Dimethyl fumarate selectively reduces memory T cells in multiple sclerosis patients.

BACKGROUND: Dimethyl fumarate (DMF) alters the phenotype of circulating immune cells and causes lymphopenia in a subpopulation of treated multiple sclerosis (MS) patients. OBJECTIVE: To phenotypically characterize circulating leukocytes in DMF-treated MS patients. METHODS: Cross-sectional observational comparisons of peripheral blood from DMF-treated MS patients (n = 17 lymphopenic and n = 24 non-lymphopenic), untreated MS patients (n = 17) and healthy controls (n = 23); immunophenotyped using flow cytometry. Longitudinal samples were analyzed for 13 DMF-treated patients. RESULTS: Lymphopenic DMF-treated patients had significantly fewer circulating CD8(+) and CD4(+) T cells, CD56(dim) natural killer (NK) cells, CD19(+) B cells and plasmacytoid dendritic cells when compared to controls. CXCR3(+) and CCR6(+) expression was disproportionately reduced among CD4(+) T cells, while the proportion of T-regulatory (T-reg) cells was unchanged. DMF did not affect circulating CD56(hi) NKcells, monocytes or myeloid dendritic cells. Whether lymphopenic or not, DMF-treated patients had a lower proportion of circulating central and effector memory T cells and concomitant expansion of naïve T cells compared to the controls. CONCLUSIONS: DMF shifts the immunophenotypes of circulating T cells, causing a reduction of memory cells and a relative expansion of naïve cells, regardless of the absolute lymphocyte count. This may represent one mechanism of action of the drug. Lymphopenic patients had a disproportionate loss of CD8(+) T-cells, which may affect their immunocompetence.

Established and novel disease-modifying treatments in multiple sclerosis.

Multiple sclerosis (MS) is a presumed autoimmune disorder of the central nervous system, resulting in inflammatory demyelination and axonal and neuronal injury. New diagnostic criteria that incorporate magnetic resonance imaging have resulted in earlier and more accurate diagnosis of MS. Several immunomodulatory and immunosuppressive therapeutic agents are available for relapsing forms of MS, which allow individualized treatment based upon the benefits and risks. Disease-modifying therapies introduced in the 1990s, the beta-interferons and glatiramer acetate, have an established track record of efficacy and safety, although they require administration via injection. More recently, monoclonal antibodies have been engineered to act through specific mechanisms such as blocking alpha-4 integrin interactions (natalizumab) or lysing cells bearing specific markers, for example CD52 (alemtuzumab) or CD20 (ocrelizumab and ofatumumab). These agents can be highly efficacious, but sometimes have serious potential complications (natalizumab is associated with progressive multifocal leukoencephalopathy; alemtuzumab is associated with the development of new autoimmune disorders). Three new oral therapies (fingolimod, teriflunomide and dimethyl fumarate, approved for MS treatment from 2010 onwards) provide efficacy, tolerability and convenience; however, as yet, there are no long-term postmarketing efficacy and safety data in a general MS population. Because of this lack of long-term data, in some cases, therapy is currently initiated with the older, safer injectable medications, but patients are monitored closely with the plan to switch therapies if there is any indication of a suboptimal response or intolerance or lack of adherence to the initial therapy. For patients with MS who present with highly inflammatory and potentially aggressive disease, the benefit-to-risk ratio may support initiating therapy using a drug with greater potential efficacy despite greater risks (e.g. fingolimod or natalizumab if JC virus antibody-negative). The aim of this review is to discuss the clinical benefits, mechanisms of action, safety profiles and monitoring strategies of current MS disease-modifying therapies in clinical practice and of those expected to enter the market in the near future.

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.

Multiple sclerosis susceptibility alleles in African Americans.

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by complex genetics and multifaceted gene-environment interactions. Compared to whites, African Americans have a lower risk for developing MS, but African Americans with MS have a greater risk of disability. These differences between African Americans and whites may represent differences in genetic susceptibility and/or environmental factors. SNPs from 12 candidate genes have recently been identified and validated with MS risk in white populations. We performed a replication study using 918 cases and 656 unrelated controls to test whether these candidate genes are also associated with MS risk in African Americans. CD6, CLEC16a, EVI5, GPC5, and TYK2 contained SNPs that are associated with MS risk in the African American data set. EVI5 showed the strongest association outside the major histocompatibility complex (rs10735781, OR=1.233, 95% CI=1.06-1.43, P-value=0.006). In addition, RGS1 seems to affect age of onset whereas TNFRSF1A seems to be associated with disease progression. None of the tested variants showed results that were statistically inconsistent with the effects established in whites. The results are consistent with shared disease genetic mechanisms among individuals of European and African ancestry.

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.

Phenotype and prognosis in African-Americans with multiple sclerosis: a retrospective chart review.

