Saturday, 25 February 2017

#ClinicSpeak & #ResearchSpeak: chubby, female and young are not a good mix

Can you reduce the chances of your children getting MS? #ClinicSpeak #ResearchSpeak #MSBlog

Obesity, in particular adolescent obesity, is a risk factor for developing MS. The study below shows that this risk, not surprisingly, extends into childhood or paediatric MS. 

Is obesity simply associated with MS due to another factor or does obesity act in the MS causal pathway? An example of an association would be that its actually low vD levels, or lack of outdoor activity and less sun exposure, that is the causal factor. People who have less outdoor activity tend to be more sedentary and hence more likely to be obese. The risk factor here is less outdoor activity and not the associated obesity. 

Obesity could be causal if some part of adipose tissue biology interacts with the MS causal pathway. An example of this is could be one of pro-inflammatory mediators that adipose tissue produces, and there are many such mediators, prime the immune system to develop autoimmunity. In other words if there was less adipose tissue, and as a result less adipose tissue induced systemic inflammation, then the risk of autoimmunity will drop.

Another way adipose tissue may interfere with the causal pathway is actually via vD metabolism. Adipose tissue may lower systemic vD levels by consuming vD as part of its metabolism. The low vitamin D level, and not the obesity, that is the risk factor here.

The only way to answer the association vs. causation question is to do a randomised controlled trial of a dietary, or pharmacological intervention, which reverses or prevents adolescent obesity, and to see if the intervention reduces the risk of developing MS. This type of trial would be very difficult to do and in my opinion is not feasible now. It may become feasible when we have a pharmaceutical that effectively treats obesity; with drugs it is easier to do randomised controlled trials. With lifestyle interventions, particularly weight loss and obesity, this is even more difficult when the outcome needs to be looked at a population level.

A cheaper, and cleverer, way to do randomised-controlled trial to prove causation is to use the Mendelian randomization method and to see if the genetic variants that are linked to obesity are risk factors for developing MS. 

An earlier study using people from California registered with the Kaiser Permanente HMO and a replication sample from Sweden showed just this. The investigators constructed a weighted genetic risk score using genetic variants previously established to predict obesity. Subjects with higher genetically-induced obesity scores had a higher risk of developing MS. Although the investigators controlled for birth year, sex, education, smoking status, ancestry, and genetic predictors of MS they clearly couldn't control for other important con-founders that are very relevant to this analysis, for example dietary factors, exercise - in particular out-door activity - and vD levels. Despite this that study suggested that obesity is probably part of the MS causal pathway and that if we want to reduce the incidence of MS in the population we need to tackle the problem of adolescent obesity. 

Tackling adolescent obesity is much easier said than done! However, if you have MS and you children are already at higher risk of developing MS you may want to think about this more seriously. 

In high prevalence areas such as Western Europe the lifetime risk of a woman developing MS is ~ 1 in 500 (background population risk). If you are a woman with MS and have children you need o be aware that the chance of your daughter(s) getting the disease is ~ 1 in 40 and your son(s) ~1 in 80. Would you want to do everything you can to lower that risk? 

Chitnis et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Ann Clin Transl Neurol. 2016 Nov 4;3(12):897-907.

OBJECTIVE: The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.

METHODS: Case-control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex- and age-stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex-stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.

RESULTS: Only 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).

INTERPRETATION: Higher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

Secondary Progressive EAE. Is it the astrocyte?

Some body asked me to comment on this paper.

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017;114(8):2012-2017.

Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.

I said that I was reluctant to do this.....The human data is out there for every one to see.

However, it did reach the news and so here is my take, which you asked for. 

I've been told I have been abit grumpy. Maybe I should enthuse more, but research is about questioning

If you are not interested in understanding science papers and their problems, then this is not for you. 

If you think every thing in science is clear cut then read on... as we make black and white become grey.

For science readers it is food for thought. 

In the above paper they say "Following immunization......NOD (non-obese diabetic) mice initially develop an acute neurological event, which is followed by a chronic progressive phase that starts at approximately day 25" 
When they looked in the CNS of animals treated for ages with fingolimod they found reduced activation of the innate immune system 

Then the study looks at the effect of the drug on isolated astrocytes and importantly human astrocytes and finds a number of pro-inflammatory genes down regulated, some are upregulated like IL-10 and neurotoxicity goes down, through blockade of one of the central transcription factors controlling inflammatory signalling. 
So they suggest that fingolimod is going to protect nerves and fingolimod will stop secondary progressive MS. 

