Neeta Garg

Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS)

Cognitive impairment occurs in roughly 50% of patients with multiple sclerosis (MS). It is well known that processing speed and episodic memory deficits are the most common neuropsychological (NP) sequelae in this illness. Consensus has emerged about the specific tests that prove most helpful for routine monitoring of MS associated cognitive impairment. The purpose of this study was to examine the validity of the Minimal Assessment of Cognitive Function in MS (MACFIMS), a recommended battery based on the findings of an international conference held in 2001. We tested 291 MS patients and 56 healthy controls. Frequencies of impairment paralleled those reported in previous work for both individual cognitive domains and general impairment. All tests were impaired in the MS group, and distinguished relapsing-remitting (RR) from secondary progressive (SP) course. Principle components analysis showed a distinct episodic memory component. Most of the MACFIMS tests discriminated disabled from employed patients. However, in regression models accounting for all NP tests, those emphasizing verbal memory and executive function were most predictive of vocational status. We conclude that the MACFIMS is a valid approach to routine NP assessment of MS patients. Future work is planned to determine its psychometric properties in a longitudinal study.

Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test.

Cognitive impairment is common in multiple sclerosis (MS), yet difficult to detect duringroutine neurologic examination. Therefore, briefscreening tests that identify patients who may benefit from a more thorough assessment or treatment are needed. We investigated the utility of the Symbol Digit Modalities Test (SDMT) as a screen for cognitive dysfunction because it can be administered and scored in about 5 minutes. One hundred MS patients and 50 healthy controls, matched on demographic variables, participated in the study. Examination procedures included the neuropsychological (NP) tests included in the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery. Patients were considered impaired if they performed one and a half standard deviations below controls on two or more MACFIMS variables, excluding theSDMT. Bayesian statistics showed that a total score of 55 or lower onthe SDMT accurately categorized 72% of patients, yielding sensitivityof 0.82, specificity of 0.60, positive predictive value (PPV) of 0.71, and negative predictive value (NPV) of 0.73. These results suggest that the effectiveness of the SDMT as a screen for cognitive impairment in MS is roughly equal to that of other psychometric and questionnaire methods.

Validity of the Wisconsin Card Sorting and Delis–Kaplan Executive Function System (DKEFS) Sorting Tests in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system that causes cognitive impairment with a frequency of roughly 50%. While processing speed and memory defects are most commonly observed, a substantial number of patients also have deficiency in higher executive ability. Two tests, the Wisconsin Card Sorting Test (WCST) and the Sorting Test from the Delis–Kaplan Executive Function System (DKEFS), have been recommended for evaluation of neuropsychological impairment in MS. We investigated the validity of these tests in 111 MS patients and 46 age- and education-matched controls. MS patients performed more poorly on both measures, but only the DKEFS discriminated the groups after controlling for depression. Both tests were modestly or strongly correlated with MRI indices of brain atrophy or lesion burden and discriminated between employed and disabled patients. While both tests appear to have good validity in the MS population, the availability of alternative forms makes the DKEFS an attractive alternative to the WCST, as was suggested by a consensus panel.

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients

BACKGROUND Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.

Interferon-β modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients

Purpose Multiple sclerosis (MS) patients have a high risk of low bone density. The purpose of this study was to examine the molecular mechanisms potentially capable of modulating bone home-ostasis in response to interferon-β-1a (IFN-β-1a) treatment and the focus was the bone-modulating system comprised of receptor activator of nuclear factor-κB (RANK), its ligand RANKL and its decoy receptor, osteoprotegerin (OPG). Methods In this open-label pharmacodynamic study, peripheral blood was obtained from relapsing remitting MS patients just prior to and at multiple time points after intramuscular injection of 30 μg IFN-β-1a. Samples were analysed for RANKL, tumour necrosis factor related apoptosis-inducing ligand (TRAIL), OPG and macrophage inflammatory protein-1α/β expression. Osteoclast precursor differentiation from peripheral blood cells of MS patients in the presence of exogenously added IFN-β-1a was also assessed. Additionally, the changes in plasma levels of osteocalcin and the C-telopeptides after 1 year of treatment were measured as surrogate markers of bone formation and degradation, respectively. Results IFN-β-1a treatment modulated RANKL and OPG in a selective, time-dependent manner. The levels of OPG protein decreased 25% at the 8-h time point, then increased 43% at the 24-h time point. The levels of free RANKL reached a maximum at the 8-h time point. Increases in the levels of macrophage inflammatory protein-1β (MIP-1β), a chemokine that increases osteolysis, were observed. The levels of the bone formation marker, osteocalcin, were lower in MS patients compared to controls and increased after one year of treatment. Ex vivo treatment of peripheral blood lymphocytes with IFN-β resulted in a marked reduction of osteoclast-like cells in the presence of RANKL and macrophage colony stimulating factor. Conclusions IFN-β treatment induces complex, specific and time-dependent changes in multiple proteins and mRNAs related to bone homeostasis in MS patients.

