Siobhan Kelly

Does natalizumab therapy worsen neuromyelitis optica

We report 3 cases of continuing disease activity and possible exacerbation of neuromyelitis optica (NMO) on natalizumab. ### Case reports. #### Case 1. A 33-year-old woman presented in June 1995 with optic neuritis, followed by left hemiparesis. Multiple sclerosis (MS) was diagnosed and she was

A pilot study of the immunological effects of high-dose vitamin D in healthy volunteers

Although vitamin D deficiency is considered an environmental factor in multiple sclerosis (MS), the immunological and clinical effects of vitamin D supplementation remain unclear. We performed a pilot study of the immunomodulatory effects of vitamin D in healthy individuals (n=4), who took 5000–10,000 IU/day of vitamin D over 15 weeks. After 15 weeks of vitamin D supplementation, serum 25(OH) vitamin D levels rose significantly from baseline, with a corresponding increase in IL-10 production by peripheral blood mononuclear cells and a reduced frequency of Th17 cells. These data provide a strong rationale for randomised trials to assess the clinical effects of vitamin D supplementation in MS.

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.

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.

Dose-related effects of vitamin D on immune responses in patients with clinically isolated syndrome and healthy control participants: study protocol for an exploratory randomized double- blind placebo-controlled trial

BackgroundThere is increasing evidence linking vitamin D deficiency to both susceptibility to, and severity of, multiple sclerosis (MS). Patients with the clinically isolated syndrome represent the initial presentation of a demyelinating disorder, and those with asymptomatic lesions on magnetic resonance imaging (MRI) are at risk of progression to clinically definite MS. The aims of this study are to examine the immunologic effects of vitamin D in both healthy individuals and in patients with clinically isolated syndrome, and in the latter group the effects on disease progression assessed by MRI and clinical measures.Methods/DesignThis is a single-center double-blind randomized placebo-controlled clinical trial. The primary endpoint is the immunologic effects of two doses of vitamin D compared with placebo over 24 weeks in both healthy control participants and patients presenting with the clinically isolated syndrome. Healthy control participants (n = 39) and patients with clinically isolated syndrome (n = 45) will be randomized to one of three arms, namely 1) vitamin D 5,000 IU daily, 2) vitamin D 10,000 IU daily, or 3) placebo, and followed up for 24 weeks. In both patients and healthy control participants, the primary outcome will be immunologic measures of the frequency of CD4 T-cell subsets and cytokine responses in peripheral blood mononuclear cells, assessed at baseline, and after 16 and 24 weeks of treatment. Secondary endpoints, in the patients with clinically isolated syndrome, will be relapse activity, and the number of new T2 lesions and gadolinium-enhancing lesions assessed by MRI in the two vitamin D-treated groups compared with the placebo-treated group over the 24 weeks of the study.Trial registrationEU Clinical Trials Register: EudraCT: 2012-000635-68. ClinicalTrials.gov identifier: NCT01728922

Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients.

OBJECTIVE To examine the correlation between the change in PASAT and the change in P3 event-related potentials (ERPs) over a 12-month period in multiple sclerosis (MS) patients, and to compare the 12-month change in the P3 ERP between MS patients and controls. METHODS Forty-four subjects (27 MS patients, 17 controls) completed visual and auditory two-stimulus oddball and three-stimulus oddball tasks at Month 0 and Month 12. Data were recorded from a 128-scalp channel electroencephalography array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Amplitude, topographical differences and correlations were then tested using statistical parametric mapping. RESULTS The change in visual and auditory P3a correlated significantly with the change in PASAT score (r=0.56, p<0.001 and r=0.48, p=0.003, respectively). Visual P3b and P3a showed greater decrease in 12 months in MS patients relative to controls. Visual P3b, auditory P3b and auditory P3a amplitudes had significantly decreased in MS patients after 12-month period. CONCLUSIONS Change in visual and auditory P3a ERP amplitudes correlate with change in PASAT scores in MS patients. Visual modality is more sensitive to changes in P3 ERP amplitudes over 12-month period. SIGNIFICANCE P3 ERPs may have utility in monitoring the change in cognitive functioning in MS.

Symptom overlap in anxiety and multiple sclerosis

Background: The validity of self-rated anxiety inventories in people with multiple sclerosis (pwMS) is unclear. However, the appropriateness of self-reported depression scales has been widely examined. Given somatic symptom overlap between depression and MS, research emphasises caution when using such scales. Objective: This study evaluates symptom overlap between anxiety and MS in a group of 33 individuals with MS, using the Beck Anxiety Inventory (BAI). Methods: Participants underwent a neurological examination and completed the BAI. Results: A novel procedure using hierarchical cluster analysis revealed three distinct symptom clusters. Cluster one (‘wobbliness’ and ‘unsteady’) grouped separately from all other BAI items. These symptoms are well-recognised MS-related symptoms and we question whether their endorsement in pwMS can be considered to reflect anxiety. A modified 19-item BAI (mBAI) was created which excludes cluster one items. This removal reduced the number of MS participants considered ‘anxious’ by 21.21% (low threshold) and altered the level of anxiety severity for a further 27.27%. Conclusion: Based on these data, it is suggested that, as with depression measures, researchers and clinicians should exercise caution when using brief screening measures for anxiety in pwMS.

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.

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.

Effects of vitamin D3 in clinically isolated syndrome and healthy control participants: A double-blind randomised controlled trial:

Background Lowserum vitamin D levels are associated with susceptibility to, and severity of, multiple sclerosis. High dose vitamin D has been proposed as a potential immunomodulator in multiple sclerosis. Objectives We performed a single centre, investigator-led, exploratory, double-blind, randomised, placebo controlled, trial of vitamin D3 in clinically isolated syndrome and healthy control participants to assess its immunological effects. Secondary end-points included clinical and magnetic resonance imaging outcomes and safety. Methods Clinically isolated syndrome patients and healthy control participants were randomised to: placebo, 5000 IU or 10,000 IU vitamin D3/day (Vigantol oil). Study duration was 24 weeks. Results The trial did not meet its primary end point, with no difference in the frequency of pro-inflammatory CD4+ T cells (interleukin (IL)-17+/interferon (IFN)-γ+) seen. A higher level of disease freedom (67% versus 50%) was seen in those with serum 1,25 (OH) vitamin D levels>100 nmol/l but this did not reach significance. High dose vitamin D3 was well tolerated with no safety signal. Conclusions High dose vitamin D3 over 24 weeks was well tolerated but without immunological, magnetic resonance imaging or clinical evidence of benefit. The hypothesised therapeutic effects in clinically isolated syndrome or multiple sclerosis patients may require longer periods of administration or may only be seen in patients treated with vitamin D3 as an adjunct to established disease modifying therapies.