Sunday, 31 May 2015

ClinicSpeak: Fingolimoders need to be aware of opportunistic infections

If you are on fingolimod please be vigilant about infections, including opportunistic infections. #ClinicSpeak #MSBlog #MSResearch

"In response to an anonymous comment on the Natalizumab retinitis post yesterday. I think it is appropriate to warn all MSers on fingolimod to be vigilant as well about infections and opportunistic infections."

"The two case studies below highlight that opportunistic infections and severe viral infections are an issue on fingolimod. The first case report below is of a near fatal case of herpes simplex virus encephalitis (HSVE). This is not surprising, in fact in the phase 3 TRANSFORMS trial there was a fatality due to HSVE in an MSer on fingolimod, albeit on the higher, 1.25mg, dose."

"The second case is of a MSers on fingolimod developing Kaposi's sarcoma, which is due to a specific herpesvirus. Kaposi's sarcoma is classified as an opportunistic infection and is seen most commonly in people with AIDS and in people who have had a transplant and are on immunosuppression. Although this patient had a lymphopenia (<500 lymphocytes per mm3, WHO Grade 3) the counts were never below 200 (WHO Grade 4, a level in Europe at which the EMA guidelines recommend interrupting fingolimod dosing). In relation to lymphocyte counts on fingolimod; there is no correlation between the absolute levels and infectious complications. Therefore it is impossible to predict who will develop infections, including opportunistic infections, based on the lymphocyte count. Therefore the only strategy is clinical vigilance; this means reporting any new skin lesions, or new symptoms, to your neurology team or family doctor. Don't take unnecessary risks; opportunistic infections in immunocompromised patients can be associated with relatively mild and indolent symptoms, at least initially. Based on these and other case reports, e.g. PML, I would predict the occurrence of other opportunistic infections in MSers on fingolimod."

"One infection that can be screened for is HPV, the cause of cervical cancer. If you are a woman on fingolimod please make sure you don't miss your regular cervical, or PAP, smears. If you live in a country in which this is not mandatory please ask your family doctor to arrange for this to happen. As always prevention is better than cure."

Kaposi's sarcoma (source Wikipedia)
Epub: Pfender et al. Reactivation of herpesvirus under fingolimod: A case of severe herpes simplex encephalitis. Neurology. 2015 May 8.

Fingolimod (FTY720 is a sphingosin-1-phosphate (S1P) receptor modulator with immunomodulatory properties that traps naive and central memory T cells in lymph nodes, leading to reduced numbers of peripheral blood lymphocytes, and is the first licensed oral drug for multiple sclerosis (MS). We report a case of a near fatal herpes simplex virus 1 (HSV-1) encephalitis under the licensed dose of fingolimod in a patient with MS.

Epub: Tully et al. Kaposi sarcoma in a patient with relapsing-remitting multiple sclerosis receiving fingolimod. Neurology. 2015 May 12;84(19):1999-2001. 

Kaposi sarcoma (KS) is a tumor derived from capillary endothelial cells associated with serologically identifiable human herpesvirus (KSHV). We report a case of KS in a patient with relapsing-remitting multiple sclerosis (RRMS) who received fingolimod for 19 months. We hypothesize that fingolimod-induced immunosuppression led to the development of KS in this patient.

CoI: multiple

So the Blog is a Blockbuster Drug

Rieckmann et al. Achieving patient engagement in multiple sclerosis: A perspective from the multiple sclerosis in the 21st Century Steering Group. Mult Scler Relat Disord. 2015; 4:202-218.

While advances in medicine, technology and healthcare services offer promises of longevity and improved quality of life (QoL), there is also increasing reliance on a patient׳s skills and motivation to optimize all the benefits available. Patient engagement in their own healthcare has been described as the 'blockbuster drug of the century'. In multiple sclerosis (MS), patient engagement is vital if outcomes for the patient, society and healthcare systems are to be optimized. The MS in the 21st Century Steering Group devised a set of themes that require action with regard to patient engagement in MS, namely: 1) setting and facilitating engagement by education and confidence-building; 2) increasing the importance placed on QoL and patient concerns through patient-reported outcomes (PROs); 3) providing credible sources of accurate information; 4) encouraging treatment adherence through engagement; and 5) empowering through a sense of responsibility. Group members independently researched and contributed examples of patient engagement strategies from several countries and examined interventions that have worked well in areas of patient engagement in MS, and other chronic illnesses. The group presents their perspective on these programs, discusses the barriers to achieving patient engagement, and suggests practical strategies for overcoming these barriers. With an understanding of the issues that influence patient engagement in MS, we can start to investigate ways to enhance engagement and subsequent health outcomes. Engaging patients involves a broad, multidisciplinary approach.

 So is the Blog just the ticket as a Blockbuster Drug?

The “MS in the 21st Century” initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm.

The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada—consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers—participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centres of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The “MS in the 21st Century Steering Group” hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS.

To realize our vision of full access to personalized treatment, with reimbursement, to achieve freedom from disease, we call upon healthcare providers and decision-makers to address simultaneously the following overarching principles that will guide patient management, in order to improve outcomes for people with MS.

Personalized care 

We need personalized treatments for all types of MS . This means developing new approaches that incorporate a wide range of pharmacological and non-pharmacological strategies that focus on the needs of people living with the disease as individuals, and aim to reduce disease activity, slow disability progression and improve management of symptoms MS care requires diverse therapies and strategies to address the complexity of the disease’s considerable symptoms and challenges [13]. Governments, healthcare decision-makers, and healthcare systems must be prepared to see MS patients as requiring interventions beyond greater access to disease-modifying agents alone, especially for those with progressive forms of MS.The best treatment regimen is often specific to the patient and best achieved through continuity of care with a team of physicians and allied professionals. Healthcare decision-makers must realize that this outcome is often compromised in modern hospitals, where, in the name of efficiency, patients will generally see a sequence of different doctors and may receive increasingly fragmented care. To overcome this barrier, we call on healthcare policy-makers to prioritize the development of centers of excellence for improved access to personalized treatment and to empower MS nurses as central coordinators for patient care.Patients also have the right to be informed about, and involved in, all decisions regarding their treatment, including early therapy options. All available therapies and their respective risks and benefits should be communicated to patients by their physicians, and patients should also have access to other reliable, independent sources to ensure that they are empowered to make informed decisions. In addition, affording patients psychological and social support as part of their treatment package is likely to ensure the greatest possible mitigation of the potential financial, social, and psychosocial burdens associated with MS.

