M Duggan

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.

Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype

Background The relationship between prevalence of multiple sclerosis (MS) and latitude may be due to both genetic and environmental factors. The hypothesis that, in Ireland, MS prevalence is increasing and that north–south differences relate to variation in serum 25-hydroxyvitamin D (25(OH)D) levels was tested in this study. Patients and methods Patients and matched control subjects were identified in counties Donegal, Wexford and South Dublin through multiple sources. Prevalence was determined. Blood samples were taken for serum 25(OH)D and serum intact parathyroid hormone measurement, and DNA was extracted. Results Prevalence in 2007 was significantly greater in Donegal (northwest) (290.3/105, 95% CI 262.3 to 321.7) compared with 2001 (184.6/105; 162 to 209.5). In Wexford (southeast), there was a non-significant increase in prevalence in 2007 compared with 2001. Prevalence was significantly higher in Donegal than in Wexford (144.8/105; 126.7 to 167.8, p<0.0001) and South Dublin (127.8/105; 111.3 to 148.2, p<0.0001). Overall, mean 25(OH)D levels were low and did not differ between patients (38.6 nmol/l) and controls (36.4 nmol/l) However, significantly more patients than controls had 25(OH)D levels <25 nmol/l (deficiency) (p=0.004). Levels of 25(OH)D (mean 50.74 nmol/l) were significantly higher in South Dublin (area with lowest prevalence) (p<0.0001) than in Donegal or Wexford. HLA DRB1*15 occurred most frequently in Donegal (greatest MS prevalence) and least frequently in South Dublin. Conclusion Vitamin D deficiency is common in Ireland. Latitudinal variation in MS probably relates to an interaction between genetic factors and environment (25(OH)D levels), and MS risk may be modified by vitamin D in genetically susceptible individuals.

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.

Discontinuing disease-modifying therapy in progressive multiple sclerosis: can we stop what we have started?

Disease-modifying therapy is ineffective in disabled patients (Expanded Disability Status Scale [EDSS] > 6.5) with secondary progressive multiple sclerosis (MS) without relapses, or in primary progressive MS. Many patients with secondary progressive MS who initially had relapsing MS continue to use disease-modifying therapies. The enormous associated costs are a burden to health services. Regular assessment is recommended to guide discontinuation of disease-modifying therapies when no longer beneficial, but this is unavailable to many patients, particularly in rural areas. The objectives of this study are as follows: 1. To observe use of disease-modifying therapies in patients with progressive multiple sclerosis and EDSS > 6.5. 2. To examine approaches used by a group of international MS experts to stopping-disease modifying therapies in patients with secondary progressive MS without relapses. During an epidemiological study in three regions of Ireland (southeast Dublin city, and Wexford and Donegal Counties), we recorded details of disease-modifying therapies in patients with progressive MS and EDSS > 6.5. An e-questionnaire was sent to 26 neurologists with expert knowledge of MS, asking them to share their approach to stopping disease-modifying therapies in patients with secondary progressive MS. Three hundred and thirty-six patients were studied: 88 from southeast Dublin, 99 from Wexford and 149 from Donegal. Forty-four had EDSS > 6.5: 12 were still using disease-modifying therapies. Of the surveyed neurologists, 15 made efforts to stop disease-modifying therapies in progressive multiple sclerosis, but most did not insist. A significant proportion (12 of 44 patients with progressive MS and EDSS > 6.5) was considered to be receiving therapy without benefit. Eleven of the 12 were from rural counties, reflecting poorer access to neurology services. The costs of disease-modifying therapies in this group (>170,000 yearly) could be re-directed towards development of neurology services to optimize their management.

Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy.