It is however pointed out that fingolimod actually failed to affect primary progressive MS, but there was some effect in secondary progressive MS with siponimod. This study sponsored by Novartis, makes it look promising. Maybe Siponimod works via blocking astrocytes

However whilst the message in the paper is crystal clear, the supporting EAE is perhaps not quite as clear cut as it seems.

We have a read round the subject because if this study highlights a quick way to find treatments for progressive MS, we need to be doing this. 

However, NOD mice develop diabetes and so are classed as a harmful mutants, creating more problems to use them. Generally however the adjuvants used to cause EAE, block NOD mice from becoming diabetic. Anyway back to the study.

First thing to be said, in contrast to the suggestion tin the paper, there were studies looking at chronic EAE, years before this current report.

It was not mentioned...wonder why I get grumpy:-)

Al-Izki S, Pryce G, Jackson SJ, Giovannoni G, Baker D. Immunosuppression with FTY720 is insufficient to prevent secondary progressive neurodegeneration in experimental autoimmune encephalomyelitis. Mult Scler. 2011;17(8):939-48

In a similar experiment in ABH mice treated with fingolimod, there was a marked effect on disease with treated animals. So the results look the similar but perhaps the treatment effect was much more marked.

There was less nerve damage and less myelin loss, however              the interpretation was somewhat different. 

It was not that this was about astrocytes, they were not looked at, but it was that fingolimod was blocking relapses.

This is because the model in relapsing progressive, where relapses occur but animals recover with increasing deficit. The relapses burn out after 3-4 attacks and you get a very slow worsening of disease (secondary progression starting months after disease onset) that does not respond to T cell inhibition and incidentally did not respond to fingolimod treatment, so suggesting that fingolimod may fail in progressive MS, which it was subsequently shown to do.

ProfG has mentioned the importance of "Thinkhand" as a treatment option and has reported that ocrelizumab and natalizumab have protected hand function in the none hole peg test. However the trials with S1P1 modulators have not reported effects on hand function. Why not?

It must tell us something but what?

Anyway in the first study (above) the beasties were treated from day 40 and "FTY720 ameliorated progressive NOD EAE without significant effects on the peripheral T-cell response".  So we have a difference in World View.

However, this was measured by monitoring T cell responses from the spleen. However, as the response of the drug is to keep cells in lymphoid organs, would we be expecting a decrease in T cell function..maybe if we looked at the blood there may had been an effect. However the inference is clear this is workig via blockade of astrocytes and not T cells  

However, we need to look at the history of the generation of the progressive model.

We studied EAE in NOD mice many years ago, where it was clear that this was a low-EAE susceptibly strain

Genetic analysis of experimental allergic encephalomyelitis in mice. Baker D, Rosenwasser OA, O'Neill JK, Turk JL. J Immunol. 1995;155(8):4046-51.

We also showed that the mice would respond to MOG.

Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. Amor S, Groome N, Linington C, Morris MM, Dornmair K, Gardinier MV, Matthieu JM, Baker D. J Immunol. 1994;153(10):4349-56.

The NOD mice and ABH mice share a transplantation antigen called H-2Ag7 that is used to recognise the myelin oligodendrocyte glycoprotein. The MOG 35-55 epitope is a minor disease causing epitope. Similar it may not be the major target in C57BL/6 mice (type of mouse) either.

Delarasse C, Smith P, Baker D, Amor S.Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunology. 2013;140(4):456-64.

Yes I know I'm just gettin gthe altmetrics up:-)

Anyway back to NOD mouse EAE and the suggestion that is a progressive EAE model. 

Basso AS, Frenkel D, Quintana FJ, Costa-Pinto FA, Petrovic-Stojkovic S, Puckett L, Monsonego A, Bar-Shir A, Engel Y, Gozin M, Weiner HL. Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis. J Clin Invest. 2008;118:1532-4

They said when 10-week-old NOD mice were immunized with MOG35–55 ..., the first signs of disease appeared at days 11–12 (peaking at days 16–18), and after partial recovery from this initial acute attack, there was a progressively worsening relapse without full remission. This was then followed by a secondary progressive course characterized by chronic clinical impairment. 

