Multiple Sclerosis Journal

The objective of this study was to analyze whether inhibitory and activating killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I alleles defined by their KIR binding motifs are associated with multiple sclerosis (MS) susceptibility or severity.

We performed a population-based case–control study in 321 patients with clinically isolated syndrome (CIS) and clinically definite MS (CDMS) and 156 healthy blood donors (HD). Inhibitory and activating KIRs and HLA class I alleles were genotyped using polymerase chain reaction (PCR) sequence-specific primers. Allelic frequencies were correlated with prevalence, age of onset, disability and disease duration of CIS and CDMS.

The frequency of the inhibitory KIR2DL3 gene was significantly reduced in patients with CIS and CDMS (p = 3.1 × 10⁻⁵). KIR2DL3-dependent risk reduction remained significant after elimination of patients carrying MS-associated DRB1*15, DRB1*03, DRB1*01 alleles. In addition, individuals carrying two copies for KIR2DL2/KIR2DS2 but lacking KIR2DL3 were overrepresented in the CIS/CDMS cohort. However, both genes did not affect disease risk in presence of KIR2DL3. We did not detect any association between the presence or absence of KIR genes with clinical disease parameters.

Absence of the inhibitory KIR2DL3 gene is associated with the development of CIS/CDMS. These findings, if confirmed in larger cohorts, suggest that KIR-mediated recognition of HLA class I molecules should be further explored as potential disease mechanism in MS.

Ten genes previously showing different evidence of association with multiple sclerosis have been selected to validate.

Eleven polymorphisms were genotyped with the iPLEX™ Sequenom in a well-powered collection of Spanish origin including 2863 multiple sclerosis cases and 2930 controls.

Replication extended to the following polymorphisms: PKN2 (rs305217), GTF2B (rs7538427), EPHA4 (rs1517440), YTHDF3 (rs12115114), ANKFN1 (rs17758761) and PTPRM (rs4798571), which did not reach the threshold of significance in a follow-up of the first genome-wide association study (GWAS) conducted in multiple sclerosis; TMEM39A (rs1132200), which appeared as a newly identified susceptibility gene in the same study; a gene previously reaching GWAS significance in Italy, CBLB (rs9657904); IL12B (rs6887695, rs10045431), a susceptibility gene shared by diverse autoimmune diseases and, finally, another gene showing inconclusive association with multiple sclerosis, CNR1 (rs1049353).

Pooled analysis corroborated the effect on MS predisposition of three genes: TMEM39A [rs1132200: p_M-H=0.001; OR_M-H (95% CI)= 0.84 (0.75–0.93)], IL12B [rs6887695: p_M-H=0.03; OR_M-H (95% CI)= 1.09 (1.01–1.17)] and CBLB [rs9657904: p_M-H=0.01; OR_M-H (95% CI)= 0.89 (0.81–0.97)].

Higher serum levels of at least one of a panel of four α-glucose IgM antibodies (gMS-Classifier1) in clinically isolated syndrome (CIS) patients are associated with imminent early relapse within 2 years.

The objective of this study was to determine the prognostic value of gMS-Classifier1 in a large study cohort of CIS patients.

The BEtaseron^® in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) 5-year study was designed to evaluate the impact of early versus delayed interferon-β-1b (IFNβ-1b; Betaseron^®) treatment in patients with a first event suggestive of multiple sclerosis (MS). Patients (n = 258, 61% of total) with a minimum of 2 ml baseline serum were eligible for the biomarker study. gMS-Classifier1 antibodies’ panel (anti-GAGA2, anti-GAGA3, anti-GAGA4 and anti-GAGA6) levels were measured blinded to clinical data. Subjects were classified as either ‘positive’ or ‘negative’ according to a classification rule.

gMS-Classifier1 was not predictive for the time to clinically definite MS or time to MS according to the revised McDonald’s criteria, but did significantly predict an increased risk for confirmed disability progression (log-rank test: p = 0.012).

We could not confirm previous results that gMS-Classifier1 can predict early conversion to MS in CIS. However, raised titres of these antibodies may predict early disability progression in this patient population.

With the advent of MRI scanning, the value of lumbar puncture to assess oligoclonal band (OCB) statusfor the diagnosis of multiple sclerosis (MS) is increasingly uncertain. One major issue is that the reported frequency of cerebrospinal fluid (CSF)-restricted oligoclonal banding for the diagnosis of MS varies considerably in different studies. In addition, the relationship between OCB positivity and disease outcome remains uncertain, as reported studies are generally too small to assess comparative disability outcomes with sufficient power.

In order to further investigate variation of OCB positivity in patients with MS, we utilized MSBase, a longitudinal, Web-based collaborative MS outcomes registry following clinical cohorts in several continents and latitudes. We also assessed whether OCB positivity affects long-term disability outcome.

