Lymphopenia and DMTs for relapsing forms of MS: Considerations for the treating neurologist.

PURPOSE OF REVIEW: To provide neurologists with an update on the proposed mechanisms of action (MOAs) of disease-modifying therapies (DMTs) for the treatment of relapsing MS, and their effect on peripheral blood leukocytes, in order to inform treatment decisions. RECENT FINDINGS: DMTs have vastly differing MOAs, including effects on peripheral blood leukocyte counts, particularly lymphocytes. The clinical implications of changes in lymphocyte counts need to be understood in the context of the underlying MOAs of each respective DMT, with treatment tailored to individual patient needs. SUMMARY: DMTs can alter lymphocyte counts, subsets, activation, and distribution, and thus can influence immune surveillance. Serial monitoring of total leukocytes and absolute lymphocyte counts (ALCs) is advisable in patients receiving DMTs. ALCs should be interpreted regarding expected immunologic changes and individual patient characteristics. Any decision to switch DMTs should consider these factors, along with drug efficacy, safety, and effect on quality of life.

Characterizing Clinical and MRI Dissociation in Patients with Multiple Sclerosis.

BACKGROUND AND PURPOSE: Two common approaches for measuring disease severity in multiple sclerosis (MS) are the clinical exam and brain magnetic resonance imaging (MRI) scan. Although most patients show similar disease severity on both measures, some patients have clinical/MRI dissociation. METHODS: Subjects from a comprehensive care MS center who had a concurrent brain MRI, spinal cord MRI, clinical examination, and patient reported outcomes were classified into three groups based on the Expanded Disability Status Scale (EDSS) and cerebral T2 hyperintense lesion volume (T2LV). The first group was the low lesion load/high disability group (LL/HD) with T2LV < 2 ml and EDSS ≥ 3. The second group was the high lesion load/low disability group (HL/LD) with T2LV > 6 ml and EDSS ≤ 1.5. All remaining subjects were classified as not dissociated. The three groups were compared using regression techniques for unadjusted analyses and to adjust for age, disease duration, and gender. RESULTS: Twenty-two subjects were classified as LL/HD (4.1%; 95% CI: 2.6%, 6.2%), and 50 subjects were classified as HL/LD (9.4%; 95% CI: 7.0%, 12.2%). Subjects in the LL/HD group were more likely to have a progressive form of MS and had significantly lower physical quality of life in adjusted and unadjusted analysis. Subjects in HL/LD had significantly more gadolinium-enhancing lesions, and subjects in the LL/HD group had significantly more cervical spinal cord lesions. CONCLUSIONS: Our results indicate that dissociation may occur between physical disability and cerebral lesion volume in either direction in patients with MS. Type of MS, brain atrophy, and spinal cord lesions may help to bridge this dissociation.

An observational comparison of natalizumab vs. fingolimod using JCV serology to determine therapy.

BACKGROUND: The lack of prospective trial data comparing certain multiple sclerosis (MS) therapies could be addressed with observational research. OBJECTIVE: The objective of this paper is to investigate outcomes of natalizumab versus fingolimod treatment in an MS cohort using a novel method of patient selection. METHODS: We reviewed entries from our clinic's database for all relapsing-remitting MS patients started on fingolimod and natalizumab where JCV serology was used to determine treatment. We analyzed each group for time to first relapse and in a second analysis, time to first relapse or gadolinium-enhancing lesion. RESULTS: Sixty-nine patients on natalizumab and 36 on fingolimod met our inclusion criteria and had adequate follow-up for analysis. The baseline clinical characteristics at the time of treatment switch were similar. With a mean follow-up of 1.5 years for both treatment groups, there was a trend favoring natalizumab in time to first relapse, although this was not statistically significant (2.20 (0.87, 5.55) p = 0.095). There was a significant difference in the secondary outcome, time to relapse or gadolinium-enhancing lesion (2.31 (1.03, 5.17) p = 0.041), favoring natalizumab. Adjusted analyses favored natalizumab for both outcomes (p < 0.05). CONCLUSION: This work employed an observational study design where treatment allocation by JCV serology allowed for treatment groups with well-balanced characteristics.

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis.

OBJECTIVE: To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). METHODS: We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy >18 months, 6 on interferon ß-1a monotherapy >36 months, and 5 untreated controls. We performed quantitative real-time polymerase chain reaction in cerebrospinal fluid (CSF), blood, and urine for JCV DNA, and we determined JCV-specific T-cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. RESULTS: JCV DNA was detected in the CSF of 2 of 27 (7.4%) natalizumab-treated MS patients who had no symptoms or magnetic resonance imaging-detected lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12 of 43 (27.9%) and in urine of 11 of 43 (25.6%) subjects without a difference between natalizumab-treated patients and controls. JC viral load was higher in CD34(+) cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot. JCV-specific T-cell responses, mediated by both CD4(+) and CD8(+) T lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4(+) T cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34(+) (p = 0.05) and B cells (p = 0.03). INTERPRETATION: Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34(+) cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4(+) T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

An RNA profile identifies two subsets of multiple sclerosis patients differing in disease activity.

