Saturday, 31 August 2013

Clinic Speak: predicting cognitive problems and depression in MS

Are you depressed? Do you have executive dysfunction? #MSBlog #MSResearch #ClinicSpeak

"For those us who see a lot of MSers we aware that there is strong link between depression and cognitive dysfunction and that both tend to get worse with increasing MS disability. Therefore this study's results are not surprising; depression, as measured with the Beck Depression Index, was the strongest predictor of executive complaints. It is also well know that executive dysfunction is associated with depression. Therefore what comes first, depression or executive dysfunction, or vise versa? Another chicken or egg paradigm."

"What is executive dysfunction? Executive dysfunction is a disruption to the efficiency of the executive functions, which is a group of cognitive processes that regulate, control, and manage other cognitive processes. Executive dysfunction can refer to both neurocognitive deficits and behavioural symptoms, for example deficiencies in planning, abstract thinking, flexibility and behavioural control and the occurrence of impulsive, hyperactive, disorganized, and sometimes aggressive behaviour. Executive dysfunction, particularly in relation to working memory, may also lead to varying degrees of emotional dysregulation, which can manifest as chronic depression, anxiety, or a state in which you are over-emotional (hyperemotionality). Severe executive dysfunction can have devastating effects on cognition and behaviour for MSers in particular in social contexts."

"There are several measures that can be employed to assess the executive functioning capabilities of MSers. These are usually done by a neuropsychologist and include: (1) the Clock drawing test, (2) Stroop task, (3) the Wisconsin Card Sorting test, (4) the Trail-making test, etc. For more information on these tests I suggest you read the Wikipedia entry on testing for executive dysfunction."

"More importantly, are you depressed? Depression is a state of low mood that causes you to avoid activities that can affect your thoughts, behavior, feelings and sense of well-being. Depressed MSers may feel sad, anxious, empty, hopeless, worried, helpless, worthless, guilty, irritable, hurt, or restless. They typically lose interest in pleasurable activities, for example going-out, socialising with friends, loss of libido, etc., i.e. you lose your 'joie de vivre'. Depression also affects other aspects of brain function and you may develop vegetative features of depression; i.e. loss of appetite or overeating, poor concentrating, forgetfulness, poor decision making, insomnia, excessive sleeping, fatigue, loss of energy, aches & pains, digestive problems, and other systemic symptoms. MSers who are depressed may contemplate or even attempt suicide. Depression is very common in MS and if you are depressed you need to seek help as soon as possible. There are effective psychological and medical therapies and in my experience both work and they often synergise."

"How do you know if you are depressed? I have uploaded a copy of the Beck Depression Inventory for you. It is at the bottom of this post. You can download it and complete and score it yourself. Some psychiatrists don't like using the Beck Depression Inventory in MSers; they prefer the Hospital Anxiety and Depression Scale or HAD. Unfortunately the HAD is difficult to self-score and interpret yourself. What is important is to screen yourself and if you are depressed to seek help."

Epub: Hanssen et al. Predictors of executive complaints and executive deficits in multiple sclerosis.Acta Neurol Scand. 2013 Aug 23.

OBJECTIVES: To investigate executive complaints and objective executive deficits and their relations to both depression and neurological function in MS.

MATERIALS AND METHODS: 120 MSers participating in multidisciplinary rehabilitation underwent assessment with the EDSS, neuropsychological tests of executive function, self-report measures of executive function (BRIEF-A), and depression (BDI-II).

RESULTS: Multivariate regression analysis showed that moderate depression and above (BDI-II > 20) significantly predicted a high degree of subjective executive complaints. Multivariate regression analysis showed that EDSS scores above 4.3 significantly predicted executive cognitive deficit, measured by neuropsychological tests.

CONCLUSION: Among the study variables, depression was the strongest predictor of executive complaints. A high degree of neurological disability was the strongest predictor for executive deficit, measured by neuropsychological tests.

Electrically Active Stem Cells

Pluripotent stem cells (PSCs) have been differentiated into oligodendroglial progenitor cells (OPCs), providing promising cell replacement therapies for many CNS disorders. Studies from rodents have shown that brain OPCs express a variety of ion channels, and that a subset of brain OPCs express voltage-gated sodium channel (NaV ), mediating the spiking properties of OPCs. However, it is unclear whether PSC-derived OPCs exhibit electrophysiological properties similar to brain OPCs and the role of NaV in the functional maturation of OPCs is unknown. Here, using a mouse embryonic stem cell (mESC) GFP-Olig2 knockin reporter line, we demonstrated that unlike brain OPCs, all of the GFP+ /Olig2+ mESC-derived OPCs (mESC-OPCs) did not express functional NaV and failed to generate spikes (hence termed "non-spiking mESC-OPCs"), while expressing the delayed rectifier and inactivating potassium currents. By ectopically expressing NaV 1.2 α subunit via viral transduction, we successfully generated mESC-OPCs with spiking properties (termed "spiking mESC-OPCs"). After transplantation into the spinal cord and brain of myelin-deficient shiverer mice, the spiking mESC-OPCs demonstrated better capability in differentiating into MBP expressing oligodendrocytes and in myelinating axons in vivo than the non-spiking mESC-OPCs. Thus, by generating spiking and non-spiking mESC-OPCs, this study reveals a novel function of NaV in OPCs in their functional maturation and myelination, and sheds new light on ways to effectively develop PSC-derived OPCs for future clinical applications.

Shiverer mice do not make proper myelin basic protein and develop neurological problems...not surprisingly they shake or shiver. This team have added a sodium channel to the OPC and apparently this makes them better myelinating cells. 

These cells become electrically active and this has been seen before when another molecule called NMDA is introduced. This allows the cells to respond to glutamate, which responds to stimulation with ionic movements in and out of the cells following electrical stimulation of nerves. This allows oligodendrocytes to mature in some peoples hands and not others. 

The electrically active oligodendrocytes can cross talk with nerves. Neurons can no longer be considered the only cells that fire electric impulses in the brain. and Synapses between neurons are not the only way electrical information is regulated as it propagates through neural circuits: oligodendrocytes can cause rapid activity-dependent changes in nerve firing. Nerve impulses can be rapidly regulated by oligodendrocytes. 

Nav1.2 is  developmentally expressed in the nervous system by is not really a feature of nervous expression in adults, which is the domain of Nav 1.6 (There are at least 8 different channel types), however it is found in astrocytes. This study may suggest the importance of stimulating Nav 1.2 but this could have side-effects. May be one can selectively simulate this in oligodendrocytes. 

At present there are studies on the use of sodium channel bloggers in MS and they block Nav1.2. To date there is no evidence to suggest a deterioration. 

However this shows you can engineer stem cells to promote more myelin,we are doing similar things using a differnt approach. However this is some way  away from an option for human use

American-based scientists tend to big it up.

Fanelli D, Ioannidis JP. US studies may overestimate effect sizes in softer research. Proc Natl Acad Sci U S A. 2013 Aug 26. [Epub ahead of print]

Many biases affect scientific research, causing a waste of resources, posing a threat to human health, and hampering scientific progress. These problems are hypothesized to be worsened by lack of consensus on theories and methods, by selective publication processes, and by career systems too heavily oriented toward productivity, such as those adopted in the United States (US). Here, we extracted 1,174 primary outcomes appearing in 82 meta-analyses published in health-related biological and behavioral research sampled from the Web of Science categories Genetics & Heredity and Psychiatry and measured how individual results deviated from the overall summary effect size within their respective meta-analysis. We found that primary studies whose outcome included behavioral parameters were generally more likely to report extreme effects, and those with a corresponding author based in the US were more likely to deviate in the direction predicted by their experimental hypotheses, particularly when their outcome did not include additional biological parameters. Non-behavioral studies showed no such "US effect" and were subject mainly to sampling variance and small-study effects, which were stronger for non-US countries. Although this latter finding could be interpreted as a publication bias against non-US authors, the US effect observed in behavioral research is unlikely to be generated by editorial biases. Behavioral studies have lower methodological consensus and higher noise, making US researchers potentially more likely to express an underlying propensity to report strong and significant findings.

So non-behavioural science such as genetics are no so easy to big-up. There it is difficult to manipulate the results such as say reading a genetic code, but behavioural sciences such as drug tests are woolly and one can pick different ways to analyse the results. 

The results in behavioural studies had more extreme positive biases, suggesting that people are sexing-up their results by over extending their analysis.

Furthermore the work that had US-based authors (remember the US is a magnet for the World's best scientists) showed a greater tendency for the more extreme examples to occur. Therefore they are more likely to find that Whacky drug effect.

Why? Probably pressure to get that all important result. This can be the make or break for the people doing the work. Dull grants. It can be the survival of the fittest.

I suspect in a few years this regional influence will decrease as more and more pressure is heaped on global scientists to deliver the goods and get those eye catching headlining papers.

Taylor-made for non-reproducible studies.

CCSVI August

#MSResearch CCSVI
Leone C, D Amico E, Cilia S, Nicoletti A, Di Pino L, Patti F. Cognitive impairment and "invisible symptoms" are not associated with CCSVI in MS. BMC Neurol. 2013 Jul;13(1):97. [Epub ahead of print]

BACKGROUND:We investigated the association between chronic cerebrospinal venous insufficiency (CCSVI) and cognitive impairment (CI) inmultiple sclerosis (MS). Moreover, we evaluated the association between CCSVI and other frequent self-reported MS symptoms.
METHODS:We looked at the presence of CI in incident MS patients with CCVSI in a population-based cohort of Catania, Italy. All subjects were group-matched by age, sex, disease duration and EDSS score with MS patients without CCSVI, serving as controls. CI was assessed with the Brief Repeatable Battery (BRB) and the Stroop Test (ST) and it was defined by the presence of at least three impaired tests. Fatigue and depressive symptoms were assessed with Fatigue Severity Scale (FSS) and Hamilton Depressive Rating Scale (HDRS), respectively. Bladder and sexual symptoms were assessed with the respective items of the Italian version of Guy's Neurological Disability Scale (GNDS). Quality of life was evaluated with Multiple Sclerosis Quality of Life-54 Instrument (MSQOL-54).
RESULTS:Out of 61 MS patients enrolled in the study, 27 were CCSVI positive and 34 were CCSVI negative. Of them, 43 were women (70.5%); the mean age was 43.9 +/- 11.8 years; the mean disease duration was 159.7 +/- 113.7 months; mean EDSS was 3.0 +/- 2.6. Of them, 36 (59.0%) were classified relapsing-remitting (RR), 12 (19.7%) secondary progressive (SP), seven (11.5%) primary progressive (PP) and six (9.3%) Clinically Isolated Syndrome (CIS). Overall, CI was detected in 29/61 (47.5%) MS patients; particularly 13/27 (48.1%) in the CCSVI positive group and 16/34 (47.0%) in the CCSVI negative group. Presence of CCSVI was not significantly associated with the presence of CI (OR 1.04; 95%CI 0.37-2.87; p-value = 0.9). Not significant differences were found between the two groups regarding the other MS symptoms investigated.
CONCLUSIONS:Our findings suggest a lack of association between CCSVI and CI in MS patients. Fatigue, depressive, bladder/sexual symptoms and self-reported quality of life are not associated with CCSVI.

Go figure

Laukontaus SJ, Kagayama T, Lepäntalo M, Atula S, Färkkilä M, Albäck A, Inoue Y, Tienari P, Venermo M.Doppler Ultrasound Examination of Multiple Sclerosis Patients and Control Participants: Inter-observer Agreement and Association with Disease.Eur J Vasc Endovasc Surg. 2013 Aug. doi:pii: S1078-5884(13)00444-9. 10.1016/j.ejvs.2013.07.003. [Epub ahead of print]

