Sunday, 28 August 2016

Does the early bird get the worm in CIS? The 11 year follow-up to the BENEFIT study

The paper
Kappos, Ludwig, et al. "The 11-year long-term follow-up study from the randomized BENEFIT CIS trial." Neurology (2016): 10-1212.

Multiple Sclerosis (MS) often starts as an individual episode of neurological dysfunction. At this early stage, termed a clinically isolated syndrome (CIS), it is often difficult to predict who will go on to develop definite MS, and who will have no further episodes. Previous trials have shown that early treatment with disease-modifying therapies like interferon β-1b can delay the conversion from CIS to clinically-definite MS. However, it is not known whether early treatment reduces disability and disease progression in the long-term.

To assess the effect of early vs. delayed treatment on long-term outcomes at 11 years after onset of CIS.

The initial BENEFIT trial was a randomised, double-blind, placebo-controlled trial in which participants received either early (n=292) or delayed (n=176) treatment with interferon β-1b after onset of CIS. The early treatment group began treatment within 60 days of onset. The delayed treatment group received placebo until either 2 years after onset of CIS or onset of clinically-definite MS.

After the initial 2 year trial, patients were invited to participate in a 3-year open-label extension. In the 3 year extension period, patients could choose to have any disease-modifying drug/s, or to have no drugs at all. Patients are investigators were not blinded to treatments in this stage.

The 11 year follow-up study reassessed patients who were part of the original trial 11 years after onset of CIS. 278 of the original 468 patients were assessed. This was a cross-sectional, observational study that compared several outcome measures in the early vs delayed treatment groups. The outcomes measured were: risk of conversion to clinically-definite MS, time to conversion, relapse rate, conversion to secondary progressive MS, disability scores, neuropsychometric scores, MRI appearance, and health resource utilisation.

Patients in the early treatment group had a lower risk of conversion to clinically definite MS (66.6% vs 75.0%), a longer lag time until the conversion to clinically definite MS, a lower average annualised relapse rate over the whole study period (0.21 vs 0.26), and a lower risk of conversion to secondary progressive MS (4.5% vs 8.3%). Average EDSS scores were similar in the early and delayed treatment groups.

The early treatment group performed better on the Paced Auditory Serial Addition Task-3 (PASAT-3), in which patients have to add up a series of numbers presented to them via audio at 3-second intervals. There was little difference between early and delayed treatment groups’ MRI appearances or health resource utilisation.

Early treatment (within 6 months) of CIS with interferon β-1b leads to clinical benefit over delayed treatment, and this benefit is sustained 11 years after the onset of CIS.

This impressive study provides a fascinating insight into the long-term consequences of different treatment strategies in early MS/CIS. What these results appear to show is that an aggressive, ‘see and treat’, approach in CIS is better than a ‘watch and wait’ strategy. We knew already from previous incarnations of BENEFIT that early interferon β-1b treatment delays the onset of and reduces the risk of conversion to clinically-definite MS. This 11 year follow-up allows us to work out whether these benefits actually translate into better long-term quality of life for patients.

It is therefore interesting that EDSS scores – a commonly-used measure of disability in MS – were almost identical in the early and delayed treatment groups. This implies that while early treatment may stave off the onset of definite MS, it does not improve long-term disability. There are several possible explanations for this finding. Firstly, the EDSS scores are very low and stable in the study population, and so the study might not be sufficiently powered to detect small differences between the groups. Even still, a small difference in EDSS scores, which might be missed if the study were underpowered, would not necessarily be clinically significant. A biological explanation for the lack of obvious benefit in terms of EDSS score is that the processes involved in disability progression in MS, such as neuronal and synaptic loss, might be quite separate to the processes responsible for relapses.

Another interesting observation is that whilst the overall annualised relapse rate (ARR) was lower in the early treatment group, the ARR was actually slightly lower in the delayed treatment group in the final year of follow-up. This might imply that early treatment produces a long-term but not indefinite reduction in relapse rate, which levels off by year 11. Intuitively, this makes sense, as the participants spent 9 years on whatever treatment they and their doctors opted for, and only 2 years in the stringent, double-blind study period.