CONTEXT: There is an emerging body of literature regarding multiple sclerosis (MS) in African-Americans (AA) that suggests more rapid progression and a worse prognosis in this group. A phenotype of opticospinal MS has been proposed by some publications. OBJECTIVE: To determine whether AA with MS have a different clinical phenotype, different distribution of clinical subtypes, and/or different levels of disability than Caucasians (CA) with MS. Specifically, is the disability attributable to severe cerebellar disease, which limits ambulation and function? DESIGN: Retrospective chart analyses of a patient cohort from an academic MS center. PATIENTS: A total of 86 AA were identified with MS, 79 were followed for > or = 5 years. The control group consisted of 80 randomly-selected CA with MS and similar follow-up. OUTCOME MEASURES: EDSS at diagnosis, five-year follow-up, and last follow-up; time to walking assistance device; disease subtype; involved functional systems. RESULTS: AA MS patients displayed more cerebellar dysfunction, and worse EDSS scores at diagnosis, at four to six years follow-up from diagnosis, and at last follow-up compared to the CA MS patients with similar length of follow-up. AA MS patients had earlier and more frequent gait difficulty requiring use of a cane or wheelchair. AA MS patients had a higher prevalence of primary progressive (PP) MS (22 versus 9%) and a lower rate of relapsing-remitting (RR) MS (30 versus 52%) compared to CA. CONCLUSIONS: Compared to CA patients, MS in AA is characterized by a higher incidence of cerebellar dysfunction and a more rapid accumulation of disabilities. In this cohort, AA patients had a relatively higher rate of the PPMS subtype. These data suggest the presence of fundamental differences in the clinical phenotype and the natural history of MS in AA.

Oligoclonal band number as a marker for prognosis in multiple sclerosis.

The natural course of disease in multiple sclerosis varies. Multiple sclerosis that is clinically apparent but causes minimal disability over time has been labeled benign multiple sclerosis. The ability to predict the subsequent clinical course of multiple sclerosis on the basis of clinical and other supportive data at presentation would be invaluable. In this article we report our findings based on a retrospective analysis of 1800 patients diagnosed as having multiple sclerosis, of which 44 patients met our inclusion criteria. There was a suggestion that a low or absent number of oligoclonal bands in the cerebrospinal fluid at the time of diagnosis predicts a better prognosis. However, quantification of oligoclonal bands in cerebrospinal fluid remains an insensitive prognostic indicator and must not be used to influence decisions regarding therapeutic options.

Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency.

Two adult brothers, one documented to have methylmalonic acidemia with homocystinuria, or cobalamin C deficiency, after autopsy, displayed severe but divergent neurological presentations. One exhibited a myelopathy and the other chronic endocrine problems (Schmidt's syndrome) followed by a neuropsychiatric and dementing disorder owing to cerebral perivascular demyelination. The recognition of cobalamin C deficiency has practical implications because it is one of the few inherited diseases of central white matter that is treatable.

B cells and antibodies in CNS demyelinating disease.

There is much evidence to implicate B cells, plasma cells, and their products in the pathogenesis of MS. Despite unequivocal evidence that the animal model for MS, EAE, is initiated by myelin-specific T cells, there is accumulating evidence of a role for B cells, plasma cells, and their products in EAE pathogenesis. The role(s) played by B cells, plasma cells, and antibodies in CNS inflammatory demyelinating diseases are likely to be multifactorial and complex, involving distinct and perhaps opposing roles for B cells versus antibody.

Astrocytes and central nervous system endothelial cells do not express B7-1 (CD80) or B7-2 (CD86) immunoreactivity during experimental autoimmune encephalomyelitis.

The identity of cell types within the central nervous system (CNS) capable of activating T lymphocytes is a fundamental issue in the understanding of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). To become fully activated, a T cell must recognize its antigen and receive co-stimulation, the latter being optimally delivered via B7-1 and/or B7-2 molecules expressed by the antigen presenting cell (APC). There are conflicting reports regarding whether astrocytes or CNS endothelial cells (EC) can act as fully competent APCs. The present studies were performed to determine whether astrocytes or CNS EC express B7-1 or B7-2 immunoreactivity during EAE. No expression of B7-1 or B7-2 by either astrocytes or EC was detected during acute, remitting, relapsing or chronic EAE, whether EAE was induced by active immunization or cell transfer using five different myelin antigens. These results suggest that neither astrocytes nor CNS EC can deliver co-stimulatory signals via B7 molecules in the setting of murine EAE, rendering them incapable of acting as fully competent APCs.

Acute aphasia in multiple sclerosis.

Acute aphasia is rare in multiple sclerosis. We describe 3 patients with multiple sclerosis who had acute exacerbations presenting as aphasias. One patient had a mixed transcortical aphasia, 1 had a transcortical motor aphasia, and 1 had a Broca aphasia. Magnetic resonance imaging scans of the brain with contrast enhancement revealed new white matter lesions in the left hemisphere in all 3 patients. Two of the 3 patients had a good response to treatment with methylprednisolone sodium succinate. Arch Neurol. 2000;57:1207-1209

A catalyst of peroxynitrite decomposition inhibits murine experimental autoimmune encephalomyelitis.

Peroxynitrite (PN), the product of nitric oxide (NO) reacted with superoxide, is generated at sites of inflammation. Nitrotyrosine (NT), a marker of PN formation, is abundant in lesions of acute experimental autoimmune encephalomyelitis (EAE), and in active multiple sclerosis (MS) plaques. To determine whether PN plays a role in EAE pathogenesis, mice induced to develop EAE were treated with a catalyst specific for the decomposition of PN. Because this catalyst has no effect upon NO, using it allowed differentiation of PN-mediated effects from NO-mediated effects. Mice receiving the PN decomposition catalyst displayed less severe clinical disease, and less inflammation and demyelination than control mice. Encephalitogenic T cells could be recovered from catalyst-treated mice, indicating that the PN decomposition catalyst blocked the pathogenic action of PN at the effector stage of EAE, but was not directly toxic to encephalitogenic T cells. PN plays an important role distinct from that of NO in the pathogenesis of EAE, a major model for MS.