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a major risk factor for multiple sclerosis (MS). The aim of this study was to assess inter-observer agreement between two ultrasound examiners and to compare findings in MS patients and control participants.
METHODS: A prospective, blinded, controlled study of MS patients diagnosed within 2 years (MS ≤ 2, n = 39), patients diagnosed more than 10 years ago (MS > 10, n = 43) and age- and sex-matched control participants (n = 40). Ultrasound examinations were performed by two independent examiners. CCSVI criteria 1, 3, 4 and 5 as proposed by Zamboni were explored: (1) reflux in the internal jugular (IJV) and vertebral veins (VV), (3) IJV cross-sectional area (CSA) ≤0.3 cm2, (4) absence of flow in IJV and VV, and (5) reverted postural control of venous outflow.
RESULTS: Criteria 1, 4 and 5 were met in less than 10% of the MS patients and control participants as studied by both examiners. The level of inter-observer agreement was poor for all parameters except assessment of the CSA of IJV at the thyroid level. Findings meeting CCSVI criterion 3 (CSA ≤ 0.3 cm2) were observed in 18/40 (45%) of the control participants, in 24/37 (65%) of MS ≤ 2 patients (p = 0.09 vs. control participants) and in 30/43 (70%) of the MS > 10 patients (p = 0.022 vs. control participants).
CONCLUSIONS: The feasibility of the CCSVI criteria for common use is questionable because of low inter-observer agreement. Small-calibre IJVs meeting the CCSVI criterion 3 appear common in both Finnish control participants and MS patients, but the clinical significance of this finding is questionable.
Oh my.....Not good news

Lupattelli T, Bellagamba G, Righi E, Di Donna V, Flaishman I, Fazioli R, Garaci F, Onorati P.
Feasibility and safety of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Vasc Surg. 2013 Aug 12. doi:pii: S0741-5214(13)01144-0. 10.1016/j.jvs.2013.05.108. [Epub ahead of print]
OBJECTIVE:Chronic cerebrospinal venous insufficiency (CCSVI) is a recently discovered syndrome mainly due to stenoses of internal jugular (IJV) and/or azygos (AZ) veins. The present study retrospectively evaluates the feasibility and safety of endovascular treatment for CCSVI in a cohort of patients with multiple sclerosis (MS).
METHODS:From September 2010 to October 2012, 1202 consecutive patients were admitted to undergo phlebograpy ± endovascular treatment for CCSVI. All the patients had previously been found positive at color Doppler sonography (CDS) for at least two Zamboni criteria for CCSVI and had a neurologist-confirmed diagnosis of MS. Only symptomatic MS were considered for treatment. Percutaneous transluminal angioplasty was carried out as an outpatient procedure at two different institutes. Primary procedures, regarded as the first balloon angioplasty ever performed for CCSVI, and secondary (reintervention) procedures, regarded as interventions performed after venous disease recurrence, were carried out in 86.5% (1037 of 1199) and 13.5% (162 of 1199) of patients, respectively. Procedural success and complications within 30 days were recorded.
RESULTS:Phlebography followed by endovascular recanalization was carried out in 1999 patients consisting of 1219 interventions. Balloon angioplasty alone was performed in 1205 out of 1219 (98.9%) procedures, whereas additional stent placement was required in the remaining 14 procedures (1.1%) following unsuccessful attempts at AZ dilatation. No stents were ever implanted in the IJV. The feasibility rate was as high as 99.2% (1209 interventions). Major complications included one (0.1%) AZ rupture occurring during balloon dilatation and requiring blood transfusion, one (0.1%) severe bleeding in the groin requiring open surgery, two (0.2%) surgical openings of the common femoral vein to remove balloon fragments, and three (0.2%) left IJV thromboses. The overall major and minor complication rates at 30 days were 0.6% and 2.5%, respectively.
CONCLUSIONS: Endovascular treatment for CCSVI appears feasible and safe. However, a proper learning curve can dramatically lower the rate of adverse events. In our experience, the vast majority of complications occurred in the first 400 cases performed.

So make sure you ask how many procedures they have done 

These have been discussed.

Karmon Y, Zivadinov R, Weinstock-Guttman B, Marr K, Valnarov V, Dolic K, Kennedy CL, Hojnacki D, Carl EM, Hagemeier J, Hopkins LN, Levy EI, Siddiqui AH. Comparison of Intravascular Ultrasound with Conventional Venography for Detection of Extracranial Venous Abnormalities Indicative of Chronic Cerebrospinal Venous Insufficiency.J Vasc Interv Radiol. 2013 Aug 13. doi:pii: S1051-0443(13)01106-8. 10.1016/j.jvir.2013.06.012. [Epub ahead of print]

Rodger IW, Dilar D, Dwyer J, Bienenstock J, Coret A, Coret-Simon J, Foster G, Franchetto A, Franic S, Goldsmith CH, Koff D, Konyer NB, Levine M, McDonald E, Noseworthy MD, Paulseth J, Ribeiro L, Sayles MJ, Thabane L. Evidence against the Involvement of Chronic Cerebrospinal Venous Abnormalities in Multiple Sclerosis. A Case-Control Study. PLoS One. 2013 Aug 14;8(8):e72495. doi: 10.1371/journal.pone.0072495.

Friday, 30 August 2013

Guest post: the postcode lottery

The postcode lottery: join the debate. #MSBlog #MSReseach

Thousands of MSers are not getting DMTs or the care and support they need, according to a report launched by UK MS Society.

Click here to download the report

The MS Society wants equal access for all to treatments. However, not everyone was happy about this approach; the following article explains why.

‘A lottery of treatment and care – MS services across the UK’ report by the MS Society: who does it represent? Paul J. Bull (Hon Visiting Fellow, Anglia Ruskin University )

This paper challenges the findings of the report by the MS Society ‘A lottery of treatment and care’ by arguing that they cannot be supported by the research methods used to produce them. In particular, it shows that the sample of members of the MS Society with MS used for the research cannot be regarded as representative either of all people with MS in the UK or of all members of the MS Society with MS. Furthermore, it cannot be thought to offer meaningful results for either of these two cohorts of people at sub-national spatial scales either. It is therefore suggested that much more rigorous scrutiny of future projects by the MS Society must be undertaken in the future to stop such tawdry research being repeated.

Click here to download the full article

In the interests of transparency and good debate we have asked the MS Society to respond.

MS Society response to ‘A lottery of treatment and care – MS services across the UK: who does it represent?’ paper by Dr Paul Bull

We’re surprised to see this criticism of our study. We planned the work carefully, and overall the reception has been overwhelmingly positive. A number of scientists, clinicians, health professionals, politicians and professional organisations have praised our methodology, and supported our work to improve access to vital services and support for people affected by MS in the UK. Many of these groups formally endorsed our report. It is a shame to see this ill-informed critique distract from this important work, particularly as it comes from Dr Bull who, when a member of our Research Strategy Committee, had substantial opportunity to shape this work. We have responded in full directly to the author of the critique, but we’re grateful for the opportunity to post a shorter response here on your blog.

It seems that the author makes two main points regarding our methodology. The first is that we used a survey of members of the MS Society to describe the broader situation for people with MS in the UK. The second is that instead of only including a small sample of our members we invited everyone to take part.

On the first point, ideally we would have a perfect list of all people with MS in the UK we could write to for such research. But such a list doesn’t exist, and in its absence many researchers have used the MS Society’s membership list as a way to understand the experiences of people with MS. This includes people such as Professor Ray Fitzpatrick of Oxford University, who is Director of the Government’s Health Service Research Programme. He used a very similar methodology to understand people with MS’s experiences of health services in England - We note that the author of this critique was a co-author on another study which used the same methodology – writing to MS Society members to understand the services they are accessing - These are just two examples of the many studies which have used this technique. We are not sure why he now criticises so strongly a methodology that he himself has used. As the author acknowledges our respondents were broadly representative of people with MS in the UK in terms of age and gender, so it is unclear in what way he thinks our 10,530 respondents misrepresent the experiences of people with MS.

On the second point, this seems to indicate a fundamental misunderstanding of research methodology. The reason for sampling a population, instead of including everyone, is normally because it allows you to get close to the ‘true’ result for the whole population whilst saving on time (both for the researchers and participants) and money. The author states that a smaller sample is somehow better than a whole population survey, but this simply isn’t the case. It can produce similar results, and often the results are close enough, but they are always less representative. Had we only wanted national level statistics a smaller sample would have probably been enough, but because we wanted to understand people’s experiences at a local level we needed every one of those 10,530 responses.

The author also makes some further allegations which are simply untrue. He states that we ‘berated’ local health professionals and health authorities, when we did no such thing. Indeed in the author’s own area the Clinical Commissioning Group stated in the local press that they ‘welcome the Society’s determination to work closely with us’. He also describes our failure to involve our own local staff as ‘inept’, whereas of course we involved our hard-working local staff throughout the project.

We believe that the conclusions of our research are profound – it cannot be fair that where you live in the UK plays such a part in whether or not you are prescribed disease modifying therapy, or that the more you are struggling financially the less likely you are to be able to access powered wheelchairs, home adaptations or even information about your MS. We are immensely proud of our work in this area, the research we conducted and the campaign we launched to make things better Over 7,000 people so far have joined our campaign to stop the MS Lottery, and we would urge the author, and readers of your blog, to join us.

Ed Holloway
Head of care and services research
MS Society

Growing mini brains

Lancaster MA et al. Cerebral organoids model human brain development and microcephaly. Nature (2013) doi:10.1038/nature12517

The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

An "organoid" showing different brain regions, all cells are in blue, neural stem cells in red, and neurons in green. In a real brain most of the tissue would be nerves

iPS cells are induced pleuripotent stem cells, which means that they can take any cell and revert it back to a stem cell which is capable of becoming any type of cell.With the right mix of nutrients and a little bit of coaxing, human stem cells derived from skin can assemble spontaneously into brain-like chunks of tissue called the mini brains and a step closer to artificial brain. 

The stem cells were grown on a gel that resembled natural connective tissues found in the brain and then infused it with nutrients and oxygen using a spinning culture. The mini brains developed distinct brain regions and functional electrical activity.

Hear the scientists here (Click)

Under a microscope, researchers saw discrete brain regions that seemed to interact with one another. But the overall arrangement of the different proto-brain areas varied randomly across tissue samples — amounting to no recognizable physiological structure and lacked blood vessels. They only grew to 3-4 mm in as much as ten months. They did the same from someone who had a genetic condition that meant they had a small brain and the chunks grow less.

We have been growing nerves, and myelinating cells and microglia and astrocytes in 3D structures, but it is technically challenging and a slow laborious process for hunting for remyelinating cues. This new study is the beginning of an exciting process, but it is just the beginning. 
However, there are other implications also.

To do work on animals, researchers have to jump through hoops and go through a lot of red tape and get ethical approval to do experiments. 

You may be interested to know that scientists working on cell cultures do not and often do not need ethical approval for their work. 

This is perhaps a shame as sometimes there is a load of old tosh coming out of some labs that solely focus on cell culture. 

Once an animal is dead is is not protected by the laws that protect living animals that are used in research. 

Each year you hear how many animals are used in research. However, this is a fudge and a massive under-representation because many animals that are killed for tissues do not need to be reported.

In neuroscience, this often may mean foetal or neonatal (freshly-born) animals are used e.g. to study myelination because they can be used to grow nerves and myelinating cells more easily as development in ongoing in these animals. e.g. Mice have little myelin on their nerves when they are born. 

However, with the ability to grow human cells into brain tissue then becomes a very strong ethical argument against using animals for research in cell cultures. Why use a model when you can use the real thing? With iPS cells you could grow the brain tissue from MSers. 

Yes it will be expensive to grow the human cells, but the cost-saving exercise has not been a valid reason to do living animal experiments when there is an alternative from the ethical standpoint. It is perhaps time that everybody using animal tissue, live or dead go through a full ethical review.  

Maybe in your country they do already

Mesenchymal Stem cells promoting myelination

Jadasz JJ, Kremer D, Göttle P, Tzekova N, Domke J, Rivera FJ, Adjaye J, Hartung HP, Aigner L, Küry P.Mesenchymal stem cell conditioning promotes rat oligodendroglial cell maturation. PLoS One. 2013 Aug 12;8(8):e71814. doi: 0.1371/journal.pone.0071814.