Patient engagement

Patients should be engaged as advocates. They should be empowered to drive negotiations with regulators and payers In addition, patient organizations should work more closely with clinicians, industry, and regulatory bodies to petition for and secure research funds.
Commitment to research We need to embed a culture of research in all aspects of MS care. The continued progress of basic research is currently under threat due to reduced charity income and governmental funding. However, research across all domains is key for a better understanding of disease mechanisms, which ultimately leads to more effective new treatment options (pharmacological and non-pharmacological), including therapies for progressive forms of MS. We recommend the development of an international network of MS centers of excellence (see below the MS centers of excellence) as a platform for establishing research networks and leveraging funding. In addition, without compromising patient safety, we call upon regulators to re-evaluate the existing European Commission (EC) requirement for investigator-led hypothesis-generating studies to meet the same standards as industry-funded clinical trials, as this criterion has severely limited the scope of such investigator-led studies.

Regulatory body education and reimbursement issues 

The authors believe that patient groups, clinicians, and industry need to have greater access to regulatory bodies at a national and local level in order to: Improve the regulator’s understanding of the complexities associated with the treatment and care of MS patients Align perceptions of the risks of the disease and its treatment. The introduction of a conditional license, allowing several thousand patients to be treated for a number of years, would allow safety data to be formally gathered from people with MS who are willing to take greater risks and be exposed to greater uncertainty. Regulatory bodies need to consider how escalating regulatory requirements, including increasing demands for long-term safety data, could be major drivers for spiraling development costs. This leads to increasing drug prices, limited innovation, and delays in getting promising drugs to patients. Reimbursement agencies should consider the substantial indirect costs associated with MS and the related burden to society in their calculation of cost:benefit ratios. 
New endpoints in clinical trials

Clinical trials in MS are still largely based on single-parameter measures of disease relapses or disability progression . Other parameters, such as subclinical inflammatory activity, neuroprotection, lesion burden detected by MRI, health economics, cognitive impairment, and fatigue are regarded only as secondary endpoints or are rarely measured at all. Employing the use of single-parameter measures in clinical trials can fail to measure the effect of treatment on the actual disease process, and these strategies only partly reflect real-world treatment scenarios. Developing better patient- and physician-reported tools are needed for the assessment of these parameters, and using those within composite endpoints may, therefore, improve measures of treatment efficacy. In fact, a number of groups have recently used composite endpoints in phase 3 clinical trials with success. New clinical trial designs and endpoints that enable effective treatment development and evaluation to achieve relevant benefits are needed. Such endpoints should include patient-reported measures, clinical and functional assessments, and biomarkers. We encourage the development of initiatives involving regulatory authorities, expert groups, and industry, which will amalgamate these disparate elements into new composite endpoints/scales. 
More therapy options

Although there are already multiple pharmacological treatment options available for MS, the high costs of these treatments may limit patient access. Governments, regulators, funding agencies, clinicians, the pharmaceutical industry, and patient groups need to work together to develop strategies to deliver more cost-effective medicines. They also need to widen the focus of research to ensure the continuous development of better therapy options with improved efficacy, safety, and tolerability profiles. Patients should have greater access to comprehensive care regimens that include symptomatic care, rehabilitation, and psychological support alongside pharmacological solutions. Non-responding patients and those with aggressive disease should be allowed access to experimental treatment options in well-controlled programs. We petition regulatory bodies and funders to provide this access. In addition, we ask regulators and funders to consider the relevance of the placebo arm and the assimilation of more long-term data on the therapy options available. In this regard, we support the European Commission’s consideration for a patient registry. 
MS centres of excellence

We need a network of dedicated MS centres of excellence that meet a set of predetermined minimum standards and demonstrate a will to contribute to research and to share resources. This is to improve diagnosis and treatment, as well as to provide optimum patient support.

CoI: Prof G is a coauthor on this paper

Saturday, 30 May 2015

Prognosis after clinically isolated syndrome

Jokubaitis VG, Spelman T, Kalincik T, Izquierdo G, Grand'Maison F, Duquette P, Girard M, Lugaresi A, Grammond P, Hupperts R, Cabrera-Gomez J, Oreja-Guevara C, Boz C, Giuliani G, Fernández-Bolaños R, Iuliano G, Lechner-Scott J, Verheul F, van Pesch V, Petkovska-Boskova T, Fiol M, Moore F, Cristiano E, Alroughani R, Bergamaschi R, Barnett M, Slee M, Vella N, Herbert J, Shaw C, Saladino ML, Amato MP, Liew D, Paolicelli D, Butzkueven H, Trojano M. Predictors of disability worsening in clinically isolated syndrome. Ann Clin Transl Neurol.;2(5):479-91
OBJECTIVE:To assess demographic, clinical, magnetic resonance imaging, and treatment exposure predictors of time to 3 or 12-month confirmed disability worsening in clinically isolated syndrome (CIS) and early multiple sclerosis (MS).
METHODS: We utilized the MSBase Incident Study (MSBasis), a prospective cohort study of outcome after CIS. Predictors of time to first 3 and 12-month confirmed expanded disability status scale worsening were analyzed using Cox proportional hazards regression.
RESULTS: About 1989 patients were analyzed, the largest seen-from-onset cohort reported to-date. A total of 391 patients had a first 3-month confirmed disability worsening event, of which 307 were sustained for 12 months. Older age at CIS onset (adjusted hazard ratio: aHR 1.17, 95% 1.06, 1.30), pyramidal (aHR 1.45, 95% CI 1.13, 1.89) and ambulation (HR 1.60, 95% CI 1.09, 2.34) system dysfunction, annualized relapse rate (aHR 1.20, 95% CI 1.18, 1.22), and lower proportion of observation time on treatment were associated with 3-month confirmed worsening. Predictors of time to 12-month sustained worsening included pyramidal system dysfunction (Hazard ratio: aHR 1.38, 95% CI 1.05, 1.83), and older age at CIS onset (aHR 1.17, 95% CI 1.04, 1.31). Greater proportion of follow-up time exposed to treatment was associated with greater reductions in the rate of worsening.
INTERPRETATION: This study provides evidence for a strong protective effect of disease-modifying treatment to reduce disability worsening events in patients with CIS and early MS, and confirms age and pyramidal dysfunction at onset as risk factors.

