Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD.

BACKGROUND: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. OBJECTIVE: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. METHODS: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. RESULTS: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. CONCLUSION: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial.

BACKGROUND: No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. METHODS: We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150-0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. INTERPRETATION: Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. FUNDING: MedImmune and Viela Bio.

Optical coherence tomography reflects brain atrophy in multiple sclerosis: A four-year study.

OBJECTIVE: The aim of this work was to determine whether atrophy of specific retinal layers and brain substructures are associated over time, in order to further validate the utility of optical coherence tomography (OCT) as an indicator of neuronal tissue damage in patients with multiple sclerosis (MS). METHODS: Cirrus high-definition OCT (including automated macular segmentation) was performed in 107 MS patients biannually (median follow-up: 46 months). Three-Tesla magnetic resonance imaging brain scans (including brain-substructure volumetrics) were performed annually. Individual-specific rates of change in retinal and brain measures (estimated with linear regression) were correlated, adjusting for age, sex, disease duration, and optic neuritis (ON) history. RESULTS: Rates of ganglion cell + inner plexiform layer (GCIP) and whole-brain (r = 0.45; p < 0.001), gray matter (GM; r = 0.37; p < 0.001), white matter (WM; r = 0.28; p = 0.007), and thalamic (r = 0.38; p < 0.001) atrophy were associated. GCIP and whole-brain (as well as GM and WM) atrophy rates were more strongly associated in progressive MS (r = 0.67; p < 0.001) than relapsing-remitting MS (RRMS; r = 0.33; p = 0.007). However, correlation between rates of GCIP and whole-brain (and additionally GM and WM) atrophy in RRMS increased incrementally with step-wise refinement to exclude ON effects; excluding eyes and then patients (to account for a phenotype effect), the correlation increased to 0.45 and 0.60, respectively, consistent with effect modification. In RRMS, lesion accumulation rate was associated with GCIP (r = -0.30; p = 0.02) and inner nuclear layer (r = -0.25; p = 0.04) atrophy rates. INTERPRETATION: Over time GCIP atrophy appears to mirror whole-brain, and particularly GM, atrophy, especially in progressive MS, thereby reflecting underlying disease progression. Our findings support OCT for clinical monitoring and as an outcome in investigative trials.

Placebo-controlled study in neuromyelitis optica-Ethical and design considerations.

BACKGROUND: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. OBJECTIVE: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical-scientific integrity. METHODS: We assessed the "standard of care" for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. RESULTS: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. CONCLUSION: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.

Iatrogenic Exserohilum infection of the central nervous system: mycological identification and histopathological findings.

An outbreak of fungal infections has been identified in patients who received epidural injections of methylprednisolone acetate that was contaminated with environmental molds. In this report, we present the mycological and histopathological findings in an index case of Exserohilum meningitis and vasculitis in an immunocompetent patient, who received a cervical spine epidural steroid injection for chronic neck pain 1 week before the onset of fulminant meningitis with subsequent multiple brain and spinal cord infarcts. The fungus was recovered from two separate cerebrospinal fluid specimens collected before initiation of antifungal therapy and at autopsy on standard bacterial and fungal culture media. The mold was identified phenotypically as Exserohilum species. DNA sequencing targeting the internal transcribed spacer region and D1/D2 region of 28S ribosomal DNA enabled further speciation as E. rostratum. Gross examination at autopsy revealed moderate brain edema with bilateral uncal herniation and a ventriculostomy tract to the third ventricle. The brainstem, cerebellum, and right orbitofrontal cortex were soft and friable, along with hemorrhages in the cerebellar vermis and thalamus. Microscopic examination demonstrated numerous fungi with septate hyphae invading blood vessel walls and inducing acute necrotizing inflammation. The leptomeninges were diffusely infiltrated by mixed inflammatory cells along with scattered foci of fungal elements. This is the first report of iatrogenic E. rostratum meningitis in humans. This report describes the microbiological procedures and histopathological features for the identification of E. rostratum (a pigmented vascularly invasive fungi), the cause of a current nationwide outbreak of fatal fungal meningitis.

Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis.

