Christopher McGuigan

Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group

The use of natalizumab for highly active relapsing-remitting multiple sclerosis (MS) is influenced by the occurrence of progressive multifocal leukoencephalopathy (PML). Through measurement of the anti-JCV antibody index, and in combination with the presence or absence of other known risk factors, it may be possible to stratify patients with MS according to their risk of developing PML during treatment with natalizumab and detect early suspected PML using MRI including a diffusion-weighted imaging sequence. This paper describes a practical consensus guideline for treating neurologists, based on current evidence, for the introduction into routine clinical practice of anti-JCV antibody index testing of immunosuppressant-naïve patients with MS, either currently being treated with, or initiating, natalizumab, based on their anti-JCV antibody status. Recommendations for the frequency and type of MRI screening in patients with varying index-associated PML risks are also discussed. This consensus paper presents a simple and pragmatic algorithm to support the introduction of anti-JCV antibody index testing and MRI monitoring into standard PML safety protocols, in order to allow some JCV positive patients who wish to begin or continue natalizumab treatment to be managed with a more individualised analysis of their PML risk.

The multiple sclerosis impact scale (MSIS-29) is a reliable and sensitive measure

Objective: The aim of this study was to assess the psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) for patients in the community and in a hospital setting. Methods: During an epidemiological study, 172 people with multiple sclerosis (MS) were examined and completed the MSIS-29, the London Handicap Scale, and Beck’s Depression Inventory; disability was assessed by the Kurtzke Expanded Disability Status Score (EDSS) and the Multiple Sclerosis Functional Composite. At the hospital neurology clinic, 102 MS patients completed the MSIS-29 and EDSS assessments were performed; 41 of these patients had repeat evaluations six months later. The psychometric properties of the MSIS-29 were examined. Results: In the 172 community and the 102 hospital patients the psychometric properties of the MSIS-29 were satisfactory, with high convergent and low divergent validity. It was significantly responsive to change in the contexts of self-reported change (p<0.034) and EDSS worsening (p<0.001). The MSIS-29 physical score did not change over time when the EDSS was stable, and increased significantly in proportion to EDSS deterioration (p  =  0.014). Conclusions: The psychometric properties of the MSIS-29 are acceptable; it is a valuable outcome measure in intervention studies of patients with MS.

Confirming the validity and responsiveness of the Multiple Sclerosis Walking Scale-12 (MSWS-12).

The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a new, self-rated measure of walking ability. The scale has not been independently validated for use in differing MS populations. One hundred forty-nine patients in the community and 53 hospital outpatients with MS completed the MSWS-12 and other outcome measures. The psychometric properties of the MSWS-12 were excellent, and in particular the scale is responsive to change.

The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS‐29 physical)

Aim: The aims of this study were to determine the reliability, responsiveness and minimally important change score of the Multiple Sclerosis Impact Scale (MSIS)-29 physical using the Expanded Disability Status Scale (EDSS) as an anchor measure. Methods: 214 patients with multiple sclerosis (MS) (EDSS 0–8.5) had concurrent MSIS-29 and EDSS assessments at baseline and at up to 4 years of follow-up. Results: 116 patients had unchanged EDSS scores. Stability of the MSIS-29 physical (mean change 0.1 points) was better in the 85 patients with EDSS 0–5.0 than in the 31 patients with EDSS 5.5–8.5 in whom the MSIS-29 physical score fell by 8 points, a response shift phenomenon. A floor effect for the MSIS-29 was observed in 5% of stable patients at both time points. 98 patients experienced EDSS change with moderately strong statistically significant correlations between change scores in the EDSS and the MSIS-29 physical (r = 0.523, p<0.0001). Effect sizes for MSIS-29 physical change were moderate to large. Using receiver operating characteristic curves, the MSIS-29 change score which produced a combination of optimal sensitivity and specificity was chosen for both EDSS ranges. For EDSS range 5.5–8, a change score of 8 had a sensitivity of 87% and specificity of 67%. For EDSS 0–5.0, a change score of 7 had a sensitivity of 78% and a specificity of 51%. Conclusions: The MSIS-29 physical performs well over time, and is suitable for use in trials; a minimal change score of 8 points in the MSIS-29 is clinically significant.

Unrecognised symptoms of depression in a community–based population with multiple sclerosis

AbstractBackground and aimsThe association between multiple sclerosis (MS) and depression has been well established but prevalence estimates have varied widely. The aims of this study were to assess the point prevalence of previously unrecognised symptoms of depression in a community–based population with MS and examine their relationship to other disease characteristics.Patients and methodsThree hundred and seventy six patients with clinically definite or probable MS (Poser criteria) were ascertained during the course of an epidemiological study on two counties in Ireland. Of these 211 agreed to participate in the study. Subjects were examined and a Kurtzke Expanded Disability Status Scale Score and Multiple Sclerosis Functional Composite score rated. Participants also completed a Becks Depression Inventory–II and a Multiple Sclerosis Impact Scale.ResultsIn total 60 (28%) patients had moderate or severe symptoms of depression. Only thirty–five of the 211 patients had a history of depression as defined by a medical diagnosis of depression or prescription of an anti–depressant medication at any time prior to enrolment in the present study, of the remaining 176 patients, 41 (23.3%) had moderate or severe symptoms of depression as assessed by Becks Depression Inventory–II. The only significant clinical difference between the 41 patients with pronounced depressive symptoms and the 135 less affected was shorter disease duration in the former.ConclusionsIn this study one in four patients with MS had unrecognised and therefore untreated symptoms of depression. Disability alone is not a good indicator of the likelihood of coexistent depressive symptoms.