The implication is that the worsening occurs progressively from day 25 onwards.

This was also reported in another study. But in this case, disease was treated with myelin (MOG) to block the T cell immune response.

Levy Barazany H, Barazany D, Puckett L, Blanga-Kanfi S, Borenstein-Auerbach N, Yang K, Peron JP, Weiner HL, Frenkel D. Brain MRI of nasal MOG therapeutic effect in relapsing-progressive EAE. Exp Neurol. 2014;255:63-70.

However, remeber secondary progressive MS doesn't respond too well to immunosuppression. So if this works in the secondary progressive model then it perhaps lacks predicitve value to that occuring after treatment of MS.

Now let's look at the line graph.  Here's one of ours (below)

An attack and then it goes progressive?

Actually it does, but not at day 25 as the line graph suggests. 

The above is all caused by relapsing-remitting disease driven by T cells. The relapses show increasingly poor recovery and so deficits accumulate with time. They are also asynchronous so they are not occurring at the same time and if you only look at the "line" you think the disease is secondary progressive. It is not.

We seldom get to see the individual data. I have repeated said people should publish the number of animals that get disease, the maximal severity of disease and timing of onset so it may allow you interpret these lines.

However, there appears to be one example, when the same people reporting the secondary progressive model, report in another paper and show individual scores. It suggests that EAE in NOD mice, is if fact not really an instant secondary progressive model starting at day 25 but it is in fact a relapsing-remitting disease with poor recovery, like the ABH mouse. This accumulates deficits related to relapsing attacks. 

This is not a slow insidious progressive disease as implicated by looking at the line,which is an average of a number of animals

Levy H, Assaf Y, Frenkel D. Characterization of brain lesions in a mouse model of progressive multiple sclerosis.Exp Neurol. 2010 Nov;226(1):148-58.

So if disease is really relapsing in NOD mice it will respond to FTY720 by their suppression, causing less demyelination, nerve loss and cytokine X or Y and less astrocyte activation. 

What was found?

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM, Chao CC, Wilz A, Blain M, Healy L, Antel J, Quintana FJ. Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci U S A. 2017;114(8):2012-2017.

Why is this important because, if it is a true secondary progressive model with validity it would not respond to peripheral immunosuppression very well as occurs in MS and maybe we can use this (taking a couple of months) rather than our current model (Taking 6 months) to test agents. 

You can make your own conclusions, 

If we had the raw data we could see in an instant what is really going on. 

If we did, there would be time to eat humble pie or is this a case of MD-investigative reporter? 

We have been talking about animal work this week. We had the suggestion of multi-centre animal studies. However, for EAE research raw data files would be the type of data that would be worth more for drug development than consortia doing multi-centre studies. 

Could blocking astrocytes result in blockade of progressive EAE and MS ...absolutely.

P.S. Dear "Headmaster" hope this style of walking you through data is informative..rather than giving a sound bite. This will be important when we do the clinical posts soon.

Friday, 24 February 2017

Dodgy EAE experiments means more wasted animals

Yesterday we say that there was a desire to do multi centre animal studies.

We said if you do rubbishy animal experiments, you get rubbish.
A well planned and undertaken experiment can mean more than ten rubbish experiments.

The funny thing is that the suggestion of mutli-centre animal trails was published in the Journal Nature .

This is a bit rich, because whilst we want to get our papers published, this it is also one of the homes of unreproducible pop science. 

A while ago it was suggested that salt intake makes autoimmunity worse. This got one of the biggest altmetrics on the plantet. It was covered by loads of media and every one lapped it up.

MD2 said hang on what are they saying and worked out the doses of animals and humans and the conclusion was what a load of.......

To MD2's credit they posted a comment on the Nature website that you should take it with a pinch. Nature removed the comment twice and MD2 complained and on the third time it is still there. 

The authors were livid. How dare MD2 question this?

Because it sounded dodgey?

However dissecting the science and looking at the dose of salt used to induce the issues you are looking at the dose equivalent to half a kilo of salt a day.

This will kill the average human and make people vomit. About 8g makes you puke. However, mice & rats can't vomit and so what was the equivalent 600g must have felt like I don't know.

So you get a paper in Nature and it spawns another ten or so experiments.