Natalizumab therapy in multiple sclerosis has been associated with JC polyomavirus—induced progressive multifocal leucoencephalopathy. We hypothesized that natalizumab may also lead to reactivation of BK, a related human polyomavirus capable of causing morbidity in immunosuppressed groups. Patients with relapsing remitting multiple sclerosis treated with natalizumab were prospectively monitored for reactivation of BK virus in blood and urine samples, and for evidence of associated renal dysfunction. In this cohort, JC and BK DNA in blood and urine; cytomegalovirus (CMV) DNA in blood and urine; CD4 and CD8 T-lymphocyte counts and ratios in peripheral blood; and renal function were monitored at regular intervals. BK subtyping and noncoding control region sequencing was performed on samples demonstrating reactivation. Prior to commencement of natalizumab therapy, 3 of 36 patients with multiple sclerosis (8.3%) had BK viruria and BK reactivation occurred in 12 of 54 patients (22.2%). BK viruria was transient in 7, continuous in 2 patients, and persistent viruria was associated with transient viremia. Concomitant JC and CMV viral loads were undetectable. CD4:CD8 ratios fluctuated, but absolute CD4 counts did not fall below normal limits. In four of seven patients with BK virus reactivation, transient reductions in CD4 counts were observed at onset of BK viruria: these resolved in three of four patients on resuppression of BK replication. No renal dysfunction was observed in the cohort. BK virus reactivation can occur during natalizumab therapy; however, the significance in the absence of renal dysfunction is unclear. We propose regular monitoring for BK reactivation or at least for evidence of renal dysfunction in patients receiving natalizumab.

Economic costs associated with an MS relapse

BACKGROUND Multiple sclerosis (MS) commonly affects young adults and can be associated with significant disability resulting in considerable socioeconomic burden for both patient and society. AIMS The aim was to determine the direct and indirect cost of an MS relapse. METHODS This was a prospective audit composed of medical chart review and patient questionnaire. Relapses were stratified into 3 groups: low, moderate and high intensity. Age, gender, MS subtype, disease duration, expanded disability status scale (EDSS) score, disease modifying therapy (DMT) use and employment status were recorded. Direct costs included GP visits, investigations, clinic visit, consultations with medical staff, medication and admission costs. Indirect costs assessed loss of earnings, partner׳s loss of earnings, childcare, meals and travel costs. RESULTS Fifty-three patients had a clinically confirmed relapse. Thirteen were of low intensity; 23 moderate intensity and 17 high intensity with mean costs of €503, €1395 and €8862, respectively. Those with high intensity episodes tended to be older with higher baseline EDSS (p<0.003) and change in EDSS (p<0.002). Direct costs were consistent in both low and moderate intensity groups but varied with length of hospital stay in the high intensity group. Loss of earnings was the biggest contributor to indirect costs. A decision to change therapy as a result of the relapse was made in 23% of cases, further adding to annual MS related costs. CONCLUSIONS The cost of an MS relapse is dependent on severity of the episode but even low intensity episodes can have a significant financial impact for the patient in terms of loss of earnings and for society with higher annual MS related costs.

Using atypical symptoms and red flags to identify non-demyelinating disease

Background Red flags and atypical symptoms have been described as being useful in suggesting alternative diagnoses to multiple sclerosis (MS) and clinically isolated syndrome (CIS); however, their diagnostic utility has not been assessed. The aim of this study was to establish the predictive value of red flags and the typicality/atypicality of symptoms at presentation in relation to the final diagnosis of patients referred with suspected MS. Methods All patients referred with suspected MS over a 3-year period were assessed by the typicality of the clinical presentation and the occurrence of red flags in relation to the eventual diagnosis. The extent of agreement of trainee and consultant neurologists as to typicality of clinical presentations was determined. Results Of 244 patients referred, 119 (49%) had MS/CIS and 125 (51%) did not. 41 patients were referred because of an abnormal MRI. Of 203 with clinical symptoms, 96 patients had atypical symptoms of whom, 81 (84%) did not have MS and 15 (16%) had MS/CIS. Typical symptoms occurred in 107 patients; 10% did not have MS/CIS. Atypical symptoms had a sensitivity of 84%, specificity of 90% and positive likelihood ratio (PLR) of 8.4, whereas red flags had a sensitivity of 47%, specificity of 88% and PLR of 3.9 for the exclusion of MS/CIS. Mean percentage agreement between consultants and trainees was 73% with a range of 32–96%. Conclusions Atypical features at presentation are more sensitive, specific and have a higher PLR than red flags to refute a diagnosis of MS/CIS.