We can read the absract 

ClinicSpeak: Natalizumabers PML is not the only viral infection you need to worry about

Natalizumabers PML is not the only viral infection you need to worry about. #ClinicSpeak #MSBlog #MSResearch

"The following is a sobering reminder that we need to remain vigilant for other opportunistic CNS (central nervous system) infections in MSers on natalizumab. The case report below is of a MSer developing a severe VZV (varicella zoster virus) retinitis with significant visual loss. Presumably the virus escaped elimination in the periphery and made its way to the retina to cause damage. The virus could not be eliminated by the immune system because natalizumab blocked trafficking of lymphocytes into the eye. This type of viral retinitis is usually only seen in patients with AIDS and other diseases associated with severe immunosuppression. What this case illustrates is that natalizumab reduces trafficking of immune cells into the posterior compartment of the eye. PML is not the only infection that MSers need to worry about. Other viral infections of the brain and eye can clearly cause major problems. I am aware of least one death from herpes encephalitis in an MSer on natalizumab. The presentation of encephalitis on natalizumab tends to be indolent and come over weeks to months. Why? The immune response to the causative infections agent is usually what bring encephalitis to the attention of the patient and clinician; if you prevent an immune response the virus replicates and does its damage more slowly. In fact in the fatality the team looking after the patient thought it was a brain tumour."

Van et al. Progressive outer retinal necrosis in a multiple sclerosis patient on natalizumab. Neurology. 2015 May 26;84(21):2198-9. doi: 10.1212/WNL.0000000000001611.

A 54-year-old woman MSer, on natalizumab, reported 2 weeks of left eye redness and blurry vision, previously diagnosed as conjunctivitis. Visual acuity was 20/125. Funduscopy revealed progressive outer retinal necrosis (figure), a viral retinitis of immunocompromised patients that frequently causes vision loss. Sequential bilateral involvement is common. Etiologies include varicella zoster, herpes simplex, and rarely cytomegalovirus; aqueous PCR revealed varicella. Natalizumab was held. IV and intravitreal antivirals were administered. After repair of retinitis-induced retinal detachment and resolution of retinitis, visual acuity was 20/125. In immunocompromised patients with ocular symptoms, clinicians should consider infectious retinitis and obtain prompt funduscopic evaluation.

CoI: multiple

Friday, 29 May 2015

Headache, hmm?

Neurol Sci. 2015 May;36(Supplement 1):75-78.

Headache in multiple sclerosis and autoimmune disorders.

La Mantia L, Prone V.

The headache may be considered among the neuropathic pain syndromes of multiple sclerosis (MS). Several studies have showed that it is more frequent in MS patients than in controls or general population. Headache may occur at the pre-symptomatic phase, at clinical onset and during the course of the disease. Tension-type headache and migraine without aura are the most common primary headaches reported in MS patients. The disease-modifying therapies, such as interferons, may cause or exacerbate headache, although the new available treatments do not seem to increase the risk of pain. Pharmacological and not pharmacological approach may be considered in selected patients to prevent the risk of headache, ameliorate quality of life and increase the adherence to treatment.

Are headaches simply a nuisance, bad luck or an imprecation of divine punishment? It's a disease with 100% penetrance in the human population. 

The association between headache and MS ranges anywhere between 4 and 69% (the wide reported ranges are due to differences in study design, participants etc.) but it's still higher than in the control groups (by more than 50%).

The most commonly reported headaches according to this article are:
  • Tension-type headache - a dull ache across your forehead, or on the sides and back of your head
  • Migraine without aura - usually one-sided (but not always) throbbing headache associated with light sensitivity, noise sensitivity, nausea, irritability etc. 
They even report that there is a correlation with the type of MS - migraine is more commonly reported in RRMS, while tension type headaches are more frequent in progressive MS. 

Headache at onset of MS is considered a 'minor' symptom with frequencies of 1.6-28.5%, and wait for it...has also been reported in 'asymptomatic MS' or the so-called radiologically isolated syndrome/RIS.

What about the pathology? 

Headache during an attack of MS appears more likely if there is brain stem involvement, particularly a lesion in the periaqueductal gray matter (PAG) with migraine-like headaches.

What about DMTs?

Interferon-beta (IFN) has had more reports of headache than placebo, and to a smaller extent so has Copaxone, but not the newer drugs (natalizumab, fingolimod, tecfidera, teriflunomide).

So should we opt to scan people presenting with a migraine/tension type headache who also happen to be of the female gender? 

Over 50% of people with brain tumours experience headaches at some stage, but even here it's not considered routine practice...

ClinicSpeak: benign MS is a misnomer

Should we stop using the term benign MS? #ClinicSpeak #MSBlog #MSResearch

"The study below on benign MS illustrates a point that we have made many times before; benign MS is a very difficult call. A significant proportion of benign MSers have cognitive impairment and associated fatigue, depression and anxiety. Therefore is it correct to simply call someone as having benign disease based on the EDSS, when the EDSS is not a very good way of capturing the impact of MS early on? To diagnose someone as having benign MS is very difficult; it can only be done retrospectively after you have had the disease for 15 years or longer. Even after  waiting 15 years to diagnose MS the majority of people with benign disease will end up acquiring disability over time."

"The good news is that most of what we know about benign MS comes from natural history studies and with new and emerging treatments and treatment strategies (treat-2-target of NEDA) the proportion of MSers with benign disease will increase. It is our treatment aim to make everyone with MS have benign disease."

Epub: Gajofatto et al. Benign multiple sclerosis: physical and cognitive impairment follow distinct evolutions. Acta Neurol Scand. 2015 May 26. doi: 10.1111/ane.12442.

BACKGROUND: Benign multiple sclerosis (BMS) definitions rely on physical disability level but do not account sufficiently for cognitive impairment which, however, is not rare.

OBJECTIVE: To study the evolution of physical disability and cognitive performance of a group of MSers with BMS followed at an University Hospital Multiple Sclerosis Center.

METHODS: A consecutive sample of 24 BMS cases (diagnosis according to 2005 McDonald's criteria, relapsing-remitting course, disease duration ≥10 years, and expanded disability status scale [EDSS] score ≤2.0) and 13 sex- and age-matched non-BMS patients differing from BMS cases for having EDSS score 2.5-5.5 were included. Main outcome measures were as follows: (i) baseline and 5-year follow-up cognitive impairment defined as failure of at least two tests of the administered neuropsychological battery; (ii) EDSS score worsening defined as confirmed increase ≥1 point (or 0.5 point if baseline EDSS score = 5.5).

RESULTS: At inclusion, BMS subjects were 41 ± 8 years old and had median EDSS score 1.5 (range 0-2), while non-BMS patients were 46 ± 8 years old and had median EDSS score 3.0 (2.5-5.5). At baseline 16% of patients in both groups were cognitively impaired. After 5 years, EDSS score worsened in 8% of BMS and 46% of non-BMS patients (P = 0.008), while the proportion of cognitively impaired subjects increased to 25% in both groups.

CONCLUSIONS: MSers with BMS had better physical disability outcome at 5 years compared to non-BMS cases. However, cognitive impairment frequency and decline over time appeared similar. Neuropsychological assessment is essential in MSers with BMS given the distinct pathways followed by disease progression in cognitive and physical domains.

Dr Giles does Diagnosis

MS Society Press Release: World MS Day - Diagnosis Story

Survey reveals many people are misdiagnosed and
live in uncertainty for years before MS diagnosis

·        1 in 4 people with MS misdiagnosed with having a trapped nerve
·        1 in 10 people with MS told they'd had a stroke
·        39% of people with MS left waiting a year or more for diagnosis

DrGiles said in a comment
"This is important data; we need timely accurate diagnosis of MS. It is important also to consider the other side of the coin - those people who are given an incorrect diagnosis of MS, often from over-interpretation of non-specific MRI changes. Any push for faster diagnosis tends to risk over-diagnosis. At least one person has died from DMD complication and was found to not have MS.

You can watch Dr Giles making the surprise Diagnosis of Simon Donald on film.

Simon is one of the founders of an Comic called Viz and is currently a stand-up comic and was helping some people making a film about MS, when things went as he says "proper tits up"-Excuse the language.

Dr.Giles picked up Simon's MS that he didn't know he had, 
No scans, just knowledge!

Asthma and MS...Little effect on the disease course

Manouchehrinia A, Edwards LJ, Roshanisefat H, Tench CR, Constantinescu CS.Multiple sclerosis course and clinical outcomes in patients with comorbid asthma: a survey study.
BMJ Open. 2015 May 20;5(5):e007806. doi: 10.1136/bmjopen-2015-007806.

OBJECTIVE:To determine if comorbid asthma is associated with accumulation of multiple sclerosis (MS)-related impairment and disability.
METHOD:We sent a comprehensive questionnaire to a cohort of patients with MS and examined the association between comorbid asthma and reaching Expanded Disability Status Scale (EDSS) scores 4.0 and 6.0. Multiple Sclerosis Impact Scale (MSIS-29) scores were compared between patients with MS with and without comorbid asthma.
RESULTS:680 patients participated in our study of whom 88 (12.9%) had comorbid asthma. There was no difference in the prevalence of asthma between our MS cohort and the England general population (OR: 0.89, 95% CI 0.68 to 1.17). We did not observe a significant association between having asthma and the risk of reaching EDSS scores 4.0 and 6.0 (HR: 1.29, 95% CI 0.93 to 1.77, and HR: 1.33, 95% CI 0.93 to 1.89, respectively) after controlling for confounders. Patients with MS with asthma reported higher level of psychological impairments (coefficient: 2.29, 95% CI 0.1 to 4.49).
CONCLUSIONS:Asthma is a prevalent condition among patients with MS and it may contribute to the psychological impairment in MS. Although we did not observe significant association between comorbid asthma and physical disability in MS, it seems that the two conditions influence one another.

The aim of many immunologists is the drive a Th1/Th17 response towards a Th2 response. It is thought that Asthma is associated with a Th2 biased response. So what is the influence of having asthma and MS. Will a Th2-Asthma response slow MS. 

Well the answer is no, not that much. Most EAE experiments are not done for long enough for proper B cell responses to develop, so it is considered that a Th2 response should be desirable in two legged EAE (If you ask people to describe MS they tell you about EAE). However, it probable that both Th1 and Th2/B responses are undesirable and so far studies aimed at driving Th2 (B cell  promoting) responses in MS have yet to show the promise of that hoped.

This is the basis of the many studies, trying to give MSers parasitic worms, in the hope that it drives a TH2 responses such as in the TRIOMS (Germany) trial. The HINT (USA) and WIRMS (UK) trials should have been finished by now.  Do we know that has happened?  

Thursday, 28 May 2015

Anyone got a home for a few million mice?

Recently we sent you to an anti-vivisection website campaigning against animal experiments in Europe. So in the spirit of balance there are sites that support animals research such as

Speaking for Research.. 

There is a debate on the use of animals in research
A transcript and summary of the key points made by the European Animal Research Association and put together the key points that were said during the meeting (download here) indicates that the initiative is almost certain to fail in its objective of persuading the EU Commission to repeal Directive 2010/63/EU.
Here is Speaking for Research version of accounts (click) and one point they quite rightly say is "Throughout the hearing one very important voice was conspicuous by its absence, that of the patients who rely on medical research".

There are some choice comments like "On top of the 3Rs we should be looking to rehome those animals used in Research"

When having a debate you need to show reasoning. This is perhaps rather IG11, given that millions of meeces are used in research each year. I wonder if they would be calling in the Vermin Inspectors if research animals were rehomed in a place near them.

Would you have the facilities to care for an MS mouse after being used in an experiment. I know where you can get a wheelchair:-)
The results of the debate will be reported soon.

MS Society Press Release: World MS Day - Diagnosis Story

Survey reveals many people are misdiagnosed and
live in uncertainty for years before MS diagnosis

·        1 in 4 people with MS misdiagnosed with having a trapped nerve
·        1 in 10 people with MS told they'd had a stroke
·        39% of people with MS left waiting a year or more for diagnosis
The survey of over 1,500 people with MS in the UK found that 81% had been misdiagnosed by their GP; more than a quarter were told they had a trapped nerve (28%) and about 1 in 10 people were misdiagnosed with depression or anxiety or stress (14%) or told they'd suffered a stroke (11%).
There are over 100,000 people living with MS in the UK – 5,000 are newly diagnosed every year. It is the most common disabling neurological condition in young adults with symptoms usually starting in the 20s and 30s, yet awareness remains low.
1 in 5 (20%) people had to wait between 1 and 3 years for a diagnosis following their first visit to their GP with early MS symptoms. 1 in 4 people (25%) visited their GP over four times before they were referred to a neurologist for further examination. While MS can be difficult to diagnose, delays such as these can be harmful; they prevent people from taking the necessary steps to manage their condition effectively and there is evidence that early treatment has long-term benefits.  
Michelle Mitchell, Chief Executive at the MS Society said:  "Our findings highlight the struggle people go through for years before they get an MS diagnosis. Being misdiagnosed or experiencing symptoms that can't be explained can put a considerable strain on people's emotions and health. A fast, accurate diagnosis enables people to take steps to begin to manage their condition, access treatment and take greater control of their lives again.
"People often experience symptoms which interfere with daily life whilst in their prime, when families and careers are developing. While we are aware that MS is a complex condition that isn't easy to diagnose, we don't want thousands of people to be left in 'limbo' suffering needlessly.
"It's important for GPs to recognise the warning signs and refer people promptly to a consultant neurologist who can then make an accurate diagnosis. Most people who experience MS-like symptoms won't have the condition but if you're concerned for any reason your GP should still be your first port of call."
Professor Alan Thompson, Consultant Neurologist at the National Hospital for Neurology and Dean of the UCL Faculty of Brain Sciences, said: "I've seen a number of people in my clinic who have never heard of MS so it doesn't surprise me that 1 in 3 people in the survey say they didn't know what it was before diagnosis. Early symptoms of MS can fluctuate and can be attributed to a number of other things, which is why awareness of the condition is so crucial – both for GP's and the general public.
"We've moved on so much in terms of the treatments that are available to slow the long term damage that relapsing forms of MS cause, so a prompt and accurate diagnosis of MS can make an enormous difference. It is only once someone is diagnosed that they can begin to understand and manage their condition."
Out of the 1,515 people surveyed, the most common early symptoms of MS were reported as being:
·        Numbness and altered sensations in different parts of body (tingling/pins and needles) – 53% (800 people)
·        Difficulties with walking – 41% (623 people)
·        Eye and vision problems – 47% (709 people)
·        Fatigue – 38% (570)
·        Problems with balance and coordination – 35% (531)
·        Muscle weakness – 31% (473)
·        Muscle stiffness and spasms – 20% (306)
World MS Day is the only global awareness raising campaign for MS. Every year, it brings the community together to provide the public with information about MS and how it affects the lives of more than two million people around the world. 
The MS Society is the UK's leading MS charity for people living with MS in the UK. It is funding research and fighting to improve treatment and care to help people with the condition take control of their lives.   
  • For more information about MS visit:
  • The MS Society has played a pivotal role by investing over £150 million in MS research to date which has led to major advances in treatment development
  • The MS Society launched the Treat Me Right campaign in April 2014 to call for the right treatment at the right time for people with MS. For further information visit

Effect of DMT in Portugal

Sá MJ, de Sá J, Sousa L.Relapsing-remitting multiple sclerosis: patterns of response to disease-modifying therapies and associated factors: a national survey. Neurol Ther. 2014;3(2):89-99. doi: 10.1007/s40120-014-0019-4. eCollection 2014

INTRODUCTION:Current treatments for relapsing-remitting multiple sclerosis (RRMS) are only partially effective. The objective of this study was to characterize treatment response in RRMS patients in Portugal to 12-month therapy with first-line disease-modifying therapies.
METHODS:In this retrospective study, neurologists at participating centers completed survey questionnaires using records of patients with RRMS who had received first-line treatment with one of five European Medicine Agency-approved agents in the 12 months prior to inclusion in the survey. Sub-optimal responders included patients treated for at least 1 year, and who had ≥1 relapse(s) or an increase of 1.5 points on the Expanded Disability Status Scale (EDSS; if baseline EDSS was 0) or an increase of ≥0.5 points (baseline EDSS ≥1). Optimal responders included patients treated for at least 1 year without relapse and who had an increase of <1.5 points on EDSS (if baseline EDSS was 0) or no increase in EDSS (baseline EDSS ≥1).
RESULTS: Data for 1,131 patients from 15 centres were analyzed. Twenty-six percent (95% confidence interval 23-28%) of patients had sub-optimal treatment response. Duration of therapy (P < 0.001), age at the start of therapy (P = 0.03), and baseline EDSS score (P < 0.001), were significantly different among treatments. Sub-optimal treatment response appeared to be related only to a more severe EDSS score at baseline and did not differ among therapies.
CONCLUSION: Neurologists should closely monitor patients to optimize treatment strategies and better control disease, improving prognosis

This study documents the real-life effects of old DMT, I wonder what DrM&M things of this?

Wednesday, 27 May 2015

World MS Day 2015

Together we're #strongerthanMS

"I arrived safely in Indianapolis last night and was up working at 2.30am; the advantages of jet lag. I have just had a pile of things popped through my door. One was a reminder that today is World MS Day with an orange lapel ribbon."

"If you are interested I suggest checking-out the dedicated World MS Day website; there are lots of activities going on across the world. The CMSC meeting in Indianapolis is only one of many events."

ClinicSpeak: aspirin for DMF flushing

Does aspirin work for your DMF-related flushing? #ClinicSpeak #MSBlog #MSResearch

"The following study shows that pretreatment (30 minutes before) with aspirin (325mg) reduces the flushing some MSers have when they start DMF (dimethyl fumarate or tecfidera). The response seems to be relatively small, but does provide a pragmatic option in managing this transient side effect. In my experience warning MSers about the flushing and educating them about the transient nature of flushing (usually disappears within 8-12 weeks of starting treatment) seems to help. We have not had many patients stop DMF because of flushing. I think GI symptoms are more problematic than the flushing, in particular the diarrhoea. Any of you want to share your personal experiences?"

Epub: O'Gorman et al. Effect of Aspirin Pretreatment or Slow Dose Titration on Flushing and Gastrointestinal Events in Healthy Volunteers Receiving Delayed-Release Dimethyl Fumarate. Clin Ther. 2015. pii: S0149-2918(15)00188-5. doi: 10.1016/j.clinthera.2015.03.028.

PURPOSE: In Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in RRMSers. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events.

METHODS: The 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1-4), then placebo DMF alone (weeks 5-8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1-4), then DMF alone (weeks 5-8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2-8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4-8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales.

FINDINGS: Flushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events.

IMPLICATIONS: ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials.

CoI: multiple

Will European Democracy get rid of Animal Research?

Having Democracy allows citizens to protest and within the European Union there are methods to have a debate heard. In the UK a 100,000 signatures in a population of 60 million triggers parliament to discuss the issue. In the European Union you need 1,000,000 signatures out of a population of 500,000,000 to trigger the debate. 

STOP VIVISECTION is a European Citizens' Initiative (ECI) that has collected more than 1.150.000 certified signatures asking people to support a paradigm shift in the way biomedical and toxicological research are being conducted. This is the text of our request which advocates the replacement of animal testing with more accurate, reliable, human-relevant methods:
They say "We urge the European Commission to abrogate directive 2010/63/EU on the protection of animals used for scientific purposes and to present a new proposal that does away with animal experimentation and instead makes compulsory the use - in biomedical and toxicological research - of data directly relevant for the human species".

In the UK animals in research have been protected by Law since 1876 and Directive 2010/63/EU is the directive that protects animals used for science. This brings Europe to a standard that has been enforced in the UK for many years. Abolishing protection of animals in research seems rather retrograde 

This week the European Union had this debate and it seems from probably biased centres that it was a bit dull, Apparently "the claims, that animal models have no predictive value for human disease, drew thin and only occasional ripples of agreement from a cluster of supporters seated at the back of the half-filled aud"itorium.

Apparently The European Parliament has until 3 June 2015 to decide what to do. 

Perhaps it should listen to the loud (Ho-Ho) and unified voice of the continent’s scientists.....and then do precisely nothing, otherwise it may simply cause things to move East and Westwards where less regulation and animals rights are in place.

MS Pharma are already moving.

They are closing or moving their MS research elsewhere maybe to countries where they think it is OK to tie mice upside down by its tail for a month. 

What you you think?....Do you care? ... You Should

It seems you don't have to go too far East to find terrible abuse.
                                              RIP Allan 

Blood cells as a maker of inflammation

Demirci S, Demirci S, Kutluhan S, Koyuncuoglu HR, Yürekli VA. The Clinical Significance of the Neutrophil-to-Lymphocyte Ratio in Multiple Sclerosis. Int J Neurosci. 2015 May 22:1-24. [Epub ahead of print]

Multiple sclerosis (MS) is one of the main chronic inflammatory diseases of the central nervous system that causes functional disability in young people. The aim of this study was to investigate the neutrophil-to-lymphocyte ratio (NLR) in patients with MS and the relationship between the NLR and the severity of the disease. One hundred two MS patients (31 patients were in relapse; 71 patients were in remission) and 56 healthy controls were included. Complete blood counts as well as demographic and clinical data from MS patients were evaluated retrospectively. The NLRs were calculated for all participants and were compared; the cut-off value was also determined for the NLR and Expanded Disability Status Scale (EDSS). MS patients had a significantly higher NLR (p < 0.001) than the control group. The NLR levels were significantly higher in patients that were in relapse than patients in remission (p = 0.039). The cut-off value for the NLR to predict a MS diagnosis and activity were determined to be 2.04 and 3.90 respectively. The NLRs were directly correlated with erythrocyte sedimentation rate (ESR) levels (r = 0.795, p < 0.001). Logistic regression analysis with dichotomous EDSS score showed that a high NLR was an independent predictor of the progression of disability. The NLR may be a biomarker that has simple, quick, inexpensive, and reproducible properties in MS to predict patient's prognosis.

Neutrophil granulocytes (also known as neutrophils) are the most abundant (40% to 75%) type of white blood cells in mammals and form an essential part of the innate immune system. They are short-lived and highly motile. The name neutrophil derives from staining characteristics on hematoxylin and eosin (H&E) histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes.

Neutrophils are a type of phagocyte and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP and Leukotriene B4 in a process called chemotaxis. They are the predominant cells in pus, accounting for its whitish/yellowish appearance.Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation.

MS is considered to be chronic inflammation and are rare in MSand are also a rare in EAE,that is unless its mouse EAE. I has been suggested that Th17 T cells can induce EAE has lots of neutrophils and if you look in some mouse strains, neutrophils can make up about 80% of the white cells. Neutrophils are common in mouse inflammatory skin lesions and are rare in rats lesions and guinea pig skin lesions. its a mouse thing. But because of neutrophils in mouse and so some people think that they are important in MS and maybe they are, but it is important that we look at MS,rather than make MS mouse EAE. Neutrophils are more common in neuromyelitis optica lesions

In this study they look at the neutrophil to lymphocyte ratio (NLR) and find that it is elevated in MS and active MS. However the NLR is used as a marker of subclinical inflammation and occurs in a number of conditionsBlood nu

Tuesday, 26 May 2015

What do USA and Gabon have in Common?

Apparently, it is that they research on Great Apes

In light of ProfGs comments (below), some may wonder where Gabon is

for those who don't know where the USA is

There are no groups in the UK, who use non-human primates for MS research.

A couple of days ago someone asked in the comments about the fate of Tab008, this is also known as TGN1412 and was a disaster. 

Although, it inhibited EAE in mice, anybody with Immunology 101 should have been aware that if you give a T cell mitogenic (makes them proliferate) get a cytokine storm in humans causing the blood system to shut down in the extremities (This led to gangrene). Such an effect could also lead to death although thankfully this did not happen in the TGN1412 trial. 

Mice live in bacterial city and can cope with CD28 super agonists like TGN1412 and apparently so could cynomolgus monkeys, used in the safety tests before human studies which lack CD28, the target of TGN1412..oops. 

If they had tested the effect of TGN1412 in Chimpanzees, this terrible side effect would have been known. 

Which is more disturbing the picture at the top or the bottom?

With a bit of thought, maybe both can be avoided.

ClinicSpeak: Is your neurologist burnt out?

How real is burnout? #ClinicSpeak #MSResearch #MSBlog

"Last week was one of the hardest I have had working as a clinical academic, administrator, teacher and MSologist. My diary was simply sea of blue space with virtually no free time. I did manage to work from home last Wednesday on an urgent grant application; the deadline is the 3rd June and it will be touch and go if we make it. The grant is a large programme of research tackling progressive MS. Despite booking the day off work, I still had teleconferences and the endless avalanche of emails to deal with. After clocking in 18 hours at my desk I think we may have a chance of getting it in on time and in good enough shape to convince the reviewers to recommend funding it. May be I am fooling myself; the success rate with MRC grants is less than 10%."

"Thursday started with a strategy meeting on our MS sevice at Barts and finished with a very long and emotionally draining MS clinic. I had to rush home quickly to look after my daughter's needs as my wife was away at an important company meeting. I had to get up at 5am on Friday to get to the Sofitel at Heathrow airport to chair an International meeting on a policy paper to promote brain health in MSers and to treat MS holistically. We are hoping to launch the policy document at a satellite symposium at ECTRIMS this year. Overall, I think the meeting went well, but by the time I go back home I was exhausted. I am beginning to understand the meaning of burnout (see abstract below)."

"Saturday started with a quiet walk on the common with my dog, listening to a BBC Radio 4 debate on animal welfare. I was recommended by a colleague of mine and friend who recently retired from the hustle and bustle of academic life. It is well worth listening to if you have access to BBC podcasts."

At the end of May 2015, there will be a debate in a New York court about whether two chimpanzees kept in a university laboratory are being illegally detained, and should be released into a sanctuary. Laboratory research on chimpanzees is banned in most of the world, though the US, along with Gabon, still allows it. Hear a discussion on whether animals, including primates, should be used for research, and whether they are entitled to “rights” - or just “humane treatment”. The debate is chaired by Owen Bennett Jones and includes the leading philosopher opponent to the concept of animal rights Professor Carl Cohen, as well as a distinguished philosopher Colin McGinn, a lawyer and a leading animal rights advocate Steven Wise, a neurobiologist Sir Colin Blakemore and someone who grew up with Nim Chimpsky - a New York resident Jenny Lee. 

"Just when I thought I was free of thinking-MS I saw a man with a walking frame trying to walk his dog. He had a spastic paraparesis (weak in both legs) and a foot drop. He nearly fell several times getting from his car to the bench next to the bandstand on Clapham Common. He had a small dog, it looked like a Scottish Terrier, on one of those long extendable leads. The dog simply wound the lead around the bench and got it knotted around the walker. It was then I noticed the man was also very incoordinate and was having difficulty dealing with the lead and the his dog. The sad thing he was younger than me, I would have guessed in his early 40s, and based on simple deductive reasoning most likely had MS. It was clear to me that as hard as I tried the week was destined to be MS and nothing else. It was at this exact moment that I decided not to do any work over the weekend and almost got there if it wasn't for my usual insomnia that got me up at 2.30am on Monday morning. Thankfully, the remainder of yesterday was a holiday in England, the so called second May Bank holiday so I had the day off to spend with the family and friends visiting from Malaysia. I am about to leave for the airport to travel to the CMSC meeting in Indianapolis; I have two platform and several poster presentations, so it is back to my day job. I will keep you posted on what happens at the CMSC meeting."

Sigsbee & Bernat. Physician burnout: A neurologic crisis. Neurology. 2014 Dec 9;83(24):2302-6. d

The prevalence of burnout is higher in physicians than in other professions and is especially high in neurologists. Physician burnout encompasses 3 domains: (1) emotional exhaustion: the loss of interest and enthusiasm for practice; (2) depersonalization: a poor attitude with cynicism and treating patients as objects; and (3) career dissatisfaction: a diminished sense of personal accomplishment and low self-value. Burnout results in reduced work hours, relocation, depression, and suicide. Burned-out physicians harm patients because they lack empathy and make errors. Studies of motivational factors in the workplace suggest several preventive interventions: (1) Provide counseling for physicians either individually or in groups with a goal of improving adaptive skills to the stress and rapid changes in the health care environment. (2) Identify and eliminate meaningless required hassle factors such as electronic health record "clicks" or insurance mandates. (3) Redesign practice to remove pressure to see patients in limited time slots and shift to team-based care. (4) Create a culture that promotes career advancement, mentoring, and recognition of accomplishments.

Are all Cops created equal....seems not

Kolitz S, Hasson T, Towfic F, Funt JM, Bakshi S, Fowler KD, Laifenfeld D, Grinspan A, Artyomov MN, Birnberg T, Schwartz R, Komlosh A, Hayardeny L, Ladkani D, Hayden MR, Zeskind B, Grossman I. Gene expression studies of a human monocyte cell line identify dissimilarities between differently manufactured glatiramoids. Sci Rep. ;5:10191. doi: 10.1038/srep10191.

Glatiramer Acetate (GA) has provided safe and effective treatment for multiple sclerosis (MS) patients for two decades. It acts as an antigen, yet the precise mechanism of action remains to be fully elucidated, and no validated pharmacokinetic or pharmacodynamic biomarkers exist. In order to better characterize GA's biological impact, genome-wide expression studies were conducted with a human monocyte (THP-1) cell line. Consistent with previous literature, branded GA upregulated anti-inflammatory markers (e.g. IL10), and modulated multiple immune-related pathways. Despite some similarities, significant differences were observed between expression profiles induced by branded GA and Probioglat, a differently-manufactured glatiramoid purported to be a generic GA. Key results were verified using qRT-PCR. Genes (e.g. CCL5, adj. p < 4.1 × 10-5) critically involved in pro-inflammatory pathways (e.g. response to lipopolysaccharide, adj. p = 8.7 × 10-4) were significantly induced by Probioglat compared with branded GA. Key genes were also tested and confirmed at the protein level, and in primary human monocytes. These observations suggest differential biological impact by the two glatiramoids and warrant further investigation.

The Cop-wars are set to begin as the patents of glaterimer expire and the biosimilars arrive. However the cop-wars have been going for some time in the courts. Glaterimer is a random mix of cop-polymer and so is not the same from one batch to another however, the generics companies argue that their stuff is just as good the original. However this may not be the case. 

They took 4 batches of GA and compared it with a single batch of probioglat and looked at the effect on a macrophage line and they show it activates a different set of cytokines over 120 were upregulated and over 20 down regulated(remember there is 30,000 genes. So they may not e the same.

It is argued that the efficacy rate in Mexico has dropped since the generics entered the Market. However as to highlight the conflicts in this paper this is by Teva employees and they do not compare GA verses Probioglat, which surely they have done as they want to convince us that "it is rubbish throw it in the bin". 

So it can be argued if it is different would more batches give the same answer and now there other Cop Me-toos and these need to be checked

One company may argue that you are not paying more just for the packaging

Genetics or ambiguous scientific evidence? The genetic roulette.

Int J Biochem Cell Biol. 2015 May 19. pii: S1357-2725(15)00131-4. doi: 10.1016/j.biocel.2015.05.010. [Epub ahead of print]
Genomic Imprinting: A Missing Piece of the Multiple Sclerosis Puzzle? Stridh P, Kular L, Jagodic M.

Evidence for parent-of-origin effects in complex diseases such as Multiple Sclerosis (MS) strongly suggests a role for epigenetic mechanisms in their pathogenesis. In this review we describe the importance of accounting for parent-of-origin when identifying new risk variants for complex diseases and discuss how genomic imprinting, one of the best-characterized epigenetic mechanisms causing parent-of-origin effects, may impact etiology of complex diseases. While the role of imprinted genes in growth and development is well established, the contribution and molecular mechanisms underlying the impact of genomic imprinting in immune functions and inflammatory diseases are still largely unknown. Here we discuss emerging roles of imprinted genes in regulation of inflammatory responses with a particular focus on the Dlk1 cluster that has been implicated in etiology of experimental MS-like disease and Type 1 Diabetes. Moreover, we speculate on the potential wider impact of imprinting via the action of imprinted microRNAs, which are abundantly present in the Dlk1 locus and predicted to fine-tune important immune functions. Finally, we reflect on how unrelated imprinted genes or imprinted genes together with non-imprinted genes can interact in so-called imprinted gene networks (IGN) and suggest that IGNs could partly explain observed parent-of-origin effects in complex diseases. Unveiling the mechanisms of parent-of-origin effects is therefore likely to teach us not only about the etiology of complex diseases but also about the unknown roles of this fascinating phenomenon underlying uneven genetic contribution from our parents.

A hypothetical model explaining the role of parent-of-origin effects in Multiple Sclerosis and other complex diseases with similar etiologies. A well-recognized contribution of environmental factors and multiple (non-imprinted) genes to the etiology of Multiple Sclerosis might further be modulated by a contribution from genes that depend on parental origin and involve classically imprinted genes as well as non-imprinted genes that form networks with other imprinted genes. Abbreviations: IGN, imprinted gene network

Over a decade of genetic studies in MS have not provided clear answers, in fact the contributing factors maybe even more complex than imagined. The first ever genetic link identified in the 1970 was the HLA (Human Leukocyte Antigen) complex. And to date over 110 non-HLA and HLA effects are known to explain only 20% of the sibling recurrence risk!!! 

It begs the question whether their are hidden heritability residues? In a recent meta-analyses, the estimated heritability has been found to be 54% using a model of inheritance consistent of one locus with moderate effect and many loci of modest effects...The search for the modest effects has begun.

In this review the researchers focus on one such modest effect - the concept of parent-of-origin effects expressed through genomic imprinting. Parent-of-origin effects is the uneven genetic contribution from parents where phenotype depends on the parental origin of the associated allele, whilst, imprinting is the way a gene is expressed only from a maternally or paternally inherited chromosome. DNA methylation (the addition of a methyl group to DNA) is a form of imprinting which modifies the DNA resulting in an alteration in gene expression without actually changing the DNA sequence. The authors use another example, DLK1, a gene which affects the development and function of B cells and moreover can affect the expression of many immune-related genes. 

A piece of mind boggling research which lends its support to this way of thinking is that maternal half-siblings of MS-affected persons have a significantly higher risk of developing MS compared to paternal half siblings. 

It is uncertain how much of this hidden heritability may have already influenced findings from published conventional genetic studies. But what is certain is that this area of research is not for the faint hearted.

Dark Matter Garden (Chelsea Flower Show 2015), also not for the amateur horticulturist!