A total of 13,242 patient records were obtained from 37 MS specialist centres in 19 different countries. OCB status was documented in 4481 (34%) patients and 80% of these were OCB positive. The presence of OCB was associated with degree of latitude (p = 0.02). Furthermore, the outcome of patients negative for CSF-specific OCB was significantly better in comparison to the OCB positive patients, as assessed by Expanded Disability Status Scale change (p < 0.001).

The results of this study indicate that latitude could explain some of the inconsistencies in OCB status reported in different populations. The study confirms that OCB positivity in MS is associated with a worse long-term prognosis.

Chitinase 3-like 1 (CHI3L1) is upregulated in a wide variety of inflammatory conditions. Recent studies have pointed to a role of CHI3L1 in multiple sclerosis (MS) pathogenesis.

The objective of this study was to investigate the role of plasma CHI3L1 in MS clinical course and disease activity and to evaluate the effect of interferon-beta (IFNβ) treatment on protein levels.

Plasma CHI3L1 levels were determined by ELISA in 57 healthy controls (HC), 220 untreated MS patients [66 primary progressive MS patients (PPMS), 30 secondary progressive MS patients (SPMS), and 124 relapsing–remitting MS patients (RRMS), 94 during clinical remission and 30 during relapse], and 32 MS patients receiving IFNβ treatment. A polymorphism of the CHI3L1 gene, rs4950928, was genotyped in 3274 MS patients and 3483 HC.

Plasma CHI3L1 levels were significantly increased in patients with progressive forms of MS compared with RRMS patients and HC. CHI3L1 levels were similar between RRMS patients in relapse and remission. A trend towards decreased CHI3L1 levels was observed in IFNβ-treated patients. Allele C of rs4950928 was significantly associated with PPMS patients and with higher plasma CHI3L1 levels.

These findings point to a role of CHI3L1 in patients with progressive forms of MS, particularly in those with PPMS.

Multiple Sclerosis (MS) frequently causes injury to the anterior visual pathway (AVP), impairing quality of life due to visual dysfunction. Development of biomarkers in MS is a high priority and both low-contrast visual acuity (LCVA) and time-domain optical coherence tomography (TD-OCT) have been proposed as candidates for this purpose. We sought to assess whether psychophysical assessments of color vision are similarly correlated with structural measures of AVP injury, and therefore augment measures of visual disability in MS.

We studied the association between high-contrast visual acuity (HCVA), LCVA, color vision (Hardy–Rand–Rittler plates (HRR) and Lanthony D15 tests) and OCT, using both high-resolution spectral-domain OCT (SD-OCT; Spectralis, Heidelberg Engineering, Germany) and TD-OCT (Stratus, Carl Zeiss, US) in a cohort of 213 MS patients (52 with previous optic neuritis) and 47 matched controls in a cross-sectional study.

We found that MS patients have impairments in HCVA and LCVA (p < 0.001) but that they suffer from even more profound abnormalities in color discrimination (p < 0.0001). We found strong correlation between color vision and SD-OCT measures of retinal nerve fiber layer (RNFL) thickness (average RNFL, r = 0.594, p < 0.001) and papillomacular bundle thickness (r = −0.565, p < 0.001). The correlation between OCT scores and functional visual impairments of all types was much stronger for SD-OCT than for TD-OCT.

Our results indicate that color vision is highly correlated with these OCT scores when compared with traditional measures of visual acuity. Also we found that SD-OCT is superior to TD-OCT for detecting anterior visual pathway damage in MS. This makes both color-visual measures and SD-OCT strong candidate biomarkers of disease progression.

There is an on-going controversy about venous drainage abnormalities in multiple sclerosis (MS). We applied cardiac-gated phase-contrast and venographic magnetic resonance (MR) techniques to compare venous drainage patterns in patients with MS, healthy controls, and subjects with migraine.

A total of 27 patients with MS (21 female, age 12–59 years, mean disease duration 8.4 ± 8.5 years) and 27 age- and gender-matched healthy controls (21 female, age 12–60 years) were investigated with velocity-encoded cine-phase contrast MR sequences and a 2D time-of-flight MR venography of the cervicocranial region on a 3-T MRI. The data were compared with 26 patients with chronic migraine headaches (19 female, age 17–62 years), previously investigated with the same protocol. The degree of primary and secondary venous outflow in relation to the total cerebral blood flow (tCBF) was compared both quantitatively and qualitatively. Statistical analyses were performed using linear regression models.

Secondary venous outflow was significantly increased in patients with MS compared with healthy controls, both qualitatively (p < 0.001) and quantitatively (p < 0.013). The observed changes were independent of age and disease duration. Very similar alterations of venous drainage were detectable with the same approach in patients with migraine, without significant differences between MS and migraine patients (p = 0.65).

Our MRI-based study suggests that patients with MS have alterations of cerebral venous drainage similar to subjects with chronic migraine. These non-disease-specific changes seem to a secondary phenomenon rather than being of primary pathogenic importance.

Factors determining severity and recovery of early demyelinating events in pediatric multiple sclerosis (MS) patients are unknown.

The objective of this study was to characterize the severity and recovery of early demyelinating events in pediatric MS.

