Bianca Weinstock-Guttman

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.

Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change.

Health-related quality of life (HQOL) is poor in multiple sclerosis (MS) but the clinical precipitants of the problem are not well understood. Previous correlative studies demonstrated relationships between various clinical parameters and diminished HQOL in MS. Unfortunately, these studies failed to account for multiple predictors in the same analysis. We endeavored to determine what clinical parameters account for most variance in predicting HQOL, and employability, while accounting for disease course, physical disability, fatigue, cognition, mood disorder, personality, and behavior disorder. In 120 MS patients, we measured HQOL (MS Quality of Life-54) and vocational status (employed vs. disabled) and then conducted detailed clinical testing. Data were analyzed by linear and logistic regression methods. MS patients reported lower HQOL (p<0.001) and were more likely to be disabled (45% of patients vs. 0 controls). Physical HQOL was predicted by fatigue, depression, and physical disability. Mental HQOL was associated with only depression and fatigue. In contrast, vocational status was predicted by three cognitive tests, conscientiousness, and disease duration (p<0.05). Thus, for the first time, we predicted HQOL in MS while accounting for measures from these many clinical domains. We conclude that self-report HQOL indices are most strongly predicted by measures of depression, whereas vocational status is predicted primarily by objective measures of cognitive function. The findings highlight core clinical problems that merit early identification and further research regarding the development of effective treatment.

Thalamic atrophy and cognition in multiple sclerosis

Objectives: Recent studies have indicated that brain atrophy is more closely associated with cognitive impairment in multiple sclerosis (MS) than are conventional MRI lesion measures. Enlargement of the third ventricle shows a particularly strong correlation with cognitive impairment, suggesting clinical relevance of damage to surrounding structures, such as the thalamus. Previous imaging and pathology studies have demonstrated thalamic involvement in MS. In this study, we tested the hypothesis that thalamic volume is lower in MS than in normal subjects, and that thalamic atrophy in MS correlates with cognitive function. Methods: We studied 79 patients with MS and 16 normal subjects. A subgroup of 31 MS subjects underwent cognitive testing. The thalamus was segmented in whole from three-dimensional MRI scans. We also determined whole brain atrophy (brain parenchymal fraction), third ventricular width, and whole brain T2-weighted (fluid-attenuated inversion recovery) hyperintense, T1 hypointense, and gadolinium-enhanced lesion volumes. Results: Normalized thalamic volume was 16.8% lower in the MS group (p < 0.0001) vs controls. Cognitive performance in all domains was moderately to strongly related to thalamic volume in the MS group (r = 0.506 to 0.724, p < 0.005), and thalamic volume entered and remained in all regression models predicting cognitive performance. Thalamic volume showed a weak relationship to physical disability score (r = −0.316, p = 0.005). Conclusion: These findings suggest that thalamic atrophy is a clinically relevant biomarker of the neurodegenerative disease process in multiple sclerosis.

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis

Background: Interferon beta is an effective treatment for relapsing multiple sclerosis(MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. Objectives: To determine the incidence and biological significance of NAB to interferon beta-1a (IFN-β-1a; Avonex; Biogen, Cambridge, MA) in MS patients. Methods: A two-step assay for NAB to IFN-β-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-β-1a, and from patients in an ongoing open-label study of IFN-β1a. The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b. Results: In patients in the open-label study, development of NAB to IFN-β-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in β-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-β-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-β-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. Conclusions: NAB directed against IFN-β have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β-1a therapy. Treatment decisions in MS patients treated withIFN-β should take into account development of NAB.

The incidence and significance of anti-natalizumab antibodies : Results from AFFIRM and SENTINEL

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p ≤ 0.05), relapse rate (p = 0.009), and MRI (p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.

Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study

BACKGROUND The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. METHODS 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. FINDINGS MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7.4 [SD 4.2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11.2 [4.5] years; p<0.0001) or monofocal (12.0 [3.8] years; p=0.0005) presentations. Permanent physical disability (EDSS>or=4.0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0.02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0.025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. INTERPRETATION Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology.

Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis

Background: The relationship of gray and white matter atrophy in multiple sclerosis (MS) to neuropsychological and neuropsychiatric impairment has not been examined. Methods: In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain whole brain normalized volumes of gray and white matter, as well as measured conventional lesion burden (total T1 hypointense and FLAIR hyperintense lesion volume). The whole brain segmentation was corrected for misclassification related to MS brain lesions. To compare the effects of gray matter, white matter, and lesion volumes with respect to brain-behavior relationships, the MS group (disease duration = 11.2 ± 8.8 years; EDSS score = 3.3 ± 1.9) underwent neuropsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83). Results: The MS group had smaller gray (p = 0.009) and white matter volume (p = 0.018), impaired cognitive performance (verbal memory, visual memory, processing speed, and working memory) (all p < 0.0001), and greater neuropsychiatric symptoms (depression, p < 0.0001; dysphoria, p < 0.0001; irritability, p < 0.0001; anxiety, p < 0.0001; euphoria, p = 0.006; agitation, p = 0.02; apathy, p = 0.02; and disinhibition, p = 0.11) vs controls. Hierarchical stepwise regression analysis revealed that whole gray and white matter volumes accounted for greater variance than lesion burden in explaining cognitive performance and neuropsychiatric symptoms. White matter volume was the best predictor of mental processing speed and working memory, whereas gray matter volume predicted verbal memory, euphoria, and disinhibition. Conclusion: Both gray and white brain matter atrophy contribute to neuropsychological deficits in multiple sclerosis.

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.

Reliable screening for neuropsychological impairment in multiple sclerosis

In an earlier study, we developed the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) to assist in the screening for neuropsychological (NP) impairments. Self-report MSNQ scores correlated significantly with measures of depression, whereas informant-report MSNQ scores correlated with cognitive performance, but not depression. This study was criticized for use of a small sample and lack of data regarding normal performance and test -retest reliability. The present study was designed to replicate the earlier work with a larger sample of patients and normal controls obtained from multiple sites. We also evaluated the test -retest reliability and predictive validity of the MSNQ. The sample included 85 multiple sclerosis (MS) patients and 40 normal controls, matched on demographic variables. All participants completed the MSNQ and underwent NP testing. Thirty-four patients were re-examined at one week. Pearson and ANOVA techniques were utilized for univariate comparisons. Bayesian statistics were calculated to assess predictive validity. Patient self- and informant-report MSNQ scores differed from normal and test -retest reliability indices were high. Both self- and informant-reports were correlated with cognitive dysfunction and depression scales. Self-report MSNQ scores correlated more strongly with depression than cognitive performance, whereas the opposite pattern was observed with informant-report scores. Bayesian statistics showed that informant-report MSNQ scores predict cognitive impairment and patient self-report scores identify patients with cognitive impairment or depression. It is concluded that the MSNQ is useful, although patient self-reports may be exaggerated in depressed patients or reduced in patients with severe cognitive impairment.

Health-related quality of life in multiple sclerosis: Effects of natalizumab

To report the relationship between disease activity and health‐related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab.