Thursday, 31 July 2014

Employment: Norway is tragically the exception

Is Norway's runaway success in relation to MSer employment linked to their top ranking in the Human Development Index? #MSBlog #MSResearch

"Yesterday Mouse Doc discussed the article below that showed the employment rate amongst MSers living in county of Norway was 45% at 19 years. These are by far the best figures I have seen to date. I am hoping they indicate a trend that may be driven by early access to DMTs and an alteration in the natural history of MS. In other words by preventing relapse and the accrual of disability MSers are more likely to be staying in employment. On the other side of the coin these figures may be unique to Norway. Norway Ranks number 1 in the world in relation to the Human development Index (HDI). HDI is considered a better measure of a country's progress than income growth. I have embedded key data slides in relation to HDI for your information; it will allow you to see how well your country is doing. It is tragedy, but not surprising, that a large part of your outcome in relation to MS is probably related to which country you live in. The UK comes, embarrassingly, 27th in the league table; which is kind of where I would expect it be, based on the EMSP's barometer data, if  these figures referred directly to MS outcomes."

"Is being employed a badge of health for MSers? Should we be including relative employment rates when we compare the effectiveness of DMTs? Which DMT is likely to maximize your chances of staying employed, or becoming employed? If only we had this data."

Bøe-Lunde et al. Employment among Patients with Multiple Sclerosis-A Population Study. PLoS One. 2014 ;9(7):e103317. 

OBJECTIVE: To investigate demographic and clinical factors associated with employment in MS.

METHODS: The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS.

RESULTS: After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed.

CONCLUSIONS: Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

No Oligoclonal bands in your CSF means that you do better

Multiple sclerosis patients lacking oligoclonal bands in the cerebrospinal fluid have less global and regional brain atrophy.
Ferreira D, Voevodskaya O, Imrell K, Stawiarz L, Spulber G, Wahlund LO, Hillert J, Westman E, Karrenbauer VD.
J Neuroimmunol. 2014. pii: S0165-5728(14)00181-7. doi: 10.1016/j.jneuroim.2014.06.010. [Epub ahead of print]

To investigate whether multiple sclerosis (MS) patients with and without cerebrospinal fluid (CSF) oligoclonal immunoglobulin G bands (OCB) differ in brain atrophy. Twenty-eight OCB-negative and thirty-five OCB-positive patients were included. Larger volumes of total CSF and white matter (WM) lesions; smaller gray matter (GM) volume in the basal ganglia, diencephalon, cerebellum, and hippocampus; and smaller WM volume in corpus callosum, periventricular-deep WM, brainstem, and cerebellum, were observed in OCB-positives. OCB-negative patients, known to differ genetically from OCB-positives, are characterized by less global and regional brain atrophy. This finding supports the notion that OCB-negative MS patients may represent a clinically relevant MS subgroup.

If MSers did not have oligoclonal bands they appeared to do better, is this cause and effect. If there is limited immune activation in the CNS then there appears to be less damage, but should this be a different subset of MS?. If there is no difference in response to therapy, which currently appears to be the case then surely there is limited merit in this but it could be of relevance when recruiting for trials such that this subset is equally represented in studies

Progression is this an easy mountain to CLIMB

Raghavan K, Healy BC, Carruthers RL, Chitnis T. Progression rates and sample size estimates for PPMS based on the CLIMB study population. Mult Scler. 2014 Jul. pii: 1352458514541976. [Epub ahead of print]

BACKGROUND: The clinical trial design for primary progressive multiple sclerosis (PPMS) requires understanding of disability progression in modern patient cohorts.
OBJECTIVE: The objective of this paper is to characterize demographic and clinical characteristics of PPMS and assess rate of disability progression.
METHODS: We studied PPMS (n = 73) and relapsing-onset MS (ROMS) patients (n = 1541) enrolled in CLIMB, a longitudinal study of MS patients at the Brigham and Women's Hospital (Boston, MA). Disability progression for each group was compared using interval-censored survival analysis and time to six-month sustained progression.
RESULTS: The PP group had a 1.09:1 male:female ratio compared to 1:2.89 for the RO group and greater mean age of onset (PP: 44.4±9.6; RO: 32.7±9.9; p < 0.0001). Motor symptoms at onset and first symptoms localized to spinal cord were each strongly associated with PPMS (p < 0.001). Median time from onset to EDSS 6.0 was faster in PPMS (p < 0.001). PPMS patients progressed faster to EDSS 3 (p < 0.001) and from EDSS 3 to 6 (p < 0.001). Median time to sustained progression in the PP group was 4.85 years (95% CI 2.83-8.35), significantly faster than the RO group (p < 0.001).
CONCLUSIONS: Our modern PPMS cohort is demographically similar to previously studied cohorts. PPMS is associated with faster disability accrual than ROMS. Current real-world observations of time to sustained progression will inform design of new clinical trials for PPMS.

CLIMB (Comprehensive Longitudinal Investigation of Multiple Berosis) is based at Harvard. The CLIMB study is a large-scale, long-term study of patients with MS. It is designed to investigate the course of the disease in the current era of treatment. The main goals of the study are to:

1. Identify predictors of future disease course when patients are at the beginning of their illness.

They found males and age of onset and spinal disease

2. Determine the effects of treatment on disease progression and accumulation of disability.

I suspect you are asking what treatments..need to do better
In this study people with progressive MS were behaving as predicted in terms of their progression rates, is this to be expected because they are not recieving any effective treatments. 

However the question is if PPMSers are in trials then will this rate be the same. In the CUPID trial of tetrahydrocannabinol people in the trial progressed at at much slower rate than predicted.

I am sure the key aspect on your tounge is where are the treatments?

Mice work may send you down the wrong path becuase of the mouse you use

Kraev A. Parallel universes of Black Six biology. Biol Direct. 2014 Jul 19;9(1):18

Creation of lethal and synthetic lethal mutations in an experimental organism is a cornerstone of genetic dissection of gene function, and is related to the concept of an essential gene. Common inbred mouse strains carry background mutations, which can act as genetic modifiers, interfering with the assignment of gene essentiality. The inbred strain C57BL/6J, commonly known as "Black Six", stands out, as it carries a spontaneous homozygous deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene [GenBank: AH009385.2], resulting in impairment of steroidogenic mitochondria of the adrenal gland, and a multitude of indirect modifier effects, coming from alteration of glucocorticoid-regulated processes. Over time, the popular strain has been used, by means of gene targeting technology, to assign "essential" and "redundant" qualifiers to numerous genes, thus creating an internally consistent "parallel universe" of knowledge. It is unrealistic to suggest phasing-out of this strain, given the scope of shared resources built around it, however, continuing on the road of "strain-unawareness" will result in profound waste of effort, particularly where translational research is concerned. The review analyzes the historical roots of this phenomenon and proposes that building of "parallel universes" should be urgently made visible to a critical reader by obligatory use of unambiguous and persistent tags in publications and databases, such as hypertext links, pointing to a vendor's strain description web page, or to a digital object identifier (d.o.i.) of the original publication, so that any research done exclusively in C57BL/6J, could be easily identified.

To many of the readers of the blog will say who cares...mice don't get MS but to the few interested read on
With the the development of transgenic technology, where by we can add or delete genes to worms, fruitflies, mice and almost any other species has given us a revolution in the understanding of biology. 

The transgenic technology in mice including transgenic (addition of gene) and gene knockout (removal of gene) involves taking embryonic stem cells and blastocyst (a very young embryo) usually from two strains of mice.

The C57BL/6  (little black mice that like to bite you) and the 129 strains. After this the gene knockout or transgene is put onto the C57BL/6 strain background.

This is amongst the most resistant strain in relation to developing CNS autoimmunity, yet is becoming the most used for MS research because of the transgenic technology.

The C57BL/6 mouse develops CNS autoimmunity following sensitization to myelin oligodendrocyte glycoprotein. 

In the UK to work with transgenic or mutant mice, like Shiverer (MBP myelin mutant that shivers), rumpshaker (PLP myelin mutant that sakes its booty), Jimpy (PLP myelin mutant that shakes with time) you need a licence from the UK government and have to record these details. Howevert you don't with standard lab strains. Therefore many animals used in science go missing from statistics! 

However, the silly thing is many of these so called standard lab mice also have mutations and are mutants, but because they are not obvious mutants that effect obvious health issues they slip through the net. 

The SJL mouse used in MS research has a slow retinal degeneration and go blind slowly, the C3H strain goes blind quickly, the C57BL/6 mouse prefers to drink alcohol to water Others are deaf and maybe explains why they wont; do as they are told.  

Likewise many transgenics and knockouts have no effect on animal health, but they are recorded and this is why the number of animals used in research is growing...A major government relation to the fudge factor of animal statistics. 

If transgenics that had no deleterious effect were excluded from statistics the number of animals used in animal experiments would be falling. 

I say record them all and stop the fudge!..this will put pressure on people doing cell culture with meaningless experiments to justify what they do, because at the moment becuase they are not doing experiments on a living animal it is not recorded as an experiment if you kill the animal and use its tissues.

Anyway what this paper says is that C57BL/6 have natural mutations and that these may influence the effect of the introduction of another transgene or gene knockout.

This may make some genes seem important when they may not be that essential and may make you develop a strange "world view of biology". Therefore, ideally you would want to see the effect of the gene knockout in other strains to be convinced that the transgenic is having a consistent effect.

Even within the strain obtained from different commercial breeders there can be different mutations present. So it is important when reporting work to say where the animals come from. 

As we have said many times and reported (click) that EAE in C57BL/6 can be a bit dodgy and so it is well to remember this when you are reading the scientific literature as some things may not be that reproducible. You are looking at the effect of an experiment done many times in the genetically the same individual...just remember another mouse strain is just another individual and which one behaves like most humans is key

PLEG RIDY arrives in Europe

It has been announced that the European Regulators have approved Plegridy for MS.
Plegridy is an interferon drug, the same type of treatment as Biogen Idec’s first multiple sclerosis therapy, Avonex. While Avonex typically is injected into the muscle once a week, Plegridy can be taken by injection once every two weeks and administered under the skin with a prefilled auto-injector. 

This is a pegylated interferon.PEG poly ethylene glycol is an anti-freeze, but in this application it causes the interferon to hang around for longer. So less injections......more patent life

So another interferon on the market, which makes it hang around longer,but doesn't make it work better. So just as the Patent life of avonex for MS comes to an end, it has metamorphosis into a new product..surprise, surprise.

What a name...who comes up with them? 


Wednesday, 30 July 2014

Employment in MSers (Norway)

Bøe Lunde HM, Telstad W, Grytten N, Kyte L, Aarseth J, Myhr KM, Bø L. Employment among Patients with Multiple Sclerosis-A Population Study. PLoS One. 2014 ;9(7):e103317. doi: 10.1371/journal.pone.0103317. eCollection 2014.
OBJECTIVE:To investigate demographic and clinical factors associated with employment in MS.
METHODS: The study included 213 (89.9%) of all MS patients in Sogn and Fjordane County, Western Norway at December 31st 2010. The patients underwent clinical evaluation, structured interviews and completed self-reported questionnaires. Demographic and clinical factors were compared between patients being employed versus patients being unemployed and according to disease course of MS.
RESULTS: After a mean disease duration of almost 19 years, 45% of the population was currently full-time or part- time employed. Patients with relapsing -remitting MS (RRMS) had higher employment rate than patients with secondary (SPMS) and primary progressive (PPMS). Higher educated MS patients with lower age at onset, shorter disease duration, less severe disability and less fatigue were most likely to be employed.
CONCLUSIONS: Nearly half of all MS patients were still employed after almost two decades of having MS. Lower age at onset, shorter disease duration, higher education, less fatigue and less disability were independently associated with current employment. These key clinical and demographic factors are important to understand the reasons to work ability in MS. The findings highlight the need for environmental adjustments at the workplace to accommodate individual 's needs in order to improve working ability among MS patients.

There are many post on unemployement amongst MS on this blog and in many cases it is about 50% in about 8-10 years, but the figure from this Norwegian study shows that it takes twice as long, therefore society can change to accommodate peoples disabilities

MS on the up globally

Melcon MO, Correale J, Melcon CM. Is it time for a new global classification of multiple sclerosis? J Neurol Sci. 2014 Jun 29. pii: S0022-510X(14)00421-3
BACKGROUND: The geographic distribution of multiple sclerosis (MS) is classically divided into three zones based on frequency that were established by Kurtzke in the early 1970s. In recent years, an increasing number of epidemiological studies have shown significantly higher MS prevalence and incidence rates.
OBJECTIVE: The aim of this study was to review and update the geographic distribution of MS using incidence, prevalence and disease duration from the latest epidemiology surveys.
METHODS: We conducted a systematic review of articles on MS epidemiology published between January 1, 1990 and December 31, 2012.
RESULTS: MS studies were grouped by continent: the Americas, Europe, Asia, Australia/New Zealand, and Africa. A total of 101 studies were identified according to the inclusion criteria, and 58 reported incidence estimates. Globally, the median estimated incidence of MS was 5.2 (range: 0.5-20.6) per 100,000p-yrs, the median estimated prevalence of MS was 112.0 (with a range of 5.2-335) per 100,000p-yrs, and the average disease duration was 20.2years (range: 7.6-36.2).
CONCLUSION: In the past few decades, the global prevalence and incidence patterns of MS have changed dramatically. Regardless of the reason of increasing prevalence and incidence rate, we suggest the need for a novel classification system based on global MS disease burden. Adopting such a system would improve economic efficiency and prioritization in health policy planning for MS.
Is there really a need for a global classification when we know MS drugs cost too much.

Charcot Project: INSPIRE Trial fully recruited

The INSPIRE Study is now fully recruited. #MSBlog #MSResearch

"In response to several requests, I can now confirm that recruitment for the INSPIRE Study is now complete. The study will be closed when the last subject completes 6 months, i.e. early January. Hence the results of the study will only be know in April/May. It takes this long to clean the data, lock the database and for our statistician to complete the analysis."

"I would like to thank all the staff for their dedication and hard work at getting to this point in time, my colleagues for referring patients for the study, Merck for funding the study, Queen Mary University of London for sponsoring the study and last but not least for the participants for volunteering for the study. Without volunteers we could never have got this far; thank you!"

A Phase II Baseline Versus Treatment Study to Determine the Efficacy of Raltegravir (Isentress) in Preventing Progression of Relapsing Remitting Multiple Sclerosis as Determined by Gadolinium-enhanced MRI

There is accumulating research evidence that Human Endogenous Retrovirus (HERV) and herpes viruses (in particular Epstein-Barr Virus) are involved in the pathogenesis of MS. People with active MS have higher levels of HERVs than people either without MS or who have other neurological conditions. It has been shown that HERVs may produce neurotoxic proteins/antigens associated with MS activity and disease progression. This is the first clinical trial investigating the hypothesis that the antiretroviral drug raltegravir may suppress HERV activity and ameliorate progression of relapsing remitting MS. Raltegravir is an integrase inhibitor which blocks retroviral replication. A recent experimental study suggests that raltegravir may also be active against herpes viruses.

Eligible participants (see Inclusion/Exclusion Criteria) will be observed for 3 months having monthly brain Gadolinium enhanced MRIs and blood/urine/saliva sampling (baseline). Then they will be treated with raltegravir (one 400mg pill taken twice a day) for 3 months. During treatment period participants will continue to have monthly MRIs and blood/saliva/urine sampling. Participants will have monthly clinical and neurological examinations and they will complete questionnaires assessing response to treatment. Participants will have screening and study visits at The Royal London Hospital, Whitechapel. Monthly MRIs will be performed at the Institute of Neurology, UCL, Queen Square, London.

Inclusion Criteria:
  1. Patients between 18-55 years of age.
  2. Diagnosis of MS, according to the revised McDonald Criteria 2010.
  3. EDSS score of 0-6.0 inclusive.
  4. Documented at least one relapse within the past 12 months or at least one Gd-enhanced lesion on the brain MRI detected within 3 months prior to screening date
  5. Gd-enhanced lesion on screening MRI (if MRI not used to meet screening criteria above).
  6. Female patients of childbearing potential will be expected to be on appropriate contraception (hormonal or barrier method of birth control; abstinence) from time of consent until 6 weeks after treatment discontinuation. (the repeated administration of gadolinium and MRI are not recommended during pregnancy). NOTE: Subjects are considered not of child bearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  7. Females of childbearing potential must have a negative urine pregnancy test prior to every MRI scan/ within 7 days prior to being registered for protocol therapy.
  8. Must give written informed consent and authorize the release and use of protected health information, as required by local law.
  9. Able and willing to undergo blood, saliva and urine sampling at regular intervals as defined by the protocol.
  10. Able and willing to receive Gadolinium enhanced MRI's at regular intervals as defined by the protocol.
  11. Able to comply with study requirements.
Exclusion Criteria:
  1. Pregnant or breastfeeding or unwilling to use contraception.
  2. Treatment with immunosuppressive, immunomodulatory or experimental treatments within the last 6 months of enrolment in the study, but excluding pulsed intravenous or oral steroids for treatment of MS relapse.
  3. No pulsed intravenous or oral steroids in the 30 days preceding the baseline assessment.
  4. Patients presenting with medical disorder deemed severe or unstable by the CI such as poorly controlled diabetes or arterial hypertension, severe cardiac insufficiency, unstable ischemic heart disease, abnormal liver function tests (>2.5 times ULN) and abnormal complete blood count (in particular leukopenia, as defined by a lymphocyte count <500, neutrophil <1.5 or platelet count < 100, or thrombocytopenia < 1.5 LLN), or any medical condition which, in the opinion of the chief investigator, would pose additional risk to the patient.
  5. Presence of human immunodeficiency virus antibodies.
  6. Patients receiving proton pump inhibitors (e.g. omeprazole/esomeprazole)
  7. Patients with active hepatitis B or/and C with liver function tests >2.5 times ULN
  8. Exposure to any other investigational drug within 30 days of enrolment in the study.
  9. Prior history of malignancy unless an exception is granted by the Chief Investigator.
  10. History of uncontrolled drug or alcohol abuse within 6 months prior to enrolment into the study.
  11. Patients treated with Rifampicin in past four weeks. Identifier: NCT01767701

Additional reading: raltegravir

CoI: multiple, this trial is being funded by Merck.

Surge in vitamin D deficiency rates

Wouldn't it be a tragedy if we show in 100 years that repleting the population of vD prevented a large proportion of MS? #MSBlog #MSResearch

"For those of you living in the US you may find the following non-MS-related publication of interest. It shows a surge in vitamin D deficiency diagnoses and mirrors that what is happening in the UK. We are in the process of auditing our own MS neurology practice to see how large the increase is in our outpatient setting. Why is this occurring?

Sun-blockers: It is well known that over the last 15-20 years dermatologists and the cosmetic industry have massively increased our consumption of sun blockers. Dermatologists tell us to avoid sunburn to prevent skin cancer and the cosmetic industry to prevent sun damage that is a major cause of skin aging. Sun blockers reduce the skin's production of vD and are clearly contributing to the rising incidence of vD deficiency? Men be warned the cosmetic industry are targeting you; there is an ever increasing consumption of cosmetics with sun-blockers by men, in particular the younger generation. Almost all of the new male cosmetics now include sun blockers badged as anti-aging agents.

Outdoor activities: Other behavioural changes has been the shift from outdoor activities to indoor activities. Children and teenagers now spend much less time in the sun. Why? This is the era of facebook and gaming. Young girls spend large amounts of time on social networks and boys playing computer games. There are several studies from the past that have demonstrated that outdoor activities in childhood protect against MS; reversing this trend is very worrying.

Fish consumption: It is well known that fish consumption worldwide is going down. This is based on economic factors, as we deplete fish stocks prices have risen and consumption has dropped. We are also increasingly eating farmed fish which has about a third of the vD levels of wild fish; wild fish have higher vD levels because of their diet is higher in phytoplankton which provides the vD.

Pollution and weather: Atmospheric pollution and cloud cover is another issue; this is a particular problem in certain areas of the world. In heavily polluted areas of the world air pollution exacerbates vD deficiency as it acts a ultraviolet B light filter.

Cultural changes: I have mentioned before that covering up for cultural reasons is a problem for woman. Whether or not covering up is for religious or other cultural reasons it contributes to very low vD levels in some parts of the world.

Low vD recommended daily allowance (RDA): The current RDA of vD of 400IU per day is based on rickets prevention studies in the early half of the 20th century. When these studies were done the role of vD in immune and other functions were not known. There is an international lobby that is trying to get the RDA of vD increased; however, without more data it looks as if public health doctors are reluctant to adopt the advice. We now promote physiological vD supplementation in all children and relatives of MSers as per the Vitamin D Council's recommendations. Despite this we have found that adherence to our advice is poor. Therefore we have started Digesting Science. This is a course to teach children of MSers about MS and the link between low vD and MS. The idea is to get children to be adherent to their vD supplementation regimen via education. "

Huang et al. Surge in U.S. Outpatient Vitamin D Deficiency Diagnoses. National Ambulatory Medical Care Survey Analysis. South Med J. 2014 Apr; 107 (4) :214-7.

OBJECTIVES: In light of the growing medical interest in the potential consequences of vitamin D deficiency, it is important that clinicians are informed about the varying factors that may complicate the assessment of vitamin D status and the diagnosis of deficiency. To better understand the frequency of vitamin D deficiency diagnoses in the ambulatory setting over time, the objective of this investigation was to examine unspecific, general, and bone-related vitamin D deficiency diagnoses between 2007 and 2010 and to determine whether the rate ofdiagnoses differed by patient age and sex.

METHODS: We used data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey to assess the rate of vitamin D deficiency diagnoses provided between 2007 and 2010 during outpatient visits with non-federally employed physicians in offices and hospitals. Two hundred ninety-two unweighted patient visit records were included. Trends in vitamin D deficiency diagnosis over time, diagnosis of bone disease associated with a vitamin D deficiency diagnosis, and patient age and sex were reported.

RESULTS: The number of diagnoses for vitamin D deficiency rapidly increased from 2007 to 2010. More than 97% of diagnoses were for unspecific vitamin D deficiency; 9.6% of vitamin D deficiency visits also resulted in a diagnosis of osteoporosis or bone fracture.

CONCLUSIONS: Although the rate of diagnoses for vitamin D deficiency increased between 2007 and 2010, many diagnoses rendered were for nonspecific disease; therefore, vitamin D deficiency screening may have been ordered for preventive care purposes rather than as a diagnostic aid.

Tuesday, 29 July 2014

Clearing up debris to help repair

Rajbhandari L, Tegenge MA, Shrestha S, Ganesh Kumar N, Malik A, Mithal A, Hosmane S, Venkatesan A. Toll-like receptor 4 deficiency impairs microglial phagocytosis of degenerating axons.
Glia. 2014 Jul 8. doi: 10.1002/glia.22719. [Epub ahead of print]

Microglia are rapidly activated in the central nervous system (CNS) in response to a variety of injuries, including inflammation, trauma, and stroke. In addition to modulation of the innate immune response, a key function of microglia is the phagocytosis of dying cells and cellular debris, which can facilitate recovery. Despite emerging evidence that axonal debris can pose a barrier to regeneration of new axons in the CNS, little is known of the cellular and molecular mechanisms that underlie clearance of degenerating CNS axons. We utilize a custom micropatterned microfluidic system that enables robust microglial-axon co-culture to explore the role of Toll-like receptors (TLRs) in microglial phagocytosis of degenerating axons. We find that pharmacologic and genetic disruption of TLR4 blocks induction of the Type-1 interferon response and inhibits phagocytosis of axon debris in vitro. Moreover, TLR4-dependent microglial clearance of unmyelinated axon debris facilitates axon outgrowth. In vivo, microglial phagocytosis of CNS axons undergoing Wallerian degeneration in a dorsal root axotomy model is impaired in adult mice in which TLR4 has been deleted. Since purinergic receptors can influence TLR4-mediated signaling, we also explored a role for the microglia P2 receptors and found that the P2X7R contributes to microglial clearance of degenerating axons. Overall, we identify TLR4 as a key player in axonal debris clearance by microglia, thus creating a more permissive environment for axonal outgrowth. Our findings have significant implications for the development of protective and regenerative strategies for the many inflammatory, traumatic, and neurodegenerative conditions characterized by CNS axon degeneration

Toll-like receptor 4 is a is a toll-like receptor. It detects lipopolysaccharide from Gram-negative bacteria and is thus important in the activation of the innate immune system. TLR 4 has also been designated as CD284 (cluster of differentiation 284). The protein encoded by this gene is a member of the Toll-like receptor (TLR) family, which plays a fundamental role in pathogen recognition. In this study they report that TLR4 is involved in triggering microglia to remove myelin debris, which allows remyelination to occur. P2X purinoceptor 7 is a protein that in humans is encoded by the P2RX7 gene. The product of this gene belongs to the family of purinoceptors for ATP (cellular energy molecule. The receptor is found in the central and peripheral nervous systems, in microglia, in macrophages, P2X7 receptors have been implicated in ATP-mediated cell death, regulation of receptor trafficking, and inflammation. P2X7 signalling can influence TLR4 which recognise the pathogen-associated molecular patterns (PAMPs) that are expressed by infectious agents. There are many agents that act on P2X7 receptors can they influence myelination in MS?

lentiviral anti-lingo supports remyelination

Wang CJ, Qu CQ, Zhang J, Fu PC, Guo SG, Tang RH. Lingo-1 Inhibited by RNA Interference Promotes Functional Recovery of Experimental Autoimmune Encephalomyelitis. Anat Rec (Hoboken). 2014 Jul . doi: 10.1002/ar.22988. [Epub ahead of print]

Lingo-1 is a negative regulator of myelination. Repairment of demyelinating diseases, such as multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE), requires activation of the myelination program. In this study, we observed the effect of RNA interference on Lingo-1 expression, and the impact of Lingo-1 suppression on functional recovery and myelination/remyelination in EAE mice. Lentiviral vectors encoding Lingo-1 short hairpin RNA (LV/Lingo-1-shRNA) were constructed to inhibit Lingo-1 expression. LV/Lingo-1-shRNA of different titress were transferred into myelin oligodendrocyte glycoprotein-induced EAE mice by intracerebroventricular (ICV) injection. Meanwhile, lentiviral vectors carrying nonsense gene sequence (LVCON053) were used as negative control. The Lingo-1 expression was detected and locomotor function was evaluated at different time points (on days 1,3,7,14,21, and 30 after ICV injection). Myelination was investigated by luxol fast blue (LFB) staining. LV/Lingo-1-shRNA administration via ICV injection could efficiently down-regulate the Lingo-1 mRNA and protein expression in EAE mice on days 7,14,21, and 30 (P < 0.01), especially in the 5 × 108 TU/mL and 5 × 109 TU/mL LV/Lingo-1-shRNA groups. The locomotor function score in the LV/Lingo-1-shRNA treated groups were significantly lower than the untreated or LVCON053 group from day 7 on. The 5 × 108 TU/mL LV/Lingo-1-shRNA group achieved the best functional improvement (0.87 ± 0.11 vs. 3.05 ± 0.13, P < 0.001). Enhanced myelination/remyelination was observed with 50 million to 5 billion Units of virus/mL LV/Lingo-1-shRNA groups by LFB staining (P < 0.05, P < 0.01, and P < 0.05).The data showed that administering LV/Lingo-1-shRNA by ICV injection could efficiently knockdown Lingo-1 expression in vivo, improve functional recovery and enhance myelination/remyelination. Antagonism of Lingo-1 by RNA interference is, therefore, a promising approach for the treatment of demyelinating diseases, such as MS/EAE.

Anti-Lingo-1 antibody can promote remyelination and is clinical trial. However the problem with antibodies is that they do not readily get into the CNS so about 99.9% of that delivered will probably not get there. In the early trials they gave it intravenously wonder if there would be a better effect of intrathecal delivery so more gets in the brain.

 This study uses gene therapy to deliver the therapy to block Lingo-1 and inject a genetically engineered lentiviral vector. The virus delivers something that blocks message of Lingo-1 and this blocks a non-remyelination signal.

Would you be willing to have a viral particle put into your brain?
This is a perceived problem with this type of therapy.

However it provides additional evidence that Lingo-1 blockage is useful.  In MS how will an anti-Lingo, be used given every few weeks forever or as a pulse therapy. With alemtuzumab you are being introduced to an £50,000 short course of antibody.

The phase II trial will be occurring soon.

MRI of tumefactive lesions

Did you present with tumefactive MS? #MSBlog #MSResearch

"In recent years I have become interested in the science and philosophy of how we define a disease. This may seem esoteric to you, but it is not and it has many practical implications. For example, saying someone has MS, or not, may affect their ability to get life-insurance or a pay-out from a critical illness policy."

"The paper below tackles the thorny issue of whether someone who presents with a tumefactive lesion that turns out on biopsy not to be a tumour, but an inflammatory demyelinating lesion. Another term for these lesions is pseudotumoural; i.e. the lesion mimics a tumour. The paper is trying to better define the so called clinico-pathological correlate, or more specifically the radiological-pathological correlate; i.e. what features on MRI can be used to predict the underlying pathology? Seven out of 9 of the cases went onto develop MS, i.e. they developed new lesions that fulfilled the McDonald diagnostic criteria for dissemination in time and space and no other aetiology could explain the presentation. One case was labelled as having acute hemorrhagic leukoencephalitis (AHLE) and another acute disseminated encephalomyelitis (ADEM). Unfortunately, the MRI findings were not specific enough to identify these latter two cases; hence there is no specific radiological-pathological correlate that can be used to help make a diagnosis. In short, this paper tells us that the MRI findings are non-specific when it comes to MS vs. ADEM/AHLE. The number of cases studied is small and hence the field may benefit from an International effort to pool cases."

"What does this mean for those of you reading this blog who presented with tumefactive MS? Unfortunately, nothing regarding your management or prognosis. What this paper highlights is that we academics like to describe and classify things. Sometimes we do this without a sound philosophical perspective. I would have designed this study differently and come at it from a different perspective. For one, I would have include a large number of cases who turned out to have tumours as a comparative group; the real question that needs answering is can we define any imaging features specific to mono-focal tumefactive MS that suggest the lesion is not a tumour? This may prevent unnecessary biopsies and hence has a clinical application. The second question is to differentiate those who will go onto to develop MS from those with ADEM or AHLE, which are monophasic MS. The latter will only Be answered by increasing the number of cases studied and by possibly looking at other biomarkers, e.g. CSF findings. "

J Neurol. 2014 Jul.

Background: Tumefactive demyelinating lesions (TDLs) can mimic brain tumors on radiological images. TDLs are often referred to as tumefactive multiple sclerosis (TMS), but the heterogeneous nature and monophasic course of TDLs do not fulfill clinical and magnetic resonance imaging (MRI) criteria for multiple sclerosis. 

Objective: Redefining TDLs, TMS and other inflammatory brain lesions is essential for the accurate clinical diagnosis of extensive demyelinating brain lesions. 

Methods: We retrospectively analyzed MRI from nine TDL cases that underwent brain biopsy. Patterns of gadolinium enhancement on MRI were categorized as homogenous, inhomogeneous, patchy and diffuse, open ring or irregular rim, and were compared with pathological hallmarks including demyelination, central necrosis, macrophage infiltration, angiogenesis and perivascular lymphocytic cuffing. 

Results: All cases had coexistence of demyelinating features and axonal loss. Open-ring and irregular rim patterns of gadolinium enhancement were associated with macrophage infiltrations and angiogenesis at the inflammatory border. An inhomogeneous pattern of gadolinium enhancement was associated with perivascular lymphocytic cuffing. Central necrosis was seen in cases of severe multiple sclerosis and hemorrhagic leukoencephalopathy. 

Conclusions: These results suggest that the radiological features of TDLs may be related to different pathological processes, and indicate that MRI may be useful in understanding their pathophysiology. Further investigation is needed to determine the precise disease entity of these inflammatory demyelinating brain lesions.

Monday, 28 July 2014

Low-dose naltrexone for treatment of multiple sclerosis Are clinical trials needed. Will they happen?

Every time I talk about complementary/alternative medicine to MSers someone tells me of a good luck story about low dose naltrexone. Naltrexone is an opioid receptor antagonist used primarily in the management of alcohol dependence and opioid dependence. Naltrexone should not be confused with naloxone (which is used in emergency cases of opioid overdose) nor nalorphine. Using naloxone in place of naltrexone can cause acute opioid withdrawal symptoms; conversely, using naltrexone in place of naloxone in an overdose can lead to insufficient opioid antagonism and fail to reverse the overdose. Low Dose Naltrexone or LDN as it known has been hitting the news recently. However the problem is is that there is simple not enough good data to support this use. 

Gironi M, Martinelli-Boneschi F, Sacerdote P, Solaro C, Zaffaroni M, Cavarretta R, Moiola L, Bucello S, Radaelli M, Pilato V, Rodegher M, Cursi M, Franchi S, Martinelli V, Nemni R, Comi G, Martino G.A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008;14(8):1076-83.

A sixth month phase II multicenter-pilot trial with a low dose of the opiate antagonist Naltrexone (LDN) has been carried out in 40 patients with primary progressive multiple sclerosis (PPMS). The primary end points were safety and tolerability. Secondary outcomes were efficacy on spasticity, pain, fatigue, depression, and quality of life. Clinical and biochemical evaluations were serially performed. Protein concentration of beta-endorphins (BE) and mRNA levels and allelic variants of the mu-opiod receptor gene (OPRM1) were analyzed. Five dropouts and two major adverse events occurred. The remaining adverse events did not interfere with daily living. Neurological disability progressed in only one patient. A significant reduction of spasticity was measured at the end of the trial. BE concentration increased during the trial, but no association was found between OPRM1 variants and improvement of spasticity. Our data clearly indicate that LDN is safe and well tolerated in patients with PPMS.

Sharafaddinzadeh N, Moghtaderi A, Kashipazha D, Majdinasab N, Shalbafan B. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(8):964-9.
BACKGROUND: Low-dose naltrexone (LDN) may promote psychological well-being as well as generalized health especially in autoimmune disorders. The objective of this study is to assess the effect of LDN on the Quality of Life (QoL) of patients with relapsing-remitting and secondary progressive multiple sclerosis (MS) using the scales and composite scores of the MSQoL-54 questionnaire.
METHODS: A 17-week randomized, double-blind, placebo-controlled, parallel-group, crossover-design clinical trial was conducted in two universities. A total of 96 adult patients aged between 15 and 65 years with relapsing-remitting (RR) or secondary progressive (SP) clinically definite MS with disease duration longer than 6 months enrolled into the study. The primary outcome of the study was comparison of the scores of physical and mental health by conducting independent t-test of the results obtained in the middle and at the end of study between the two groups.
RESULTS: Variables including presence of pain, energy, emotional well-being, social, cognitive, and sexual functions, role limitation due to physical and emotional problems, health distress, and overall QoL did not show any meaningful statistically difference between the two groups. Factor analysis revealed that health perception scores were statistically different between the groups before starting, in the middle, and at the end of the study.
CONCLUSION: The study clearly illustrates that LDN is a relatively safe therapeutic option in RRMS and SPMS but its efficacy is under question and probably a long duration trial is needed in the future.

Cree BA, Kornyeyeva E, Goodin DS Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010;68(2):145-50. doi: 10.1002/ana.22006.OBJECTIVE: To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients.
METHODS: This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightlynaltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients.
RESULTS: Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
INTERPRETATION: LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.

So the same odd addage...Further studies are warranted. 

However, this is the perennial problem...neuros and charities tend to fund small scale trials, which are invariably too small to give definitive answers and not large enough to make a compelling case for moving things forward

Pharma aren't really interested cos they can't make any money out of this in the present climate. 

Should we be doing small trials that need another in the hope that pharma will work out how to repurpose the drug or only support stuff that gives a definitive answer. Or should we keep the Status Quo going? often with false hope peddling.

Can pharma be incentivised to do these studies? 

Is it another fad treatment? 

What are your views?

Neural network disruption

Tewarie P, Steenwijk MD, Tijms BM, Daams M, Balk LJ, Stam CJ, Uitdehaag BM, Polman CH, Geurts JJ, Barkhof F, Pouwels PJ, Vrenken H, Hillebrand A.Disruption of structural and functional networks in long-standing multiple sclerosis. Hum Brain Mapp. 2014 Jul 22. doi: 10.1002/hbm.22596. [Epub ahead of print]

Both gray matter atrophy and disruption of functional networks are important predictors for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly understood. Graph theory provides a modality invariant framework to analyze patterns of gray matter morphology and functional coactivation. We investigated, how gray matter and functional networks were affected within the same MS sample and examined their interrelationship. Magnetic resonance imaging and magnetoencephalography (MEG) were performed in 102 MS patients and 42 healthy controls. Gray matter networks were computed at the group-level based on cortical thickness correlations between 78 regions across subjects. MEG functional networks were computed. In MS patients, we found a more regular network organization for structural covariance networks and for functional networks in the theta band (Delta (0.5-4Hz), Theta (4-8Hz), Alpha1 (8-11Hz), Alpha2 (11-14Hz, Beta1 (14-25Hz) and Beta2 (25-35Hz), whereas we found a more random network organization for functional networks in the alpha2 band. Correlation analysis revealed a positive association between covariation in thickness and functional connectivity in especially the theta band in MS patients, and these results could not be explained by simple regional gray matter thickness measurements. This study is a first multimodal graph analysis in a sample of MS patients, and our results suggest that a disruption of gray matter network topology is important to understand alterations in functional connectivity in MS as regional gray matter fails to take into account the inherent connectivity structure of the brain
Sometimes we simply don't have enough time to do our day job and do posts enough justice. It requires time to explain posts. How about this one?

BICAMS Study Feedback

Where you a participant in the UK BICAMS study? Thank You! #MSResearch #MSBlog

Dear Participant

Re: Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): UK Standardisation

Firstly I want to say a huge thank you for taking part in this research to validate a measure of memory and information processing speed in MS.  This project would not have been possible without you and I want you to know your time and efforts are appreciated.  This project brings us a step closer to making cognitive testing more widely available to people with MS.

I am writing to you as you requested an overview of the research findings.  As I explained I am not able to provide individual test scores.  You may recall completing a 90-minute, “gold standard” collection of cognitive assessments often used in MS research (Minimal Assessment for Cognitive Functioning for Multiple Sclerosis, MACFIMS).  BICAMS is a subset of MACFIMS tests that this research sought to validate.  BICAMS consists of three tests and takes 15 minutes to administer.  It can be administered by a nurse or neurologist and requires only pen and paper.

Main findings:
  1. BICAMS is comparable to MACFIMS in its ability to detect cognitive difficulties in MS. 
  2. BICAMS can differentiate between participants with MS and control participants.
  3. BICAMS offers a practical, short neuropsychological assessment tool that can be used in routine clinical practice.
  4. Once published, data from this study can be used by UK clinicians and researchers to interpret cognitive assessment scores.
  5. This research supports previous findings that people with MS who experience cognitive difficulties are most likely to have difficulties with information processing speed and learning new information.
If you think you may have cognitive difficulties please see the next two pages of this letter for some ideas on how to compensate for these problems.  See also  Please be aware it is normal to forget things every now and again!  This does not necessarily mean you have cognitive difficulties. 

Spreading the word:

I have already shared findings from the project with MS researchers and clinicians through poster presentations at the International MS Cognition conference in June 2013 (IMScogs) and a much larger conference in October 2013 (ECTRIMS). I also plan to publish the research in a journal so we can move towards making cognitive assessment more widely available to people with MS.  BICAMS is gaining international recognition and now has its own website

Thank you again for taking part.  Kind regards and best wishes for the future.
Dr Alex Orchard
Clinical Psychologist

Memory Tips

Remember it is normal to forget things every now and again; so don’t be too hard on yourself.  Factors such as a busy life, low mood, stress and anxiety can all decrease our ability to process and remember information, whether you have MS or not

The suggestions below are not exhaustive but give some ideas of what can be helpful both to people with MS and those without.  It is helpful to know yourself and work to your strengths so pick the bits that could work for you.

General tips:
·        Structure your day/have a routine
o   This lightens the load on your brain and means you have more space to focus on processing and remembering new information.

·        Pace yourself/slow down
o   Don’t pack your week full of activities so you become tired.
o   Doing too much will reduce your ability to process new information and remember things.

·        Friends, family and technology can be great aids to processing and remembering information.
Reduced processing speed tips:

·        Avoid “information overload”
o   Don’t be afraid to ask people to slow down during conversations.
o   Ask people to repeat or summarise what they have said.
o   Summarise/repeat back what people say to you.
o   Plan your day so you don’t do lots of new things at once.

·        Summarise/clarify new information
o   During conversations repeat back/summarise important points/instructions.
o   Minimise the amount of information you have to process:
§  Block out extraneous information:
·        Use easy read versions of websites.
·        Use pieces of blank paper to block extraneous information on a page.
§  Highlight important points in documents.
§  Write bullet points of conversations/documents you have read as you go along.

·        Minimise distractions
o   Reduce background noise whilst completing tasks.

·        Do one task at a time

Memory tips:

Our memory can only hold so much information so we have to be realistic in what we ask of ourselves.  Structure and routine can allow us to go through the day on autopilot and reduce the load on our memory freeing us up to deal with and remember novel information.

·        Repetition, repetition, repetition
o   Repeating information you hear or see by saying it or writing it down can significantly improve your chances of remembering it.

·        Pace yourself
o   Be realistic about what you can manage. The more you do the more there is to forget.

·        Use a range of senses
o   It often helps to receive information both verbally and visually
§  e.g. if someone shows you something, describe what you see.  This increases your chances of remembering information you are given.
External Strategies

·        Visual prompts
o   Post-it notes and whiteboards in an obvious place can provide invaluable reminders of tasks to do, birthdays, appointments etc.
o   Use bullet points to remember the most important points.
o   Make sure these are in places you will see them easily.
o   You may find drawing or taking pictures helps you remember better than writing or verbal cues.

·        Diaries and electronic organisers
o   Develop the habit of checking these regularly so you know what you have to do for the day/week.
o   Keep diaries/electronic organisers with you to note down reminders throughout the day.

·        Reminders on your mobile/electronic organiser
o   This can help you to be on time for appointments and remind you to check your diary.
o   It can help you take medication on time.

·        Lists
o   Write down things you have to do and what shopping you need to get.
o   Information on a list is information your brain doesn’t have to remember and frees your brain up to do other things.

·        Organisation
o   Everything in its place
§  Choose one place to put your possessions e.g. keys in the pot, coat on a hook.
o   Use a filing system
§  You can retrieve information when you need it rather than using memory space.
Internal Strategies

·        Repetition, repetition, repetition
o   Repeating information you hear or see by saying it or writing it down can significantly improve your chances of remembering it.

·        Categorisation
o   Categorise information to be learnt into different groups.
o   E.g. remembering a shopping list by grouping what needs to be bought into vegetables, tinned food, meat etc.

·        Chunking
o   Most people can only remember 5-7 pieces of information.
o   When reading or listening to something containing lots of information break it up into small units so you only have 5-7 small units or keywords.  These can act as prompts to help you recall all the information.
o   A common example of chunking is remembering telephone numbers
§  Instead of 02078977385 we remember 0207 697 7395.

·        Storytelling
o   Some people find making a story makes remembering a list of unrelated items easier.

·        Rhyming
o   This can help you create links with information you already know.
o   It works well for remembering names e.g. Jean-Bean, Tall-Paul etc.

·        First letter association
o   Make up a word using the first letters of the items you need to remember.
o   e.g. Colours of the rainbow become Richard Of York Gave Battle In Vain.

·        Visualisation
o   You can create a mental picture of what you need to remember
o   You may want to picture things you need to remember from a list in a series of locations e.g. in rooms in your house.