Treatment effectiveness of alemtuzumab compared with natalizumab, fingolimod, and interferon beta in relapsing-remitting multiple sclerosis: a cohort study

BACKGROUND Alemtuzumab, an anti-CD52 antibody, is proven to be more efficacious than interferon beta-1a in the treatment of relapsing-remitting multiple sclerosis, but its efficacy relative to more potent immunotherapies is unknown. We compared the effectiveness of alemtuzumab with natalizumab, fingolimod, and interferon beta in patients with relapsing-remitting multiple sclerosis treated for up to 5 years. METHODS In this international cohort study, we used data from propensity-matched patients with relapsing-remitting multiple sclerosis from the MSBase and six other cohorts. Longitudinal clinical data were obtained from 71 MSBase centres in 21 countries and from six non-MSBase centres in the UK and Germany between Nov 1, 2015, and June 30, 2016. Key inclusion criteria were a diagnosis of definite relapsing-remitting multiple sclerosis, exposure to one of the study therapies (alemtuzumab, interferon beta, fingolimod, or natalizumab), age 65 years or younger, Expanded Disability Status Scale (EDSS) score 6·5 or lower, and no more than 10 years since the first multiple sclerosis symptom. The primary endpoint was annualised relapse rate. The secondary endpoints were cumulative hazards of relapses, disability accumulation, and disability improvement events. We compared relapse rates with negative binomial models, and estimated cumulative hazards with conditional proportional hazards models. FINDINGS Patients were treated between Aug 1, 1994, and June 30, 2016. The cohorts consisted of 189 patients given alemtuzumab, 2155 patients given interferon beta, 828 patients given fingolimod, and 1160 patients given natalizumab. Alemtuzumab was associated with a lower annualised relapse rate than interferon beta (0·19 [95% CI 0·14-0·23] vs 0·53 [0·46-0·61], p<0·0001) and fingolimod (0·15 [0·10-0·20] vs 0·34 [0·26-0·41], p<0·0001), and was associated with a similar annualised relapse rate as natalizumab (0·20 [0·14-0·26] vs 0·19 [0·15-0·23], p=0·78). For the disability outcomes, alemtuzumab was associated with similar probabilities of disability accumulation as interferon beta (hazard ratio [HR] 0·66 [95% CI 0·36-1·22], p=0·37), fingolimod (1·27 [0·60-2·70], p=0·67), and natalizumab (0·81 [0·47-1·39], p=0·60). Alemtuzumab was associated with similar probabilities of disability improvement as interferon beta (0·98 [0·65-1·49], p=0·93) and fingolimod (0·50 [0·25-1·01], p=0·18), and a lower probability of disability improvement than natalizumab (0·35 [0·20-0·59], p=0·0006). INTERPRETATION Alemtuzumab and natalizumab seem to have similar effects on annualised relapse rates in relapsing-remitting multiple sclerosis. Alemtuzumab seems superior to fingolimod and interferon beta in mitigating relapse activity. Natalizumab seems superior to alemtuzumab in enabling recovery from disability. Both natalizumab and alemtuzumab seem highly effective and viable immunotherapies for multiple sclerosis. Treatment decisions between alemtuzumab and natalizumab should be primarily governed by their safety profiles. FUNDING National Health and Medical Research Council, and the University of Melbourne.

A proposed modification to the McDonald 2010 criteria for the diagnosis of primary progressive multiple sclerosis.

Background: The diagnostic criteria for primary–progressive multiple sclerosis (PPMS) have undergone revision over the last 20 years. Cerebrospinal fluid oligoclonal bands (CSFOBs) have received less emphasis in recent revisions of the McDonald criteria. The aim of this study was to examine the sensitivity of the diagnostic criteria for PPMS with particular reference to spinal cord criteria and examine the utility of CSFOBs in a cohort of PPMS patients. Methods: All new PPMS diagnoses between 1990 and 2011 were identified. Baseline clinical details and paraclinical evaluations including MRI of the brain, spinal cord, CSF and visually evoked responses (VERs) were assessed. The proportion of patients who met the requirements for diagnosis of PPMS on the basis of Thompson’s and the McDonald Criteria (2001, 2005, 2010) were determined. Results: There were 88/95 PPMS patients who had at least two diagnostic investigations. The sensitivity of Thompson’s and the McDonald 2001 criteria was 64%; the McDonald 2010 revisions gave the highest sensitivity (77%); the McDonald 2005 criteria had intermediate sensitivity (74%). The combination of CSFOBs and MRI of the brain yielded the greatest number of patients demonstrating dissemination in space (DIS) on only two investigations. VERs did not aid diagnosis. Reducing requirements for the number of spinal cord lesions (symptomatic or not) to one increased diagnostic sensitivity to 84%. Conclusion: An alternative criterion requiring two of: i) MRI of the brain with one or more lesions in two of three regions typical for demyelination; ii) the presence of one T2-weighted spinal cord plaque (typical for demyelination); iii) CSFOBs; would increase the diagnostic sensitivity for PPMS.