Unmet needs of multiple sclerosis patients in the community.

BACKGROUND There is no evidence that disease modifying therapies (DMTs) are beneficial in progressive (non-relapsing) MS. However, these patients may benefit from multidiscipliniary interventions, and require financial and community support. Non-pharmacological needs of MS patients may be overlooked during fund allocation, and identification of unmet needs is important to optimise care and inform governmental resource distribution. AIM To identify unmet needs of MS patients in 3 areas during an Irish epidemiology study. PATIENTS AND METHODS Observational study in 3 regions in Ireland: South Dublin SCD (an urban area), Donegal DGL and Wexford WEX (rural counties).A validated Needs Assessment Questionnaire (NAQ) was completed by MS patients at research clinics, or by telephone if unable to attend. RESULTS We identified 632 patients with multiple sclerosis: 23% SCD (urban), 30.8% WEX, and 46.2% DGL.MS subtype was relapsing remitting (RR) in 51.1%, secondary progressive (SP) in 39.7%, and primary progressive (PP) in 9.2%. EDSS was </=6 in 86% and >6.5 in 14%. NAQ was completed by 325 (49.9%).Group A: 155 (47.7%) reported no unmet needs relating to MS.Group B: 170 (52.3%) reported unmet needs relating to MS,including all in a group continuing to use disease-modifying therapy without benefit (EDSS>6.5).Number of unmet needs per patient in group B: 1 need 27%, ≥2 needs 73%, ≥5 24%.Unmet needs overall correlated with EDSS >6.5 (p<0.001),MS subtype: RR 36.4%/SP 69.8%/PP 59.5% (p<0001),increased age (p 0.003) and MS duration (p 0.003). Multivariate analysis: presence of unmet needs related to higher EDSS (p<0.001), rural residence (p<0.05), SPMS (p<0.05).Financial unmet needs frequency differed by county: DGL 23.9%, WEX 17%, SCD 10.4% (p 0.045) and marital status: 24% single, 13.5% married (p 0.03).Multivariate analysis: related to rural residence (p<0.05), being single (p<0.05).Occupational therapy (OT) unmet needs frequency differed by subtype:RR 6%/SP 24.5%/ PP 19% (p 0.001), MS duration: 19.7 v 14.8y (p 0.003)and increasing age: 52.5 v 45.8y (p 0.0006).Multivariate analysis: rural, older age, higher EDSS (p<0.05).Physiotherapy unmet needs frequency differed by subtype: RR 17.2%/SP 43.4%/PP 31.7% (p<0.001), MS duration (p<0.001), and age (p 0.002).Multivariate analysis: related to higher EDSS (p<0.001).Employment unmet needs frequency differed by gender:male 22.9%, female 12.8% (p 0.02).Social unmet needs frequency differed by subtype: RR 12%/SP 39.2%/PP 32.5%, MS duration and age (p 0.001): multivariate analysis: SPMS (p<0.001). DISCUSSION More than 50% reported unmet needs relating to MS: suggesting non-pharmacological needs are not optimally addressed, particularly in older, single, rural residents, with greater EDSS and progressive non-relapsing MS. Physiotherapy offers significant benefits, but is the most frequently reported unmet need.These findings highlight the need for increased fund allocation, especially for development of community supports and multidisciplinary/ social services.Identifying unmet needs may help inform health service planning, and emphasises particular need for improved resources in a high-risk group of MS patients.