So something that you should take with a pinch.. means you are wasting loads of animals.

So what happens in EAE? 

It has been repeated and the original study was shown partially reproduced and shown to be weak. Here we have another paper in a different disease, we will have loads more.

Read the abstract if you want

High salt intake does not exacerbate murine autoimmune thyroiditis. Kolypetri P, Randell E, Van Vliet BN, Carayanniotis G.
Clin Exp Immunol. 2014;176(3):336-40.

#PoliticalSpeak: the not so BigPharma Alternative - sorry we have let you down

We do not have enough hours, or energy, to reignite our BigPharma Alternative. #PoliticalSpeak #MSBlog

Impact when you don't expect, or deserve, to have one. I received the following email from a PhD researcher earlier this week:

Dear Prof. Giovannoni,

Your article about repurposing in ‘Multiple Sclerosis and Related Disorders’ has caught my attention.

I am a ..... researcher at the ....... and I am doing research about drug repurposing in oncology. More specifically, I am focusing on the regulation, the intellectual property right strategies, and the economic implications of drug repurposing.

I am working in close collaboration with the Anticancer Fund, a Belgian non-profit organization that is currently funding several clinical trials investigating off-patent repurposed drugs in cancer patients.

Similar as to what is described in your article, we have encountered several hurdles in getting the repurposed drugs to the patients. Please find attached our policy brief listing these hurdles and proposed action items for regulators and policy makers.
I think the proposed movement to support the “Big Pharma Alternative” as described in your article is inspiring and I was wondering whether there is any progress in the field of multiple sclerosis with regard to drug repurposing?

Thank you for your time, I look forward to hearing from you....

Sadly, I have to respond to him that the BigPharma Alternative has floundered. We have only so many hours in a day and when the repurposing, or off-patent, drug bill was filibustered out of the house of commons and we we received a stern response from George Freeman, the then Parliamentary Undersecretary of State for Life Sciences, stating that there were no hurdles for prescribing off-label we lost steam. What George Freeman was saying that Pharma, in particular Big Pharma, is such a big part of or knowledge economy that we don't want to kill the goose that lays the golden eggs. In other words let Pharma innovate and make money, we will pay them, tax them and we will all live happily ever after. What this attitude doesn't address is the difficulty people have when they live in resource-poor environments, or are part of healthcare systems that require individuals to co-pay. Two thirds of personal bankruptcies in the US are triggered by ill-health. The article below from an American lawyer highlights the other side of the story, or the underbelly of Big Pharma; i.e. their predatory behaviour to milk the system. This is something we can't ignore and it is very prevalent in the MS space. 

Can we revive our BigPharma Alternative? I am not so sure. We will continue to promote our Barts-MS Essential Off-Label DMT list for use in resource-poor environments and will provide our off-label treatment protocols to anybody who wants to use them. However, we don't have the energy or resources to take these big issue on by ourselves; the sad thing is the politicians and lobbyists seem to have won. Just may be if the health policy unit at our University had supported us we would have had a chance of building some momentum, but Professor Allyson Pollock, who has now left our University, was adamant that she thought what we were doing was wrong. The good news is that the MS International Federation, or MSIF, has agreed to carry the baton when it comes to promoting off-label DMTs in resource poor environments; at least we have some help on this front. This is the battle we are prepared to fight, with a little, or a lot of, help from our friends. 

Giovannoni et al. The problem with repurposing: Is there really an alternative to Big Pharma for developing new drugs for multiple sclerosis? Mult Scler Relat Disord. 2015 Jan;4(1):3-5.

If it is not feasible to develop licensed drugs to the stage that they can actually be prescribed for a new indication, can we justify, either ethically or economically, the undertaking of proof-of-concept studies using off-patent medications? Without a financial incentive it is very difficult to repurpose off patent drugs for a new indication. Therefore, we need a political solution to allow the repurposing of off-patent drugs by other stakeholders or Big Pharma.

Levy MS. Big Pharma Monopoly: Why Consumers Keep Landing on "Park Place" and How the Game is Rigged. Am Univ Law Rev. 2016;66(1):247-303.