The multiple sclerosis (MS) patient population is highly heterogeneous in terms of disease course and treatment response. We used a transcriptional profile generated from peripheral blood mononuclear cells to define the structure of an MS patient population. Two subsets of MS subjects (MS(A) and MS(B)) were found among 141 untreated subjects. We replicated this structure in two additional groups of MS subjects treated with one of the two first-line disease-modifying treatments in MS: glatiramer acetate (GA) (n = 94) and interferon-ß (IFN-ß) (n = 128). One of the two subsets of subjects (MS(A)) was distinguished by higher expression of molecules involved in lymphocyte signaling pathways. Further, subjects in this MS(A) subset were more likely to have a new inflammatory event while on treatment with either GA or IFN-ß (P = 0.0077). We thus report a transcriptional signature that differentiates subjects with MS into two classes with different levels of disease activity.

Magnetic resonance disease severity scale (MRDSS) for patients with multiple sclerosis: a longitudinal study.

BACKGROUND: We previously described a composite MRI scale combining T1-lesions, T2-lesions and whole brain atrophy in multiple sclerosis (MS): the magnetic resonance disease severity scale (MRDSS). OBJECTIVE: Test strength of the MRDSS vs. individual MRI measures for sensitivity to longitudinal change. METHODS: We studied 84 MS patients over a 3.2±0.3 year follow-up. Baseline and follow-up T2-lesion volume (T2LV), T1-hypointense lesion volume (T1LV), and brain parenchymal fraction (BPF) were measured. MRDSS was the combination of standardized T2LV, T1/T2 ratio and BPF. RESULTS: Patients had higher MRDSS at follow-up vs. baseline (p<0.001). BPF decreased (p<0.001), T1/T2 increased (p<0.001), and T2LV was unchanged (p>0.5). Change in MRDSS was larger than the change in MRI subcomponents. While MRDSS showed significant change in relapsing-remitting (RR) (p<0.001) and secondary progressive (SP) phenotypes (p<0.05), BPF and T1/T2 ratio changed only in RRMS (p<0.001). Longitudinal change in MRDSS was significantly different between RRMS and SPMS (p=0.0027); however, change in the individual MRI components did not differ. Evaluation with respect to predicting on-study clinical worsening as measured by EDSS revealed a significant association only for T2LV (p=0.038). CONCLUSION: Results suggest improved sensitivity of MRDSS to longitudinal change vs. individual MRI measures. MRDSS has particularly high sensitivity in RRMS.

The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis.

OBJECTIVE: To determine the interrelationships between MRI-defined lesion and atrophy measures of spinal cord involvement and brain involvement and their relationships to disability in a small cohort of patients with multiple sclerosis (MS). BACKGROUND: Although it is known that cervical spinal cord atrophy correlates with disability in MS, it is unknown whether it is the most important determinant when compared to other regions of the central nervous system (CNS). Furthermore, it is not clear to what extent brain and cord lesions and atrophy are related. DESIGN AND METHODS: 3T MRI of the whole brain and whole spinal cord was obtained in 21 patients with MS, including 18 with relapsing-remitting, one with secondary progressive, one with primary progressive, and one with a clinically isolated syndrome. Brain global gray and white matter volumes were segmented with Statistical Parametric Mapping 8. Spinal cord contour volume was segmented in whole by a semi-automated method with bins assigned to either the cervical or thoracic regions. All CNS volumes were normalized by the intracranial volume. Brain and cord T2 hyperintense lesions were segmented using a semi-automated edge finding tool. RESULTS: Among all MRI measures, only upper cervical spinal cord volume significantly correlated with Expanded Disability Status Scale score (r =-.515, P = .020). The brain cord relationships between whole or regional spinal cord volume or lesions and gray matter, white matter, or whole brain volume or whole brain lesions were generally weak and all nonsignificant. CONCLUSIONS AND RELEVANCE: In this preliminary study of mildly disabled, treated MS patients, cervical spinal cord atrophy most strongly correlates with physical disability in MS when accounting for a wide range of other CNS measures of lesions and atrophy, including thoracic or whole spinal cord volume, and cerebral gray, white or whole brain volume. The weak relationship between spinal cord and brain lesions and atrophy may suggest that they progress rather independently in patients with MS.

Brain MRI lesion load at 1.5T and 3T versus clinical status in multiple sclerosis.