Multiple Sclerosis, from referral to confirmed diagnosis: an audit of clinical practice

Background: The National Institute for Health and Clinical Excellence (NICE) guidelines recommend a timeline of 6 weeks from referral to neurology consultation and then 6 weeks to a diagnosis of multiple sclerosis (MS). Objectives: We audited the clinical management of all new outpatient referrals diagnosed with MS between January 2007 and May 2010. Methods: We analysed the timelines from referral to first clinic visit, to MRI studies and lumbar puncture (LP) (if performed) and the overall interval from first visit to the time the diagnosis was given to the patient. Results: Of the 119 diagnoses of MS/Clinically Isolated Syndrome (CIS), 93 (78%) were seen within 6 weeks of referral. MRI was performed before first visit in 61% and within 6 weeks in a further 27%. A lumbar puncture (LP) was performed in 83% of all patients and was done within 6 weeks in 78%. In total, 63 (53%) patients received their final diagnosis within 6 weeks of their first clinic visit, with 57 (48%) patients having their diagnosis delayed. The main rate-limiting steps were the availability of imaging and LP, and administrative issues. Conclusions: We conclude that, even with careful scheduling, it is difficult for a specialist service to obtain MRI scans and LP results so as to fulfil NICE guidelines within the optimal six-week period. An improved service would require MRI scans to be arranged before the first clinic visit in all patients with suspected MS.

The Importance of CSF Oligoclonal Bands in the Diagnosis of Primary Progressive Multiple Sclerosis (P01.139)

Objective: To evaluate the importance of CSF OCBs in determining a diagnosis of PPMS. Background The 2010 McDonald revisions to the diagnosis of primary progressive MS (PPMS) have amended the criteria for evidence of dissemination in space (DIS) in the brain and spinal cord. Either of the latter may be replaced by the presence of CSF oligoclonal bands (CSFOBs). Visually evoked responses (VERs) are no longer useful in confirming DIS by reducing the number of T2 lesions on brain MRI. MRI brain changes due to small vessel disease may simulate MS lesions and spinal cord lesions may be too small to visualise on standard MRI. Thus the presence of CSFOBs may have high diagnostic importance in PPMS. Design/Methods: A retrospective review of all patients with a diagnosis of PPMS seen from 1985-2010. The age and mode of presentation, results of brain and spinal cord MRI were documented. Patients who had failed to satisfy the revised McDonald criteria on baseline imaging and identified patients in whom CSF contributed to establishing the diagnosis. Results: Of 118 PPMS patients, mean age at onset 41 years, baseline imaging data (brain or cord or both) was available in 99 (84%). Of 27/99 satisfying both imaging criteria, 21/27 had CSF; 86% had CSFOBs. Only 48 patients had MRI brain, cord & CSF. Of these, 39 patients had imaging which failed to meet the revised McDonald criteria (12 brain, 27 cord MRI). In 19 of these 39 patients the presence of CSFOBs satisfied the criteria. Five patients who did not meet either brain or cord MRI criteria had positive CSFOBs. VERs were performed in 10/39, two had a positive result; both had CSFOBs. Conclusions: In our PPMS cohort, 49% did not satisfy the McDonald criteria by MRI alone and CSFOBs aided the diagnosis. CSFOBs have significant utility in confirming DIS in PPMS. Disclosure: Dr. Kelly has received personal compensation for activities with Novartis, Biogen-Idec and Tysabri as a speaker. Dr. Kinsella has received personal compensation for activities with Sanofi-Aventis Pharmaceuticals & Biogen Idec. Dr. Duggan has received personal compensation for activities with Novartis. Dr. McGuigan has received personal compensation for activities with Biogen Idec and Merck Serono. Dr. Tubridy has received research support from Bayer Pharmaceuticals Corporation, the Health Research Board of Ireland and MS Ireland. Dr. Hutchinson has received personal compensation for activities with Biogen Idec as a speaker.