Post-mortem ganglion cell dropout has been observed in multiple sclerosis; however, longitudinal in vivo assessment of retinal neuronal layers following acute optic neuritis remains largely unexplored. Peripapillary retinal nerve fibre layer thickness, measured by optical coherence tomography, has been proposed as an outcome measure in studies of neuroprotective agents in multiple sclerosis, yet potential swelling during the acute stages of optic neuritis may confound baseline measurements. The objective of this study was to ascertain whether patients with multiple sclerosis or neuromyelitis optica develop retinal neuronal layer pathology following acute optic neuritis, and to systematically characterize such changes in vivo over time. Spectral domain optical coherence tomography imaging, including automated retinal layer segmentation, was performed serially in 20 participants during the acute phase of optic neuritis, and again 3 and 6 months later. Imaging was performed cross-sectionally in 98 multiple sclerosis participants, 22 neuromyelitis optica participants and 72 healthy controls. Neuronal thinning was observed in the ganglion cell layer of eyes affected by acute optic neuritis 3 and 6 months after onset (P < 0.001). Baseline ganglion cell layer thicknesses did not demonstrate swelling when compared with contralateral unaffected eyes, whereas peripapillary retinal nerve fibre layer oedema was observed in affected eyes (P = 0.008) and subsequently thinned over the course of this study. Ganglion cell layer thickness was lower in both participants with multiple sclerosis and participants with neuromyelitis optica, with and without a history of optic neuritis, when compared with healthy controls (P < 0.001) and correlated with visual function. Of all patient groups investigated, those with neuromyelitis optica and a history of optic neuritis exhibited the greatest reduction in ganglion cell layer thickness. Results from our in vivo longitudinal study demonstrate retinal neuronal layer thinning following acute optic neuritis, corroborating the hypothesis that axonal injury may cause neuronal pathology in multiple sclerosis. Further, these data provide evidence of subclinical disease activity, in both participants with multiple sclerosis and with neuromyelitis optica without a history of optic neuritis, a disease in which subclinical disease activity has not been widely appreciated. No pathology was seen in the inner or outer nuclear layers of eyes with optic neuritis, suggesting that retrograde degeneration after optic neuritis may not extend into the deeper retinal layers. The subsequent thinning of the ganglion cell layer following acute optic neuritis, in the absence of evidence of baseline swelling, suggests the potential utility of quantitative optical coherence tomography retinal layer segmentation to monitor neuroprotective effects of novel agents in therapeutic trials.

Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography.

Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis.

AQP4-IgG-seronegative patient outcomes in the N-MOmentum trial of inebilizumab in neuromyelitis optica spectrum disorder.

BACKGROUND: The N-MOmentum trial, a double-blind, randomized, placebo-controlled, phase 2/3 study of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD), enrolled participants who were aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive (AQP4+) or -seronegative (AQP4-). This article reports AQP4- participant outcomes. METHODS: AQP4-IgG serostatus was determined for all screened participants by a central laboratory, using a validated, fluorescence-observation cell-binding assay. Medical histories and screening data for AQP4- participants were assessed independently by an eligibility committee of three clinical experts during screening. Diagnosis of NMOSD was confirmed by majority decision using the 2006 neuromyelitis optica criteria. Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) serology (using a clinically validated, flow cytometry assay) and annualized attack rates (AARs) were evaluated post hoc. Efficacy outcomes were assessed by comparing pre-study and on-study AARs in treated participants. RESULTS: Only 18/50 AQP4- screened participants (36%) were initially considered eligible for randomization; 16 were randomized and received full treatment, 4 to placebo (1 MOG-IgG-seropositive [MOG+]) and 12 to inebilizumab (6 MOG+). The most common reason for failure to pass screening among prospective AQP4- participants was failure to fulfill the 2006 NMO MRI criteria. In inebilizumab-treated AQP4- participants, on-study AARs (95% confidence interval [CI]) calculated from treatment initiation (whether from randomization or when received at the start of the open-label period) to the end of study were lower than pre-study rates: for all AQP4- participants (n = 16), mean (95% CI) AAR was 0.048 (0.02-0.15) versus 1.70 (0.74-2.66), respectively. For the subset of AQP4-/MOG+ participants (n = 7), AAR was 0.043 (0.006-0.302) after treatment versus 1.93 (1.10-3.14) before the study. For the subset of AQP4-/MOG- participants (n = 9), post-treatment AAR was 0.051 (0.013-0.204) versus 1.60 (1.02-2.38). Three attacks occurred during the randomized controlled period in the AQP4- inebilizumab group and were of mild severity; no attacks occurred in the AQP4- placebo group. The low number of participants receiving placebo (n = 4) confounds direct comparison with the inebilizumab group. No attacks were seen in any AQP4- participant after the second infusion of inebilizumab. Inebilizumab was generally well tolerated by AQP4- participants and the adverse event profile observed was similar to that of AQP4+ participants. CONCLUSION: The high rate of rejection of AQP4- participants from enrollment into the study highlights the challenges of implementing the diagnostic criteria of AQP4- NMOSD. An apparent reduction of AAR in participants with AQP4- NMOSD who received inebilizumab warrants further investigation.

Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis.

OBJECTIVE: Cross-sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON). METHODS: Patients underwent OCT measurement of RNFL thickness at baseline and at 6-month intervals during a mean follow-up of 18 months at 3 centers. Low-contrast letter acuity (2.5%, 1.25% contrast) and visual acuity (VA) were assessed. RESULTS: Among 299 patients (593 eyes) with >or=6 months follow-up, eyes with visual loss showed greater RNFL thinning compared to eyes with stable vision (low-contrast acuity, 2.5%: p < 0.001; VA: p = 0.005). RNFL thinning increased over time, with average losses of 2.9microm at 2 to 3 years and 6.1microm at 3 to 4.5 years (p < 0.001 vs 0.5-1-year follow-up interval). These patterns were observed for eyes with or without prior history of ON. Proportions of eyes with RNFL loss greater than test-retest variability (>or=6.6microm) increased from 11% at 0 to 1 year to 44% at 3 to 4.5 years (p < 0.001). INTERPRETATION: Progressive RNFL thinning occurs as a function of time in some patients with MS, even in the absence of ON, and is associated with clinically significant visual loss. These findings are consistent with subclinical axonal loss in the anterior visual pathway in MS, and support the use of OCT and low-contrast acuity as methods to evaluate the effectiveness of putative neuroprotection protocols.

Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness.

BACKGROUND: Post-mortem analyses of multiple sclerosis (MS) eyes demonstrate prominent retinal neuronal ganglion cell layer (GCL) loss, in addition to related axonal retinal nerve fiber layer (RNFL) loss. Despite this, clinical correlations of retinal neuronal layers remain largely unexplored in MS. OBJECTIVES: To determine if MS patients exhibit in vivo retinal neuronal GCL loss, deeper retinal neuronal loss, and investigate correlations between retinal layer thicknesses, MS clinical subtype and validated clinical measures. METHODS: Cirrus HD-optical coherence tomography (OCT), utilizing automated intra-retinal layer segmentation, was performed in 132 MS patients and 78 healthy controls. MS classification, Expanded Disability Status Scale (EDSS) and visual function were recorded in study subjects. RESULTS: GCL+inner plexiform layer (GCIP) was thinner in relapsing-remitting MS (RRMS; n = 96, 71.6 µm), secondary progressive MS (SPMS; n = 20, 66.4 µm) and primary progressive MS (PPMS; n = 16, 74.1 µm) than in healthy controls (81.8 µm; p < 0.001 for all). GCIP thickness was most decreased in SPMS, and although GCIP thickness correlated significantly with disease duration, after adjusting for this, GCIP thickness remained significantly lower in SPMS than RRMS. GCIP thickness correlated significantly, and better than RNFL thickness, with EDSS, high-contrast, 2.5% low-contrast and 1.25% low-contrast letter acuity in MS. 13.6% of patients also demonstrated inner or outer nuclear layer thinning. CONCLUSIONS: OCT segmentation demonstrates in vivo GCIP thinning in all MS subtypes. GCIP thickness demonstrates better structure-function correlations (with vision and disability) in MS than RNFL thickness. In addition to commonly observed RNFL/GCIP thinning, retinal inner and outer nuclear layer thinning occur in MS.

Depleting plasmacytoid dendritic cells reduces local type I interferon responses and disease activity in patients with cutaneous lupus.

Plasmacytoid dendritic cells (pDCs) not only are specialized in their capacity to secrete large amounts of type I interferon (IFN) but also serve to enable both innate and adaptive immune responses through expression of additional proinflammatory cytokines, chemokines, and costimulatory molecules. Persistent activation of pDCs has been demonstrated in a number of autoimmune diseases. To evaluate the potential benefit of depleting pDCs in autoimmunity, a monoclonal antibody targeting the pDC-specific marker immunoglobulin-like transcript 7 was generated. This antibody, known as VIB7734, which was engineered for enhanced effector function, mediated rapid and potent depletion of pDCs through antibody-dependent cellular cytotoxicity. In cynomolgus monkeys, treatment with VIB7734 reduced pDCs in blood below the lower limit of normal by day 1 after the first dose. In two phase 1 studies in patients with autoimmune diseases, VIB7734 demonstrated an acceptable safety profile, comparable to that of placebo. In individuals with cutaneous lupus, VIB7734 profoundly reduced both circulating and tissue-resident pDCs, with a 97.6% median reduction in skin pDCs at study day 85 in VIB7734-treated participants. Reductions in pDCs in the skin correlated with a decrease in local type I IFN activity as well as improvements in clinical disease activity. Biomarker analysis suggests that responsiveness to pDC depletion therapy may be greater among individuals with high baseline type I IFN activity, supporting a central role for pDCs in type I IFN production in autoimmunity and further development of VIB7734 in IFN-associated diseases.