MRI characteristics of patients with antiphospholipid syndrome and multiple sclerosis

MRI findings of primary anti-phospholipid antibody syndrome (PAPLS) are difficult to distinguish from those of multiple sclerosis (MS). Only a few previous studies have compared conventional and non-conventional MRI findings in MS and PAPLS patients. In addition, MRI differences between anti-phospholipid antibody (APLA) positive (+) and APLA negative (−) MS patients have not been reported. Therefore, the aim of this study was to investigate the differences in MRI measures among patients with PAPLS, MS and normal control (NC) subjects. We also explored non-conventional MRI measures in APLA+ and APLA− MS patients. Forty-nine (49) consecutive MS patients among whom 39 had relapsing-remitting (RR) and 10 secondary-progressive (SP) disease course, 30 patients with PAPLS and 49 NC were enrolled. Twenty-eight (28) MS patients were APLA+. MRI measures of T1- and T2-lesion volumes (LV) and brain atrophy, including fractions of whole brain (BPF), gray matter (GMF) and white matter (WMF), were evaluated. The magnetization transfer ratio (MTR) of T2- and T1-LVs and different normal-appearing brain tissue (NABT) compartments as well as diffusion-weighted imaging of whole brain mean parenchyma diffusivity (MPD) were obtained. MS patients differed significantly from NC in all MRI measures. PAPLS patients differed from NC in their T2-LV, in MTR measures and in MPD. When MS patients were compared to PAPLS patients, they showed significantly higher T2- and T1-LVs and T2-LV MTR, lower BPF and GMF and higher MPD. APLA+ RR and SPMS (all APLA+) patients showed significantly higher T2-LV, lower GMF, lower normal-appearing gray matter MTR and higher MPD when compared to APLA− patients. The results indicate that brain abnormalities can be detected in PAPLS patients with non-conventional MRI. MRI reveals more profound injury in patients with MS versus PAPLS. APLA mediates heterogeneous cerebral pathology that remains to be further investigated.

An association between autoreactive antibodies and anti-interferon-β antibodies in multiple sclerosis

Approximately 5—25% of interferon-β (IFN-β) treated multiple sclerosis (MS) patients develop anti-IFN-β neutralizing antibodies (NAb) but the patient-specific variables associated with the risk of developing anti-IFN-β antibodies are poorly understood. Anti-IFN-β NAb are a subset of anti-IFN-β binding antibodies (BAb) and all patients with NAb generally have high levels of associated BAb. The purpose of this research was to assess the association between autoreactive antibodies (ARAB) and the risk of developing anti-IFN-β BAb in MS patients. This was a retrospective study that included consecutive patients diagnosed with clinically definite MS evaluated at our center and considered appropriate for IFN-β therapy. The patients were tested for various subtypes of antiphospholipid antibodies (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), and anti-cardiolipin (ACA) antibodies, and other ARAB, antinuclear and anti-neutrophilic cytoplasmic antibodies, anti-thyroid peroxidase antibodies (ATA), anti-SS-A and anti-SS-B antibodies. BAb levels were assessed using a commercial binding ELISA assay. A total of 33 patients (mean age: 45.4 years, 85% female) were enrolled; 15 patients were negative and 18 patients were positive for BAb. APLA or ATA were present in 95% (17 of 18 patients) of patients positive for BAb. In comparison, APLA or ATA occurred in only 27% (four of 15 patients) of patients in the BAb negative group. The associations between the occurrence of BAb and the occurrence of high APLA or ATA were significant (χ2 = 13.4, P<0.001in Fisher exact test). The odds ratio for the association was 46.8 (with a 95% confidence interval range of 4.6—475). No significant correlations were found for other ARAB. The presence of autoreactive antibodies, particularly APLA and ATA is associated with increased risk of occurrence of IFN-β BAb in MS patients on long-term IFN-β therapy. Multiple Sclerosis 2007; 13: 895—899. http://msj.sagepub.com

Glatiramer acetate recovers microscopic tissue damage in patients with multiple sclerosis. A case-control diffusion imaging study.

Traditional magnetic resonance imaging (MRI) techniques have contributed to the management of multiple sclerosis (MS) but are limited in their ability to detect neuronal damage. Advanced MRI metrics provide assessment of microscopic neuronal changes; however, few studies have examined the effects of MS therapies on these measures. This prospective, open-label, observational study evaluated the effect of subcutaneous glatiramer acetate (GA) 20mg/day on the 1- and 2-year changes in diffusion-weighted imaging (DWI) measures in patients with relapsing-remitting (RR) MS and in age- and sex-matched healthy controls (HC). Inclusion criteria were age 18-65, RR disease course, expanded disability status scale (EDSS) score ≤5.5 and disease duration<20 years. MS patients and HC underwent 1.5T MRI scans and clinical examinations at baseline and at 1- and 2-year follow-up. Nineteen RRMS patients and 16 HC completed the 1-year follow-up and 16 MS patients and 13 HC the 2-year follow-up of the study. In MS patients, treatment with GA promoted recovery of DWI mean parenchymal diffusivity (MPD) at year 1 (-7.1%, p=0.007) and at year 2 (-10.1%, p=0.028). The recovery of DWI MPD was significantly higher in MS patients compared to HC at year 1 (p=0.01) and year 2 (p<0.001). GA promoted recovery of DWI entropy at 2 years (-1.2%, p=0.018). No significant DWI MPD and entropy changes were observed in HC over the follow-up. No significant deterioration in magnetization transfer ratio occurred over the follow-up in MS patients and HC. Patients on GA and HC did not develop significant global or regional atrophy over 2 years. GA significantly improved microscopic tissue damage in the brain, as measured by DWI over the 1- and 2-year follow-up.