Given that participants had received 9 years of treatment since the original study period, it is remarkable that there were sustained benefits of early treatment in terms of overall ARR, risk of conversion to clinically-definite MS, time to conversion, and risk of secondary progressive MS. This could be interpreted as evidence that there is a crucial window of opportunity when patients have their first episode suggestive of MS, and that initiating treatment at this stage produces long-lasting benefits.

On balance, there seems to be little harm in starting CIS treatment as early as possible. However, BENEFIT-11 provides no evidence that this approach leads to long-term differences in disability, the outcome which probably matters most for quality of life. It does provide some evidence that early treatment influences the course of the disease, but this is very difficult to disentangle from effects of other treatment which patients may have tried in the intervening follow-up period.

Controlling flu like symptoms with interferons

Halper J, Centonze D, Newsome SD, Huang D, Robertson C, You X, Sabatella G, Evilevitch V, Leahy L. Management Strategies for Flu-Like Symptoms and Injection-Site Reactions Associated with Peginterferon Beta-1a: Obtaining Recommendations Using the Delphi Technique. Int J MS Care. 2016; 18(4):211-8

BACKGROUND: Flu-like symptoms (FLSs) and injection-site reactions (ISRs) have been reported with interferon beta treatments for multiple sclerosis (MS). We sought to obtain consensus on the characteristics/management of FLSs/ISRs in patients with relapsing-remitting MS based on experiences from the randomized, placebo-controlled ADVANCE study of peginterferon beta-1a.
METHODS: ADVANCE investigators with a predefined number of enrolled patients were eligible to participate in a consensus-generating exercise using a modified Delphi method. An independent steering committee oversaw the development of two sequential Delphi questionnaires. An average rating (AR) of 2.7 or more was defined as consensus a priori.
RESULTS: Thirty and 29 investigators (ie, responders) completed questionnaires 1 and 2, respectively, representing 374 patients from ADVANCE. Responders reported that the incidence/duration of FLSs/ISRs in their typical patient generally declined after 3 months of treatment. Responders reached consensus that FLSs typically last up to 24 hours (AR = 3.17) and have mild/moderate effects on activities of daily living (AR = 3.34). Patients should initiate acetaminophen/nonsteroidal anti-inflammatory drug treatment on a scheduled basis (AR = 3.31) and change the timing of injection (AR = 3.28) to manage FLSs. Injection-site rotation/cooling and drug administration at room temperature (all AR ≥ 3.10) were recommended for managing ISRs. Patient education on FLSs/ISRs was advocated before treatment initiation.
CONCLUSIONS: Delphi responders agreed on the management strategies for FLSs/ISRs and agreed that patient education is critical to set treatment expectations and promote adherence.

The Delphi method is a structured communication method, originally developed as a systematic, interactive forecasting method which relies on a panel of experts. The experts answer questionnaires in two or more rounds.After each round, a  facilitator provides an anonymous summary of the experts’ forecasts from the previous round as well as the reasons they provided for their judgments. Thus, experts are encouraged to revise their earlier answers in light of the replies of other members of their panel. It is believed that during this process the range of the answers will decrease and the group will converge towards the "correct" answer. Finally, the process is stopped after a predefined stop criterion (e.g. number of rounds, achievement of consensus, stability of results) and the mean or median scores of the final rounds determine the results.

It is not my job to make comment on the findings but they may help you if you are using interferons and maybe one of the neuros may comment on this

BrainHealth & ClinicSpeak: chicken or egg?

How healthy is your lifestyle? Have you optimised your brain health? #BrainHealth #ClinicSpeak

"The cross-sectional study below suggests moderate-to-high exercise, moderate alcohol consumption, plant-based omega 3 supplementation and disease-modifying medication are all associated with less disability. Chicken or egg? A knee jerk response would be that it is obvious that all these factors, lifestyle or not must be affecting the natural history of MS. With the exception of DMTs we don't have class one evidence of this, i.e. randomised blinded intervention studies. These observations can all be reverse causation, i.e. mild MS, or less disabling MS, may simply be associated with better lifestyle choices. It is unlikely that we are going to get first class evidence anytime soon so it will need to be a judgement call you need to take. There are strong scientific arguments to support a healthy lifestyle impacting positively on MS outcomes, which is one of the pillars of our Brain Health campaign. The decision in my opinion, whether or not you have MS, is when are you going to take control of your own life and live the lifestyle that will optimise your long-term brain health? "

Jelinek et al. Associations of Lifestyle, Medication, and Socio-Demographic Factors with Disability in People with Multiple Sclerosis: An International Cross-Sectional Study. PLoS One. 2016 Aug 25;11(8):e0161701. doi: 10.1371/journal.pone.0161701. eCollection 2016.

OBJECTIVE: Emerging evidence links modifiable lifestyle risk factors to disease progression in multiple sclerosis (MS). We sought further evidence around this hypothesis through detailed analysis of the association with disability of lifestyle behaviours of a large international sample of people with MS.

MATERIALS AND METHODS: A total of 2469 people with MS from 57 countries provided self-reported data via cross-sectional online survey on lifestyle (mostly with validated tools) and the primary outcome measure, disability (Patient Determined Disease Steps), categorised from 8 steps into 3 categories, mild, moderate and major disability. Multinomial logistic regression modelling derived relative risk ratios (RRRs) for disability categories.

RESULTS: RRRs of having moderate vs mild disability were: diet (per 30 points on 100 point scale) 0.72 (95%CI 0.52-0.98), ever smoking 1.32 (1.06-1.65), exercise (moderate/high vs low) 0.35 (0.28-0.44), latitude (per degree from the equator) 1.02 (1.01-1.04), and number of comorbidities (2 vs none) 1.43 (1.04-1.95), (3 vs none) 1.56 (1.13-2.16). RRRs of having major vs mild disability were: exercise (moderate/high vs low) 0.07 (0.04-0.11), alcohol consumption (moderate vs low) 0.45 (0.30-0.68), plant-based omega 3 supplementation 0.39 (0.18-0.86), and disease-modifying medication use 0.45 (0.29-0.70).

CONCLUSIONS: Healthier lifestyle has strong associations with disability in our large international sample of people with MS, supporting further investigation into the role of lifestyle risk factors in MS disease progression.

Saturday, 27 August 2016

Cognitive Problems picked up years before diagnosis

Cortese M, Riise T, Bjørnevik K, Bhan A, Farbu E, Grytten N, Hogenesch I, Midgard R, Smith Simonsen C, Telstad W, Ascherio A, Myhr KM.Pre-clinical disease activity in multiple sclerosis- a prospective study on cognitive performance prior to first symptom.
Anals Neurology. 2016. doi: 10.1002/ana.24769. [Epub ahead of print]

OBJECTIVE: To prospectively investigate potential signs of pre-clinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.
METHODS: We linked the cognitive performance of all Norwegian men born in 1950-95 that underwent conscription examination at ages 18-19 to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study cognitive test-scores were available for 924/19530 male cases/controls. We estimated mean score differences among cases and controls and the risk of developing MS comparing lower to higher scores in strata of years to clinical onset.
RESULTS: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ=0.80, p=0.0095), corresponding to a 6 intelligence quotient (IQ)-points difference. Those scoring lowest, i.e. over 1 standard deviation below the controls' mean, had an increased MS risk during the two following years (relative risk=2.81, 95% confidence interval: 1.52-5.20). While results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored 4.6-6.9 IQ-points significantly lower than controls up to 20 years prior to first progressive symptoms.
INTERPRETATION: RRMS may start years prior to clinical presentation and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. 

This study indicates that there may be problems with MS before diagnosis with MS, and you say....yes I know. I remember this or that happening, before I was diagnosed.