Now, more than ever before, pharmacologists are contributing medical advances to confront ravaging disease. They are developing drugs to mitigate the effects of Alzheimer’s, HIV, multiple sclerosis, and various forms of cancer. To capitalize on the opportunity, brand-name pharmaceutical firms are patenting these drugs, consequently guarding formulas and, with it, profits. Patents grant brand-name firms market exclusivity, which essentially allows them to set their own prices. Even though brand-name firms are investing some of their capital to cultivate new drugs, they also are enjoying gigantic revenue streams, absurd profit margins, and seemingly unfettered control of their respective markets. Consequently, sick patients are unable to afford their medication; high prices are bankrupting consumers in the absence of reasonably-priced generic alternatives. Despite the fact that generic drugs contain identical ingredients, cure the same symptoms, and cost 70% less, brand-name drugs persistently dominate their generic counterparts. Indeed, brand-name firms are improperly preventing generic market entry. Without generic competition, no watchdog exists to curb big pharma’s prohibitive prices. Despite the Supreme Court’s fleeting fix in FTC v. Actavis, which condemned reverse payment settlements that precluded competition, brand-name firms are employing other tactics predatorily to extend their market exclusivity and charge consumers unaffordable prices. To prevent brand-name abuse and help infirm patients afford their medication, this Comment proposes that courts apply federal antitrust law to brand-name firms that attempt to monopolize a pharmaceutical market through anticompetitive means, particularly by abusing Risk Evaluation & Mitigation Strategies (REMS) and by "product hopping." To combat exclusionary conduct, courts should mirror the “rule of reason” framework set forth in Actavis and apply an "enhanced" version specifically tailored to the pharmaceutical industry, giving stronger credence to generic challengers. In addition to finding brand-name tactics exclusionary, this Comment also proposes that courts adopt a bright-line rule prohibiting brand-name firms from exploiting the "legitimate business" defense to immunize their destructive conduct. The current framework perpetuates abuse and grants brand-name firms ostensibly indefinite monopolies. Analyzing brand-name defensive tactics under federal antitrust law would facilitate generic market entry and consequently moderate drug prices. Even after sacrificing their entire financial portfolios, patients are still unable to afford their medication. This Comment interprets Actavis as prohibiting the “legitimate business” defense and provides a remedy to deserving consumers by preventing REMS abuse and product hopping, fostering generic competition, and tempering excessive drug prices.

Thursday, 23 February 2017

#ResearchSpeak & #ThinkHand: MS outcomes - are we closer to the holy grail

Are we closer to doing defining a new battery of outcome measures for progressive MS? #ThinkHand #ResearchSpeak #MSBlog

Those of you who follow this blog will realise that we are gradually developing an online suite of apps to help you self-monitor your disease. Why? To empower you to ask the right questions about your prognosis and treatments.

It is clear that when DMTs for progressive MS are licensed you will need to show that your disability is worsening. There is no way that the payers will allow all-comers access to DMTs for progressive MS. Access to treatments will be based on the inclusion criteria for the clinical trials. Most trials have required 'objective evidence' of worsening disability. 

We are also aware that most neurologists, at least in the UK, don't have time in routine clinical practice to do an EDSS, or a battery of other tests, to monitor worsening disability. The solution is to get you to monitor your own disease. We have therefore developed an online web-EDSS that we think is pretty good. We have also produced an affordable, environmentally-friendly 9-HPT and will be adding walking-distance and the self-measured 25-FTW to the battery. We are also developing visual function tests and potentially other outcome measures in the future. What we are lacking is an engaging, responsive cognitive test. The current online cognitive tests are very boring and simply not engaging enough to bring people back to repeat them over time. If you have any suggestions for creating a good online cognitive screening and monitoring tool that can be used to assess MS-related cognitive impairment please let us know.

We have chosen our self-monitoring tests carefully to map onto what is acceptable by the field. The MS Outcome Assessments Consortium (MSOAC) is an initiative that has come together to put together a battery of tests that will be acceptable to the regulators as an outcome for progressive trials. MSOAC now report on their work in a series of very well written papers in the MSJ. It is clear that the four assessments they have evaluated will now become the new 'gold-standard' for progressive trials. One thing that is not clear is how this battery will be used for assessing disease improvement. The 20% threshold for disability-worsening may be too high a bar for disability improvement.

Don't you think it is incredible that the field is now asking the community to design trials to assess improvement in disability and not just worsening disability? This just shows you how far the field has come and where it is going in the not too distant future.