Disability Outcomes in the N-MOmentum Trial of Inebilizumab in Neuromyelitis Optica Spectrum Disorder.

OBJECTIVE: To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD). METHODS: Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach. RESULTS: Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023). CONCLUSIONS: Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.

Reproducibility of high-resolution optical coherence tomography in multiple sclerosis.

Optical coherence tomography (OCT) is a non-invasive method to quantify neurodegeneration as an outcome in multiple sclerosis clinical trials; however, no data exist on Cirrus spectral domain optical coherence tomography (SD-OCT) reproducibility in patients with multiple sclerosis. The objective of this study was to determine the protocol for achieving optimal inter-visit, inter-rater, and intra-rater reproducibility for studies performed on healthy controls and multiple sclerosis patients utilizing novel high-definition SD-OCT. This is a prospective study of inter-visit, inter-rater, and intra-rater reproducibility in multiple sclerosis patients (n = 58) and healthy controls (n = 32) on Cirrus-HD SD-OCT. Excellent reproducibility of average and quadrantic retinal nerve fiber layer (RNFL) thickness values, average macular thickness (AMT), and total macular volume (TMV) [measured by intraclass correlation coefficient (ICC)] was found for inter-visit (healthy controls: mean RNFL = 0.97, quadrant range = 0.92-0.97, AMT = 0.97, TMV = 0.92), inter-rater (MS: mean RNFL = 0.97, quadrant = 0.94-0.98, AMT = 0.99, TMV = 0.96; healthy controls: mean RNFL = 0.97, quadrant = 0.94-0.97, AMT = 0.98, TMV = 0.99), and intra-rater (MS patients: mean RNFL = 0.99, quadrant = 0.83-0.99, AMT = 0.97, TMV = 0.98) reproducibility. The reproducibility of retinal measures derived by Cirrus HD-OCT, especially quadrantic values, is excellent. Specific procedures for OCT acquisition and analysis of retinal imaging metrics using SD-OCT technology may improve the application of this novel technology in multiple sclerosis.

Neuromyelitis optica spectrum disorder: Patient experience and quality of life.

Objective: To gain insights into NMOSD disease impact, which may negatively affect QoL of patients, their families, and social network. Methods: The current study used validated instruments to assess physical, emotional, and socioeconomic burden of NMOSD on QoL among 193 patients. Results: A majority of patients reported an initial diagnosis of a disease other than NMOSD. Overall, two-thirds of patients reported NMOSD as having a strong negative impact on physical health (Short Form-36 [SF-36] score 27.1 ± 39.1), whereas emotional well-being was relatively unimpaired on average (SF-36 score 54.0 ± 44.9). A subset of patients reported having the highest category of emotional health despite worse physical health or financial burden, suggesting psychological resilience. Pain (r = 0.61) and bowel/bladder dysfunction (r = 0.41) imposed the greatest negative physical impact on overall QoL. In turn, ability to work correlated inversely with worsened health (r = -0.68). Increased pain, reduced sexual function, inability to work, and reduced QoL had greatest negative impacts on emotional well-being. Dissatisfaction with treatment options and economic burden correlated inversely with QoL. Conclusions: Collectively, the current findings advance the understanding of physical, emotional, social, and financial tolls imposed by NMOSD. These insights offer potential ways to enhance QoL by managing pain, enhancing family and social networks, and facilitating active employment.

Retinal measurements predict 10-year disability in multiple sclerosis.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later. Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing (n = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status. Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm3 loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39; P = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; P trend = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models. Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status.

Patient perspectives on neuromyelitis optica spectrum disorders: Data from the PatientsLikeMe online community.

BACKGROUND: Few studies have evaluated patient perspectives on neuromyelitis optica (NMO) and NMO spectrum disorder (NMOSD). OBJECTIVE: Describe patient-reported clinical and treatment experience in NMOSD and compare disease characteristics of NMOSD with those of multiple sclerosis (MS). METHODS: This retrospective, observational study included 522 members with NMO or NMOSD (hereafter collectively referred to as NMOSD) from PatientsLikeMe (PLM), an online patient community. Data describing member demographics, symptoms, and treatments were collected, analysed descriptively, and compared with data from PLM members with MS. RESULTS: Fatigue, pain, and stiffness/spasticity were each rated as moderate to severe by more than half of NMOSD members, and 59% reported that their health limited the type of work or other activities they could perform all or most of the time. Overall, symptom severity and disability levels were comparable between NMOSD and MS members; however, NMOSD members were more likely than MS members to attribute disability to vision-related symptoms and were less likely to report moderate to severe cognitive and emotional symptoms, including brain fog, depressed or anxious mood, and emotional lability. CONCLUSION: This analysis underscores the challenges of living with fatigue, pain, stiffness/spasticity, and visual difficulties, prevalent NMOSD symptoms among members of the PLM community.