The longitudinal relationship between the patient-reported Multiple Sclerosis Impact Scale and the clinician-assessed Multiple Sclerosis Functional Composite

Background To examine the longitudinal relationship between the patient-rated Multiple Sclerosis Impact Scale (MSIS-29) and the doctor-reported Multiple Sclerosis Functional Composite (MSFC). Methods Two-hundred and four MS patients at baseline and 150 patients one to three years later had MSFC and MSIS-29 assessments. Cross-sectional correlations between these measures and correlations of change in scores were examined. Minimally important change (MIC) in the MSFC was defined at either 0.5 or 0.32 SD from baseline. Effect sizes (ES) were calculated. Results Validity: The MSIS-29 physical correlated moderately with the total MSFC score and the 25-foot timed walk and 9-hole peg test. Correlations of the MSIS-29 physical with the PASAT, and the MSFC with the MSIS-29 psychological were weak. Responsiveness: When MIC in the MSFC was defined as 0.5, mean MSIS-29 physical change was 11.26 (ES = 0.53). At MSFC change of 0.32, mean MSIS-29 physical change was 10.4 (ES = 0.52). Change in MSFC scores correlated weakly with change in the MSIS-29 scores. Stability: In patients with stable MSFC scores, the mean MSIS-29 physical scores improved minimally over time with negligible ES. Conclusions Although the MSIS-29 physical demonstrates moderate cross-sectional correlation with the MSFC, the weak correlations of change scores between the two instruments indicate that they measure different aspects of the effects of multiple sclerosis morbidity. Multiple Sclerosis 2008; 14: 255—258. http://msj.sagepub.com

Assessment and Classification of Early-Stage Multiple Sclerosis With Inertial Sensors: Comparison Against Clinical Measures of Disease State

A cross-sectional study on patients with early-stage multiple sclerosis (MS) was conducted to examine the reliability of manual and automatic mobility measures derived from shank-mounted inertial sensors during the Timed Up and Go (TUG) test, compared to control subjects. Furthermore, we aimed to determine if disease status [as measured by the Multiple Sclerosis Impact Scale (MSIS-20) and the Expanded Disability Status Score (EDSS)] can be explained by measurements obtained using inertial sensors. We also aimed to determine if patients with early-stage MS could be automatically distinguished from healthy controls subjects, using inertial parameters recorded during the TUG test. The mobility of 38 patients (aged 25-65 years, 14 M, 24 F), diagnosed with relapsing-remitting MS and 33 healthy controls (14 M, 19 F, age 50-65), was assessed using the TUG test, while patients wore inertial sensors on each shank. Reliability analysis showed that 36 of 53 mobility parameters obtained during the TUG showed excellent intrasession reliability, while nine of 53 showed moderate reliability. This compared favorably with the reliability of the mobility parameters in healthy controls. Exploratory regression models of the EDSS and MSIS-20 scales were derived, using mobility parameters and an elastic net procedure in order to determine which mobility parameters influence disease state. A cross-validated elastic net regularized regression model for MSIS-20 yielded a mean square error (MSE) of 1.1 with 10 degrees of freedom (DoF). Similarly, an elastic net regularized regression model for EDSS yielded a cross-validated MSE of 1.3 with 10 DoF. Classification results show that the mobility parameters of participants with early-stage MS could be distinguished from controls with 96.90% accuracy. Results suggest that mobility parameters derived from MS patients while completing the TUG test are reliable, are associated with disease state in MS, and may have utility in screening for early-stage MS.

Hereditary leukoencephalopathy with axonal spheroids: a spectrum of phenotypes from CNS vasculitis to parkinsonism in an adult onset leukodystrophy series

Background Hereditary diffuse leukoencephalopathy with neuroaxonal spheroids (HDLS) is a hereditary, adult onset leukodystrophy which is characterised by the presence of axonal loss, axonal spheroids and variably present pigmented macrophages on pathological examination. It most frequently presents in adulthood with dementia and personality change. HDLS has recently been found to be caused by mutations in the colony stimulating factor-1 receptor (CSF1R) gene. Methods In this study, we sequenced the CSF1R gene in a cohort of 48 patients from the UK, Greece and Ireland with adult onset leukodystrophy of unknown cause. Results Five pathogenic mutations were found, including three novel mutations. The presentations ranged from suspected central nervous system (CNS) vasculitis to extrapyramidal to cognitive phenotypes. The case histories and imaging are presented here, in addition to neuropathological findings from two cases with novel mutations. Conclusion We estimate that CSF1R mutations account for 10% of idiopathic adult onset leukodystrophies and that genetic testing for CSF1R mutations is essential in adult patients presenting with undefined CNS vasculitis or a leukodystrophy with prominent neuropsychiatric signs or dementia.