Rituximab add-on therapy for breakthrough relapsing multiple sclerosis: a 52-week phase II trial.

OBJECTIVE: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). METHODS: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m(2) weekly x 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. RESULTS: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline (p < 0.0001). Median GdE lesions were reduced from 1.0 to 0, and mean number was reduced from 2.81 per month to 0.33 after treatment (88% reduction). MSFC improved as well (p = 0.02). EDSS remained stable. CONCLUSION: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell-modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis.

Increased diffusivity in acute multiple sclerosis lesions predicts risk of black hole.

OBJECTIVE: Diffusion tensor imaging (DTI) quantifies Brownian motion of water within tissue. Inflammation leads to tissue injury, resulting in increased diffusivity and decreased directionality. We hypothesize that DTI can quantify the damage within acute multiple sclerosis (MS) white matter lesions to predict gadolinium (Gd)-enhancing lesions that will persist 12 months later as T1 hypointensities. METHODS: A cohort of 22 individuals underwent 7 brain MRI scans over 15 months. DTI parameters were temporally quantified within regions of Gd enhancement. Comparison to the homologous region in the hemisphere contralateral to the Gd-enhancing lesion was also performed to standardize individual lesion DTI parameters. RESULTS: After classifying each Gd-enhancing region as to black hole outcome, radial diffusivity, mean diffusivity, and fractional anisotropy, along with their standardized values, were significantly altered for persistent black holes (PBHs), and remained elevated throughout the study. A Gd-enhancing region with a 40% elevation in radial diffusivity had a 5.4-fold (95% confidence interval [CI]: 2.1, 13.8) increased risk of becoming a PBH, with 70% (95% CI: 51%, 85%) sensitivity and 69% (95% CI: 57%, 80%) specificity. A model of radial diffusivity, with volume and length of Gd enhancement, was associated with a risk of becoming a PBH of 5.0 (95% CI: 2.6, 9.9). Altered DTI parameters displayed a dose relationship to duration of black hole persistence. CONCLUSIONS: Elevated radial diffusivity during gadolinium enhancement was associated with increased risk for development of a persistent black hole, a surrogate of severe demyelination and axonal injury. An elevated radial diffusivity within active multiple sclerosis lesions may be indicative of more severe tissue injury.

Radial diffusivity in remote optic neuritis discriminates visual outcomes.

OBJECTIVE: Diffusion tensor imaging (DTI) quantifies Brownian motion of water within tissue. The goal of this study was to test whether, following a remote episode of optic neuritis (ON), breakdown of myelin and axons within the optic nerve could be detected by alterations in DTI parameters, and whether these alterations would correlate with visual loss. METHODS: Seventy subjects with a history of ON > or =6 months prior underwent DTI of the optic nerves, assessment of visual acuities (VA) and contrast sensitivities (CS), and laboratory measures of visual evoked potentials (VEP) and optical coherence tomography (OCT). RESULTS: Radial diffusivity (RD) correlated with visual acuity (r = -0.61), Pelli-Robson CS (r = -0.60), 5%CS (r = 0.61), OCT (r = -0.78), VEP latency (r = 0.61), and VEP amplitude (r = -0.46). RD differentiated the unaffected fellow nerves from affected nerves in all visual outcome categories. RD also discriminated nerves with recovery to normal from mild visual impairment, and those with mild impairment from profound visual loss. RD differentiated healthy controls from both clinically affected nerves and unaffected fellow nerves after ON. RD differentiated all categories of 5%CS outcomes, and all categories of Pelli-Robson CS with the exception of normal recovery from mildly affected. CONCLUSIONS: Increased optic nerve radial diffusivity (RD) detected by diffusion tensor imaging (DTI) was associated with a proportional decline in vision after optic neuritis. RD can differentiate healthy control nerves from both affected and unaffected fellow nerves. RD can discriminate among categories of visual recovery within affected eyes. Optic nerve injury as assessed by DTI was corroborated by both optical coherence tomography and visual evoked potentials.

Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis.

OBJECTIVES: Determine the utility of optical coherence tomography (OCT) to detect clinical and subclinical remote optic neuritis (ON), its relationship to clinical characteristics of ON and visual function, and whether the retinal nerve fiber layer (RNFL) thickness functions as a surrogate marker of global disease severity. METHODS: Cross-sectional study of 65 subjects with at least 1 clinical ON episode at least 6 months prior. Measures included clinical characteristics, visual acuity (VA), contrast sensitivity (CS), OCT, and visual evoked potentials (VEP). RESULTS: Ninety-six clinically affected optic nerves were studied. The sensitivity of OCT RNFL after ON was 60%, decreasing further with mild onset and good recovery. VEP sensitivity was superior at 81% (p = 0.002). Subclinical ON in the unaffected eye was present in 32%. VEP identified 75% of all subclinically affected eyes, and OCT identified <20%. RNFL thickness demonstrated linear correlations with VA (r = 0.65) and CS (r = 0.72) but was unable to distinguish visual categories <20/50. RNFL was thinner with severe onset and disease recurrence but was unaffected by IV glucocorticoids. OCT measurements were not related to overall disability, ethnicity, sex, or age at onset. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye. CONCLUSIONS: Visual evoked potentials (VEP) remains the preferred test for detecting clinical and subclinical optic neuritis. Optical coherence tomography (OCT) measures were unrelated to disability and demographic features predicting a worse prognosis in multiple sclerosis. OCT may provide complementary information to VEP in select cases, and remains a valuable research tool for studying optic nerve disease in populations.

Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis.

BACKGROUND: Neuromyelitis optica (NMO) is associated with destructive inflammatory lesions, resulting in necrosis and axonal injury. Disability from multiple sclerosis (MS) is due to a combination of demyelination and varying axonal involvement. Optical coherence tomography (OCT), by measuring retinal nerve fiber layer (RNFL) as a surrogate of axonal injury, has potential to discriminate between these two conditions. METHODS: Included were 22 subjects with NMO or NMO spectrum disorders and 47 with MS. Seventeen subjects with NMO and all with MS had a remote history of optic neuritis (ON) in at least one eye, at least 6 months before OCT. Linear mixed modeling was used to compare the two diagnoses for a given level of vision loss, while controlling for age, disease duration, and number of episodes of ON. RESULTS: After ON, NMO was associated with a thinner mean RNFL compared to MS. This was found when controlling for visual acuity (56.7 vs 66.6 microm, p = 0.01) or for contrast sensitivity (61.2 vs 70.3 microm, p = 0.02). The superior and inferior quadrants were more severely affected in NMO than MS. CONCLUSIONS: Optic neuritis (ON) within neuromyelitis optica (NMO) is associated with a thinner overall average retinal nerve fiber layer compared to multiple sclerosis, with particular involvement of the superior and inferior quadrants. This suggests that NMO is associated with more widespread axonal injury in the affected optic nerves. Optical coherence tomography can help distinguish the etiology of these two causes of ON, and may be useful as a surrogate marker of axonal involvement in demyelinating disease.

Disability in optic neuritis correlates with diffusion tensor-derived directional diffusivities.

OBJECTIVE: To determine the potential of directional diffusivities from diffusion tensor imaging (DTI) to predict clinical outcome of optic neuritis (ON), and correlate with vision, optical coherence tomography (OCT), and visual evoked potentials (VEP). METHODS: Twelve cases of acute and isolated ON were imaged within 30 days of onset and followed prospectively. Twenty-eight subjects with a remote clinical history of ON were studied cross-sectionally. Twelve healthy controls were imaged for comparison. DTI data were acquired at 3T with a surface coil and 1.3 x 1.3 x 1.3 mm(3) isotropic voxels. RESULTS: Normal DTI parameters (mean +/- SD, microm(2)/ms) were axial diffusivity = 1.66 +/- 0.18, radial diffusivity = 0.81 +/- 0.26, apparent diffusion coefficient (ADC) = 1.09 +/- 0.21, and fractional anisotropy (FA) = 0.43 +/- 0.15. Axial diffusivity decreased up to 2.5 SD in acute ON. The decrease in axial diffusivity at onset correlated with visual contrast sensitivity 1 month (r = 0.59) and 3 months later (r = 0.65). In three subjects followed from the acute through the remote stage, radial diffusivity subsequently increased to > 2.5 SD above normal, as did axial diffusivity and ADC. In remote ON, radial diffusivity correlated with OCT (r = 0.81), contrast sensitivity (r = 0.68), visual acuity (r = 0.56), and VEP (r = 0.54). CONCLUSION: In acute and isolated demyelination, axial diffusivity merits further investigation as a predictor of future clinical outcome. Diffusion parameters are dynamic in acute and isolated optic neuritis, with an initial acute decrease in axial diffusivity. In remote disease, radial diffusivity correlates with functional, structural, and physiologic tests of vision.