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.

Friday, 26 August 2016

NewsSpeak: positive SPMS trial

Siponimod reduces the rate of disease progression in SPMS. #NewsSpeak #MSBlog

"For those of you with SPMS who thought you had been forgotten some great news yesterday. Siponimod, a S1P receptor modulator, has hit its primary outcome in the EXPAND SPMS trial. This is great news for the field and for the first time progressive MSers have treatment options. This also means that it is going to become very difficult doing new studies without comparing them to existing DMTs, in this case Siponimod, in the progressive MS space."

Press release

Novartis announces positive phase III results showing efficacy of BAF312 in patients with secondary progressive MS. AUG 25, 2016
  • The Phase III EXPAND study of BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS) met its primary endpoint of reducing the risk of three-month confirmed disability progression versus placebo. 
  • There are currently very limited treatment options for SPMS, a form of MS associated with gradual worsening of symptoms and accumulation of disability, independent of relapses. 
  • EXPAND is the largest study ever conducted in SPMS, and is part of Novartis' ongoing leadership and commitment to people with MS.
Basel, August 25, 2016 - Novartis today announced the Phase III EXPAND study, evaluating the efficacy and safety of oral, once-daily, BAF312 (siponimod) in secondary progressive multiple sclerosis (SPMS), met its primary endpoint of a reduction in the risk of disability progression, compared with placebo. The EXPAND study represents the largest randomized, controlled study in SPMS to date.

"SPMS is a particularly disabling form of MS, and there is a need for effective treatment options to help delay disability progression in those living with the condition," said Vasant Narasimhan, Global Head of Drug Development and Chief Medical Officer for Novartis. "The positive EXPAND data are encouraging for a disease with such a high unmet need. We look forward to sharing the results at the upcoming ECTRIMS congress, and thank all of the study participants and investigators."

Topline results of the EXPAND study, including primary and key secondary endpoints, will be presented as a late breaking oral abstract at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), September 17th, in London, UK. Novartis will complete full analyses of the data and evaluate next steps in consultation with health authorities.

About the EXPAND study

The EXPAND study is a randomized, double-blinded, placebo-controlled Phase III study, comparing the efficacy and safety of BAF312 versus placebo in people with secondary progressive multiple sclerosis (SPMS). The EXPAND study is the largest randomized, controlled study in SPMS to date. The study included 1,651 people with SPMS from 31 countries. Patients were randomized to receive either 2mg BAF312 or placebo in a 2:1 ratio respectively.

The primary endpoint of the study was an improvement in the time to three-month confirmed disability progression, as measured by the expanded disability status scale (EDSS), versus placebo. Secondary endpoints included delay in the time to six-month confirmed disability progression versus placebo, the time to confirmed worsening of at least 20% from baseline in the timed 25-foot walk test (T25FW), T2 lesion volume, annualized relapse rate (ARR), and the safety and tolerability of BAF312 in people with SPMS.

About BAF312 (siponimod):

BAF312 (siponimod) is a selective modulator of specific types of the sphingosine-1-phosphate (S1P) receptor. The S1P receptor is commonly found on the surface of specific cells residing in the central nervous system (CNS), that are responsible for causing CNS damage that drives loss of function in secondary progressive MS (SPMS). BAF312 enters the brain and by binding to these specific receptors, may prevent the activation of these harmful cells, helping to reduce loss of physical and cognitive function associated with SPMS.

CoI: Prof G is a member of the EXPAND steering committee, Barts-MS participated in the EXPAND trial and DrK is the local principal investigator for the EXPAND study.