Multivariate logistic regression was performed to determine predictors of severe (versus mild/moderate) relapses and poor or fair (versus complete) recovery in patients aged 18 years or less with MS or clinically isolated syndrome (CIS).

Optic nerve involvement (OR 4.30, 95% CI 1.50–12.3, p = 0.007) was associated with a severe initial demyelinating event (IDE), while non-White race (OR 2.55, 95% CI 0.87–7.49, p = 0.088), localization to the cerebral hemispheres (OR 7.94, 95% CI 0.86–73.8, p = 0.068), or encephalopathy (OR 8.70, 95% CI 0.86–88.0, p = 0.067) showed a trend towards increased IDE severity. A similar association with race was found for severe second events. A severe IDE (OR 6.90, 95% CI 2.47–19.3, p < 0.001) was associated with incomplete IDE recovery, with similar trends for second and third events. Incomplete recovery from the first event predicted incomplete second event recovery (OR 3.36, 95% CI 0.98–11.6, p = 0.055).

These results may help identify children at risk for a more aggressive disease course.

It remains uncertain whether neuromyelitis optica (NMO) exhibits diffuse cerebral abnormalities or whether the pathology is truly restricted to optic nerves and spinal cord in the majority of cases. We examined NMO patients with diffusion tensor imaging (DTI) and utilized a tract-based spatial statistics (TBSS) method to analyze the data.

Twenty-seven NMO patients (25 females, age mean ± SD: 35.1 ± 12 years) and 27 age- and sex-matched normal controls were included in this study. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (λ₁) and radial diffusivity (λ₂₃).

The NMO patients had significantly increased MD (3.6%), λ₁ (2.6%) and λ₂₃ (4.6%) in their white matter (WM) skeletons compared with the controls. Furthermore, TBSS analyses revealed significantly (p < 0.05, corrected for multiple comparisons) increased diffusivities (MD, λ₁ and λ₂₃) in many cerebral WM tracts in the patients with NMO, including the superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculi, corpus callosum, cingulum bundles, corticospinal tracts, optic radiation, uncinate fasciculi, fornices, internal capsules, external capsules and cerebral peduncles. Exploratory analyses also revealed the possible associations between WM diffusion changes (MD, λ₁ and λ₂₃) and clinical variables (Expanded Disability Status Scale and disease duration) in the patients.

This study provided imaging evidence for widespread cerebral WM abnormalities. While these findings require independent replication, they potentially signify the presence of widespread, low-grade cerebral pathology in NMO.

Neuromyelitis optica (NMO) is an autoimmune condition that predominantly causes severe optic neuritis and transverse myelitis. Rituximab therapy has dramatically improved patient care, but standardized dosing regimens and guidelines are lacking.

The objective of this study was to define a rituximab dosing strategy for NMO patients that achieves the lowest rate of relapses.

This was a retrospective chart review of patients treated with various doses of rituximab.

Combining data from the NMO and multiple sclerosis (MS) patients, identified that the mean number of days after a 100 mg dose of rituximab until the CD19 population was greater than 2% was 99 days (standard deviation 36, range 43–172). When allowed to rise, the mean number of days after a 1000 mg dose of rituximab until the CD19 population was greater than 2% was 184 (standard deviation 72, range 52–288). The median number of days until a CD19 percentage of 2% was achieved was 133 days in the 100 mg dosing arm and 259 days in the 1000 mg dosing arm. Analysis of the survival curves via both the Mantel–Cox log-rank test and the Wilcoxon test determined that the difference between medial survival for 100 and 1000 mg doses was statistically significant with p-values <0.0001.

Low doses of rituximab have a high rate of early B-cell repopulation. Any NMO patient treated with rituximab should be followed with monthly CD19 counts in order to identify the rare, but clinically significant, early repopulators.

We aimed to investigate the regional distribution of grey matter (GM) and white matter (WM) atrophy in patients with relapsing–remitting (RR) MS and their relationship with gender, clinical findings, and T2 lesions.

Clinical and magnetic resonance imaging assessments were obtained from 78 patients with RRMS and 88 controls. GM and WM atrophy were estimated using voxel-based morphometry (SPM8).

Patients with RRMS experienced atrophy of the deep GM nuclei, and several cortical regions mainly located in the fronto-parietal lobes. WM atrophy involved posterior regions of the brain, including the cerebellum and brainstem. Compared with men, affected women showed atrophy of several WM tracts, while gender did not impact GM atrophy. Disease duration > 5 years was associated with atrophy of the thalami and inferior frontal gyrus, while WM atrophy was already prominent in patients with disease duration ≤ 5 years. Expanded Disability Status Scale score > 3.0 was associated with diffuse WM atrophy and basal ganglia and precentral gyrus atrophy. T2 lesions were marginally associated to focal atrophy.

In RRMS, GM and WM atrophy have distinct patterns of regional distribution, with a sparing of GM infratentorial regions. Gender, disease duration and disability affect differently the topography of GM/WM atrophy, while T2 lesions play a modest role.