BACKGROUND/PURPOSE: To assess correlation between brain lesions and clinical status with 1.5T and 3T magnetic resonance imaging (MRI). METHODS: Brain MRI fluid-attenuated inversion-recovery (FLAIR) sequences were performed in 32 multiple sclerosis (MS) patients. Expanded Disability Status Scale (EDSS) score (mean±standard deviation) was 2±2.0 (range 0-8), disease duration 9.3±8.0 (range .8-29) years. RESULTS: FLAIR lesion volume (FLLV) at 3T was higher than at 1.5T (P=.01). Correlation between 1.5T FLLV and EDSS score was poor, while 3T FLLV correlated moderately and significantly (rs=.39, P=.03). When controlling for age and depression, correlations between FLLV and cognitive measures were significant at 1.5T for the Judgment of Line Orientation test (JLO) (rs=-.44, P=.05), the Symbol Digit Modalities Test (SDMT) (rs=-.49, P=.02), and the California Verbal Learning Test Delayed Free Recall (CVLT DR) (rs=-.44, P=.04). Correlations at 3T were also significant for these tests, but of greater magnitude: JLO (rs=-.70, P=.0005), SDMT (rs=-.73, P=.0001), CVLT DR (rs=-.061, P=.003). Additional significant correlations obtained only at 3T included the 2 second-paced auditory serial addition test (rs=-.55, P=.01), the Brief Visuospatial Memory Test-Delayed Free Recall (rs=-.56, P=.007), and the California Verbal Learning Test Total Recall (rs=-.42, P=.05). CONCLUSION: MRI at 3T may boost sensitivity and improve validity in MS brain lesion assessment.

Incidence and factors associated with treatment failure in the CLIMB multiple sclerosis cohort study.

OBJECTIVE: To determine the rate of treatment failure in patients outside of a controlled treatment trial and to ascertain the factors physicians used to make this decision. METHODS: One hundred and thirty four patients with the diagnosis of relapsing-remitting (RR) multiple sclerosis (MS) or clinically isolated symptom (CIS) enrolled in the CLIMB study (Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital) were treated with either interferon beta or glatiramer acetate as their initial treatment for MS. RESULTS: The probability of failing initial treatment within 3 years was 30%. Clinical activity, defined as relapses and/or progression in disability, determined treatment failure in 35.7% (n=10) of nonresponders. New T2 hyperintense or gadolinium-enhancing lesions on MRI was used to define treatment failure in 28.6% (n=8) and new MRI lesions were used in combination with clinical activity in 35.7% (n=10). Treatment failures had a higher T2 hyperintense lesion volume (p=0.015) and number of gadolinium-enhancing lesions (p=0.0001) on the enrollment MRI than responders. CONCLUSIONS: These observations demonstrate that treating physicians use both clinical and MRI parameters to define a response to treatment and initiation of a treatment change and that baseline MRI identified those with increased risk of treatment failure.

Rate of brain atrophy in benign vs early multiple sclerosis.

BACKGROUND: Benign multiple sclerosis (MS) is defined by minimal or no disability after many years of observation, therefore a less degenerative disease process is suspected to be present in this subset of patients. OBJECTIVE: To compare brain atrophy rates in patients with long-standing benign MS vs typical early MS. DESIGN: A longitudinal prospective cohort study and a retrospective database review. SETTING: An academic MS center. PATIENTS: Thirty-nine patients with clinically defined benign MS and an age-matched group of 40 patients with early relapsing-remitting MS. MAIN OUTCOME MEASURES: Baseline demographic, treatment, brain magnetic resonance imaging measures, and annualized atrophy rates, derived from serial brain parenchymal fraction measurements across 2 years, were compared. RESULTS: In the baseline analysis, patients with benign MS were matched to the early MS group on age, sex, treatment with immunomodulatory therapy, T2 lesion volume, and brain parenchymal fraction. The mean (SD) annualized brain atrophy rate in patients with benign MS (-0.16% [0.51%]) was lower than that in patients with early MS (-0.46% [0.72%]) (P = .02). The difference remained significant after controlling for age, sex, and treatment (P = .04). CONCLUSIONS: Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in patients with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients with typical early MS. Identification of patients with a low rate of brain atrophy may indicate a benign course.

Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis.

BACKGROUND: Conventional brain MRI lesion measures have unreliable associations with clinical progression in multiple sclerosis (MS). Gray matter imaging may improve clinical-MRI correlations. METHODS: We tested if gray matter MRI measures and conventional measures of lesions/atrophy predicted clinical progression in a 4-year longitudinal study of 97 patients with MS. Baseline and follow-up brain MRI were analyzed for basal ganglia and thalamic normalized T2 signal intensity, whole brain T2-hyperintense lesion volume, and whole brain atrophy. Logistic regression tested the ability of baseline or on-study change in MRI to predict disability progression, as reported by area under the receiver operator characteristics curve (AUC). RESULTS: Lower caudate T2-intensity at baseline (P= .04; AUC = .69) and on-study decreasing T2-intensity in the putamen (P= .03; AUC = .70) and thalamus (P= .01; AUC = .71) were the MRI variables associated with clinical progression when regression modeling was adjusted for length of follow-up interval, baseline EDSS, disease duration, age, and sex. CONCLUSIONS: Gray matter T2-hypointensity, suggestive of excessive iron deposition is associated with worsening disability in patients with MS. Gray matter MRI assessment may be able to capture neurodegenerative aspects of the disease, with more clinical relevance than derived from conventional MRI measures. J Neuroimaging 2009;19:3-8.