Giant cell arteritis mimicking infiltrative leptomeningeal disease of the optic nerves.

A 67-year-old man presented with several days of progressive, painless left eye vision loss. He reported mild jaw claudication but denied headache, scalp tenderness or constitutional symptoms. Examination revealed palpable temporal arteries, blurring of the left optic disc, and 20/100 vision in the left eye with mild relative afferent pupillary defect. Inflammatory markers were sent, and methylprednisolone was initiated for presumptive giant cell arteritis (GCA). Erythrocyte sedimentation rate was normal, however, and C reactive protein was only mildly elevated, prompting further investigation. Orbital MRI revealed nodular enhancement of the optic nerve sheaths bilaterally from optic nerve head to chiasm, raising concern for an infiltrative leptomeningeal process such as sarcoidosis or lymphoma. Methylprednisolone was temporarily stopped while a broad work up for inflammatory and neoplastic causes was pursued. Fluorodeoxyglucose-positron emission tomography ultimately revealed hypermetabolism in the temporal, ophthalmic and occipital arteries suggesting GCA, which was confirmed by temporal artery biopsy. Steroids were restarted, and the patient's vision stabilised.

Multiple sclerosis symptom recrudescence at the end of the natalizumab dosing cycle.

BACKGROUND: This study was undertaken to determine how frequently patients receiving natalizumab for multiple sclerosis (MS) experience recrudescence of their MS symptoms at the end of the dosing cycle. METHODS: One hundred consecutive MS patients receiving natalizumab completed a survey evaluating changes in symptoms during the natalizumab dosing cycle. Ninety-one patients also completed questionnaires at two time points: the first week after natalizumab infusion and the last week of the dosing cycle. These included the Multiple Sclerosis Quality of Life-54 (MSQOL-54), Fatigue Visual Analog Scale (VAS), Fatigue Severity Scale (FSS), and Beck Depression Inventory-II (BDI-II). RESULTS: End of dosing interval (EDI) symptoms were reported as currently being experienced by 57% of respondents. An additional 10% reported that they previously experienced that phenomenon, but not currently, and 33% reported never experiencing this. In those with EDI symptoms, they began to occur a median of 21 days after infusion and improved again a median of 1 day after infusion. The most common symptoms reported were fatigue, weakness, walking impairment, and cognitive difficulties. No specific demographic or disease characteristics were associated with this phenomenon. In the subgroup with EDI symptoms, the MSQOL-54, Fatigue VAS, FSS, and BDI-II scores were all significantly worse in the last week of the dosing cycle when compared with the first week. No difference was seen in these scores between first and last week in the subgroup not experiencing symptom recrudescence. CONCLUSIONS: Recrudescence of fatigue, weakness, walking impairment, or cognitive difficulties at the end of the dosing cycle occurs in about two-thirds of MS patients receiving natalizumab.

Tract-specific quantitative MRI better correlates with disability than conventional MRI in multiple sclerosis.

Although diffusion tensor imaging (DTI) and the magnetization transfer ratio (MTR) have been extensively studied in multiple sclerosis (MS), it is still unclear if they are more effective biomarkers of disability than conventional MRI. MRI scans were performed on 117 participants with MS in addition to 26 healthy volunteers. Mean values were obtained for DTI indices and MTR for supratentorial brain and three white matter tracts of interest. DTI and MTR values were tested for correlations with measures of atrophy and lesion volume and were compared with these more conventional indices for prediction of disability. All DTI and MTR values correlated to an equivalent degree with lesion volume and cerebral volume fraction (CVF). Thalamic volumes correlated with all indices in the optic radiations and with mean and perpendicular diffusivity in the corpus callosum. Nested model regression analysis demonstrated that, compared with CVF, DTI indices in the optic radiations were more strongly correlated with Expanded Disability Status Scale and were also more strongly correlated than both CVF and lesion volume with low-contrast visual acuity. Abnormalities in DTI and MTR are equivalently linked with brain atrophy and inflammatory lesion burden, suggesting that for practical purposes they are markers of multiple aspects of MS pathology. Our findings that some DTI and MTR indices are more strongly linked with disability than conventional MRI measures justifies their potential use as targeted, functional system-specific clinical trial outcomes in MS.