This study confirms that reported previously in Argentinian school children, where they looked at performance in maths tests years before diagnosis.

Mult Scler. 2015;21(7):945-52.
In this study the test was when Norwegian people were being conscripted to undertake their National Service that there may be subtle changes in the brains of people with MS before they get a diagnosis.

This is hardly surprising if we pay any attention to the migration studies (e.g. from low to high risk areas) and risk of MS. These suggest that you come into contact with the trigger before the age of fifteen. That most people do not get diagnosed until their mid twenties or later says that something must be going on for years before it is noticed. 

Likewise we know about radiologically isolated syndrome, where people having a brain scan show up with MS lesions years before they get a clinical diagnosis. 

Is this the relapsing phase of people with primary progressive MS?

Is this surprising or new to you?

ClinicSpeak: anal irrigation is cost-effective

Are you suffering from intractable constipation and faecal incontinence? #ClinicSpeak #MSResearch 

"I forgot my rose-tinted spectacles at home. Some of you don't like the messy side of MS-related disability and if you are one of those please look away now."
"The paper below looks at the cost-effectiveness of transanal irrigation in patients with neurogenic bowel dysfunction. It comes as no surprise that transanal irrigation is a cost-saving treatment strategy reducing risk of stoma surgery, UTIs, episodes of  faecal incontinence and improving quality of life in patients who have failed standard bowel care. It is important to realise that to remain independent MSers need to maintain upper limb and hand function. This is particularly important if you want to manage the anal irrigation system yourself. Anal irrigation is another reason to support our #ThinkHand campaign."

"I have posted many times in the past on constipation and bowel dysfunction, so many of you may find this, and other posts like it, repetitive. If you do have bowel problems and are not coping please contact your MS team for help; there is a lot we can do."

Multiple Sclerosis Research: ClinicSpeak: constipation and MS
Mar 16, 2016 - The cause is multifactorial and related to many factors; poor diet, medication, lack of exercise, dehydration and slow bowel movements due to ...

Multiple Sclerosis Research: ClinicSpeak: rectal dysfunction
Sep 8, 2014 - #ClinicSpeak #MSBlog #MSResearch "This weekend was ... "This abstract highlights the problem of bowel dysfunction that is common in MS.

Emmanuel et al. Long-Term Cost-Effectiveness of Transanal Irrigation in Patients with Neurogenic Bowel Dysfunction. PLoS One. 2016 Aug 24;11(8):e0159394. doi: 10.1371/journal.pone.0159394. eCollection 2016.

BACKGROUND: People suffering from neurogenic bowel dysfunction (NBD) and an ineffective bowel regimen often suffer from fecal incontinence (FI) and related symptoms, which have a huge impact on their quality of life. In these situations, transanal irrigation (TAI) has been shown to reduce these symptoms and improve quality of life.

AIM: To investigate the long-term cost-effectiveness of initiating TAI in patients with NBD who have failed standard bowel care (SBC).

METHODS: A deterministic Markov decision model was developed to project the lifetime health economic outcomes, including quality-adjusted life years (QALYs), episodes of FI, urinary tract infections (UTIs), and stoma surgery when initiating TAI relative to continuing SBC. A data set consisting of 227 patients with NBD due to spinal cord injury (SCI), multiple sclerosis, spina bifida and cauda equina syndrome was used in the analysis. In the model a 30-year old individual with SCI was used as a base-case. A probabilistic sensitivity analysis was applied to evaluate the robustness of the model.

RESULTS: The model predicts that a 30-year old SCI patient with a life expectancy of 37 years initiating TAI will experience a 36% reduction in FI episodes, a 29% reduction in UTIs, a 35% reduction in likelihood of stoma surgery and a 0.4 improvement in QALYs, compared with patients continuing SBC. A lifetime cost-saving of £21,768 per patient was estimated for TAI versus continuing SBC alone.

CONCLUSION: TAI is a cost-saving treatment strategy reducing risk of stoma surgery, UTIs, episodes of FI and improving QALYs for NBD patients who have failed SBC.