg software and a Johns Hopkins University (JHU)-developed method. Agreement was analyzed using Bland-Altman analyses and intra-class correlation coefficients (ICCs). RESULTS: Using both segmentation techniques, mean differences (agreement at the cohort level) in the thicknesses of all macular layers derived from both acquisition protocols in MS patients and HCs were narrow (<1 µm), while the limits of agreement (LOA) (agreement at the individual level) were wider. Using JHU segmentation mean differences (and LOA) for the macular retinal nerve fiber layer (RNFL) and ganglion cell layer + inner plexiform layer (GCIP) in MS were 0.21 µm (-1.57-1.99 µm) and -0.36 µm (-1.44-1.37 µm), respectively. CONCLUSIONS: OCT segmentation measures of discrete retinal-layer thicknesses derived from both vertical and horizontal protocols on Spectralis OCT agree excellently at the cohort level (narrow mean differences), but only moderately at the individual level (wide LOA). This suggests patients scanned using either protocol should continue to be scanned with the same protocol. However, due to excellent agreement at the cohort level, measures derived from both acquisitions can be pooled for outcome purposes in clinical trials.