ClinicSpeak & ResearchSpeak: distinguishing PML from MS

Does your neuroradiologist know how to distinguish between PML and MS? #ClinicSpeak #ResearchSpeak #MSBlog

"If you you are JCV-seropositive and are on natalizumab (Tysabri) you are at risk of developing PML. Depending on your how long you have been on natalizumab and your anti-JCV antibody index you may be having frequent MRI scans to monitor for early asymptomatic PML. The rationale is that if you pick-up PML very early before you have any symptoms and stop natalizumab you do much better in terms of outcome. The study below identifies characteristics of early PML lesions that distinguish then from new MS lesions. The presence of punctate T2 lesions, cortical grey matter involvement, white matter lesions next to the cortex, ill-defined and mixed lesion borders towards both grey and white matter, lesions larger than >3 cm in size and interestingly contrast enhancement were all associated with PML compared to new MS lesions. In contrast, well-defined focal lesions and localisation next to the ventricles were associated with new MS lesions. This findings are not trivial and I would encourage you to make sure that the neuroradiologist(s) who is/are reading your PML-surveillance scans have read this paper."

"What this paper does not describe is how rarely new T2 lesions develop on natalizumab treatment after the first 12 months. Another point worth mentioning is that now that we have so many treatment options if you are at high-risk of developing PML you really should consider transitioning onto another DMT. I know natalizumab is very effective drug, but we really should be trying to prevent any further cases of PML."

Wijburg et al. MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance. J Neurol Neurosurg Psychiatry. 2016 Aug 16. pii: jnnp-2016-313772. doi: 10.1136/jnnp-2016-313772. [Epub]

OBJECTIVE: Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation.
METHODS: Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve.

RESULTS: Presence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm, and contrast enhancement were all associated with PML. Focal lesion appearance and periventricular localisation were associated with new MS lesions. In the multivariable model, punctate T2 lesions and cortical grey matter involvement predict for PML, while focal lesion appearance and periventricular localisation predict for new MS lesions (area under the curve: 0.988, 95% CI 0.977 to 1.0, sensitivity: 100%, specificity: 80.6%).

INTERPRETATION: The MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML.

Making MS worse more evidence for a T cell origin

Lisa Ann Gerdes, Kathrin Held, Eduardo Beltrán, Carola Berking, Jörg C. Prinz, Andreas Junker, Julia K. Tietze, Birgit Ertl-Wagner, Andreas Straube, Tania Kümpfel, Klaus Dornmair and Reinhard Hohlfeld CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis Anals Neurol 2016 | DOI: 10.1002/ana.24715

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS.

CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 is a protein receptor that, functioning as an immune checkpoint, downregulates immune responses. CTLA4 is constitutively expressed in Tregs but only upregulated in conventional T cells after activation. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.. In this study when CTLA was blocked with an antibody MS flared

They suggest that CTLA4 is an immunological checkpoint in the development of MS, that is, transition from subclinical RIS to CDMS as observed here.. This interpretation is further supported by 2 additional recent case reports.The first report describes a patient with pre-existing multiple sclerosis who had 2 clinical exacerbations and increased MRI activity shortly after initiation of ipilimumab for metastatic melanoma.The second report describes a 76-year-old patient who developed apparently de novo inflammatory CNS demyelination after treatment with ipilimumab for metastatic melanoma A third report describes a patient whose MS seemed to remain stable after treatment with ipilimumab for melanoma, but the tumor did not respond to ipilimumab, and the patient died due to melanoma progression.

In more general terms, the observations support the autoimmune pathogenesis of MS, and specifically, underline the central importance of autoreactive T cells in the pathogenesis of MS.

However if the CD28 molecule is blocked which is the "on" switch then not much appears to happen in terms of therapy of MS.

Why does it not work in MS when it appears to work in animals?
It is not clear but the T cell activation step may be occurring in the CNS and the infused antibody can't get into the CNS.

However the antibody may not have to get into the brain in all cases.

Macrez R, Ortega MC, Bardou I, Mehra A, Fournier A, Van der Pol SM, Haelewyn B, Maubert E, Lesept F, Chevilley A, de Castro F, De Vries HE, Vivien D, Clemente D, Docagne F. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain. 2016. pii: aww172. [Epub ahead of print]

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.

In this study they blocked a receptor function on the blood vessels and it stopped white blood cell migrating into the CNS. However we know what happens when you block white blood cells getting into the brain, would this be the same?