Neuroimaging in multiple sclerosis.

Since its clinical introduction in the early 1980s, MRI has transformed the practice of differential diagnosis and disease monitoring for disorders affecting the central nervous system, in particular multiple sclerosis and the allied inflammatory demyelinating diseases. Widespread and dynamic inflammatory processes of the white matter that were largely invisible by CT scanning now are rendered in exquisite detail by conventional MRI, and newer techniques are providing a wealth of information regarding axonal degeneration and functional adaptation. Overuse and over-reliance on MRI by clinicians sometimes can occur, and careful interpretation and clinical judgment remain essential in the care of multiple sclerosis.

Predicting clinical progression in multiple sclerosis with the magnetic resonance disease severity scale.

BACKGROUND: Individual magnetic resonance imaging (MRI) disease severity measures, such as atrophy or lesions, show weak relationships to clinical status in patients with multiple sclerosis (MS). OBJECTIVE: To combine MS-MRI measures of disease severity into a composite score. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Community-based and referral subspecialty clinic in an academic hospital. PATIENTS: A total of 103 patients with MS, with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom 62 (60.2%) had the relapsing-remitting, 33 (32.0%) the secondary progressive, and 8 (7.8%) the primary progressive form. MAIN OUTCOME MEASURES: Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2. RESULTS: The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV. The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the relapsing-remitting form from those with the secondary progressive form. Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)-year observation period, when adjusting for baseline EDSS score. CONCLUSION: Combining brain MRI lesion and atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.

Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.

Functional magnetic resonance imaging and multiple sclerosis: the evidence for neuronal plasticity.

Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has emerged as a powerful technique to visualize the localization of cerebral activity in both healthy and diseased brains. BOLD fMRI has been used to assess brain function in a variety of diseases, including multiple sclerosis (MS), and has shown that altered patterns of connectivity are used to recruit more widespread eloquent brain networks engaged in tasks relating to motor activity, sensory and cognitive function, and memory when compared to normal controls. This review will examine the evidence that functional reorganization is a consequence of demyelination and tissue loss in MS that may serve as an adaptive response to limit clinical disability. It remains unclear whether cerebral plasticity is a marker of permanent functional restructuring or a short-term compensatory response to injury. Long-term longitudinal studies that correlate fMRI activity with other MRI markers of disease burden and activity, as well as with clinical measures of disease activity and progression, are badly needed to determine fMRI's relevance to clinical practice and its place as a surrogate outcome measure in MS.

Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin.

The authors compared the functional activation state and cytokine secretion profile of CD8+ T cells in patients with relapsing-remitting and secondary progressive (SP) MS to those in normal controls. In addition, they examined cytokine secretion in relationship to single nucleotide polymorphism (SNP) analysis of cytokine genes. A significant increase in lymphotoxin secretion from anti-CD3-stimulated CD8+ T cells was observed in patients with SPMS as compared to normal controls. The authors found no significant differences in SNP frequency or in secretion of other cytokines.

Direct analysis of viral-specific CD8+ T cells with soluble HLA-A2/Tax11-19 tetramer complexes in patients with human T cell lymphotropic virus-associated myelopathy

Human T cell lymphotropic virus-I (HTLV-I) -associated myelopathy is a slowly progressive neurologic disease characterized by inflammatory infiltrates in the central nervous system accompanied by clonal expansion of HTLV-I-reactive CD8+ T-cells. In patients carrying the HLA-A2 allele, the immune response is primarily directed to the Tax11-19 peptide. The frequency, activation state, and TCR usage of HLA-A2/Tax11-19 binding T cells in patients with HTLV-I-associated myelopathy was determined using MHC class I tetrameters loaded with the Tax11-19 peptide. Circulating Tax11-19-reactive T cells were found at very high frequencies, approaching 1:10 circulating CD8+ T cells. T cells binding HLA-A2/Tax11-19 consisted of heterogeneous populations expressing different chemokine receptors and the IL-2R beta-chain but not the IL-2R alpha-chain. Additionally, Tax11-19-reactive CD8+ T cells used one predominant TCR beta-chain for the recognition of the HLA-A2/Tax11-19 complex. These data provide direct evidence for high frequencies of circulating Tax11-19-reactive CD8+ T cells in patients with HTLV-I-associated myelopathy.(Au)