The MS Outcome Assessments Consortium (MSOAC) includes representatives from advocacy organisations, Food and Drug Administration (FDA), European Medicines Agency (EMA), National Institute of Neurological Disorders and Stroke (NINDS), academic institutions, and industry partners along with persons living with MS. Among the MSOAC goals are acceptance and qualification by regulators of performance outcomes that are highly reliable and valid, practical, cost-effective, and meaningful to persons with MS. A critical step for these neuroperformance metrics is elucidation of clinically relevant benchmarks, well-defined degrees of disability, and gradients of change that are deemed clinically meaningful

Feys et al. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult Scler. 2017 :1352458517690824. doi: 10.1177/1352458517690824.

Impaired manual dexterity is a frequently reported disability in people with multiple sclerosis (MS) and is increasingly prevalent with worsening disease. While various tests and patient-reported outcome measures are available, the Nine-Hole Peg Test (NHPT) is considered as a gold standard measure of manual dexterity and most frequently used in MS research and clinical practice. We find that the NHPT is reliable within and between test sessions, discriminates between healthy subjects and MS patients with different levels of upper limb impairment, and shows high convergent validity with other manual dexterity as well as more comprehensive upper limb measures. Ecological validity is established by its relation to perceived upper limb use in daily life and perceived difficulty in performing activities of daily living. The NHPT is responsive to deterioration in longitudinal studies, and research suggests that a 20% change in test score is commonly used to define clinically meaningful worsening, a definition that needs further validation in all stages of the disease.

Benedict et al. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690821. doi: 10.1177/1352458517690821. [Epub ahead of print]

Cognitive and motor performance measures are commonly employed in multiple sclerosis (MS) research, particularly when the purpose is to determine the efficacy of treatment. The increasing focus of new therapies on slowing progression or reversing neurological disability makes the utilization of sensitive, reproducible, and valid measures essential. Processing speed is a basic elemental cognitive function that likely influences downstream processes such as memory. The Symbol Digit Modalities Test (SDMT), recognized as being particularly sensitive to slowed processing of information that is commonly seen in MS. The research in MS clearly supports the reliability and validity of this test and recently has supported a responder definition of SDMT change approximating 4 points or 10% in magnitude.

Balcer et al. Validity of low-contrast letter acuity as a visual performance outcome measure for multiple sclerosis. Mult Scler. 2017:1352458517690822. doi: 10.1177/1352458517690822. [Epub ahead of print]

Low-contrast letter acuity (LCLA) has emerged as the leading outcome measure to assess visual disability in multiple sclerosis (MS) research. As visual dysfunction is one of the most common manifestations of MS, sensitive visual outcome measures are important in examining the effect of treatment. Low-contrast acuity captures visual loss not seen in high-contrast visual acuity (HCVA) measurements. MS and disease-free controls have similar median HCVA, while MS patients have significantly lower LCLA. Deficits in LCLA and vision-specific quality of life are found many years after an episode of acute optic neuritis, even when HCVA has recovered. Studies reveal correlations between LCLA and the Expanded Disability Status Score (EDSS), Multiple Sclerosis Functional Composite (MSFC), retinal nerve fiber layer (RNFL) and ganglion cell layer plus inner plexiform layer (GCL + IPL) thickness on optical coherence tomography (OCT), brain magnetic resonance imaging (MRI), visual evoked potential (VEP), electroretinogram (ERG), pupillary function, and King-Devick testing. This review also concludes that a 7-point change in LCLA is clinically meaningful. The overall goal of this review is to describe and characterize the LCLA metric for research and clinical use among persons with MS.

Motl et al. Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. Mult Scler. 2017 :1352458517690823. doi: 10.1177/1352458517690823. [Epub ahead of print}

The T25FW has strong reliability over both brief and long periods of time in MS across a large range of disability levels. The outcome of walking speed from the T25FW has obvious real-world relevance and has correlated strongly with other measures of walking and lower extremity function. The T25FW is responsive for capturing intervention effects in pharmacological and rehabilitation trials and has an established value for capturing clinically meaningful change in ambulation. Directions for future research involve validating clinically meaningful improvements on the T25FW as well as determining whether 20% change is clinically meaningful across the disability spectrum. Researchers might further consider synchronizing accelerometers and motion sensors with the T25FW for capturing walking speed in everyday life and the patient's real environment.