Oligodendroglial progenitor/precursor cells (OPCs) represent the main cellular source for the generation of new myelinating oligodendrocytes in the adult central nervous system (CNS). In demyelinating diseases such as multiple sclerosis (MS) myelin repair activities based on recruitment, activation and differentiation of resident OPCs can be observed. However, the overall degree of successful remyelination is limited and the existence of an MS-derived anti-oligodendrogenic milieu prevents OPCs from contributing to myelin repair. It is therefore of considerable interest to understand oligodendroglial homeostasis and maturation processes in order to enable the development of remyelination therapies. Mesenchymal stem cells (MSC) have been shown to exert positive immunomodulatory effects, reduce demyelination, increase neuroprotection and to promote adult neural stem cell differentiation towards the oligodendroglial lineage. We here addressed whether MSC secreted factors can boost the OPC's oligodendrogenic capacity in a myelin non-permissive environment. To this end, we analyzed cellular morphologies, expression and regulation of key factors involved in oligodendroglial fate and maturation of primary rat cells upon incubation with MSC-conditioned medium. This demonstrated that MSC-derived soluble factors promote and accelerate oligodendroglial differentiation, even under astrocytic endorsing conditions. Accelerated maturation resulted in elevated levels of myelin expression, reduced glial fibrillary acidic protein expression and was accompanied by downregulation of prominent inhibitory differentiation factors such as Id2 and Id4. We thus conclude that apart from their suggested application as potential anti-inflammatory and immunomodulatory MS treatment, these cells might also be exploited to support endogenous myelin repair activities.

After my more recent negative posts on this subject here is a more upbeat view of the use of mesenchymal stem cells. Here they they are shown to produce factors that can promote remyelination.

Thursday, 29 August 2013

Tremor and deep brain stimulation

DBS or deep brain stimulation for MS tremor. #MSBlog #MSResearch

"This is a follow-on post from my recent ClinicSpeak post on tremor and describes a study on the effectiveness of deep brain stimulation on severe MS-related tremor. The results are what they are and should be interpreted in the light of how disabled these MSers are. In short DBS improved self-care (feeding, hygiene, dressing) writing and working. The fact DBS improves feeding tells you how disabling MS-related tremor can be; the majority of the MSers having DBS can't feed themselves. The problem with DBS is that it is very expensive and it is not always possible to get funding to cover the cost of the stimulator and the procedure. You have to request funding on a MSer by MSer basis and MSers are often left in limbo for several months waiting for the outcome of their IFR (individual funding request). The other problem we face is that the threshold for doing the procedure varies from neurosurgeon to neurosurgeon. I have recently had one surgeon say no to one of my MSers, this not only devastated her mood and morale, but questioned my clinical judgement. Fortunately, another neurosurgeon from another center said yes. However, to get this second opinion took months. These are the kinds of trials and tribulations we put our MSers through under the NHS; clearly not an ideal arrangement."

BACKGROUND: Tremor is an important cause of disability and poor quality of life amongst MSers. This study assessed the outcomes of ventral intermediate (VIM) nucleus deep brain stimulation for the treatment of MS-associated tremor at a single centre in a prospective fashion.

METHODS: Sixteen MSers (9 female, 7 male) with a mean age of 41.7 years (range 24-59) underwent surgery. The median duration of MS prior to surgery was 6.5 years and median duration of tremor prior to surgery was 4 years. Case selection was by multidisciplinary assessment with carers, therapists, neurosurgeons and movement disorder neurologists. Tremor was scored pre-operatively and at 6 to 12 months post-operatively using Bain and/or Fahn-Tolosa-Marin systems. The Euro-Qol 5D tool was used to assess quality of life before and after surgery.

RESULTS: The mean tremor reduction was 39 % with a range between 0 and 87 %. Five of 16 MSers achieved at least 50 % tremor reduction and 11 of 16 achieved at least 30 % tremor reduction at last follow up, mean 11.6 months (range 3-80). Tremor was significantly reduced as rated by Bain scores (Wilcoxon matched pairs, Z = 3.07, p = .002) and tended to significance as rated by Fahn scores (Wilcoxon matched pairs, Z = 1.85, p = 0.06). Sub-analysis of activities of daily living measures from the Fahn system showed post-operative improvement in feeding (statistically significant), hygiene, dressing, writing and working. Mean visual analogue scores (0-100) of MSer reported well-being increased from 54.6 to 57.4 post-operatively with a trend to significance (Student's t-test, t = 1.26, p = 0.2). Euro-Qol 5D utility values increased following surgery with a trend to significance which was greater in the group with at least 50 % tremor reduction than in those with none or at least 30 % tremor reduction.

CONCLUSIONS: VIM DBS may reduce severe, disabling tremor in MSers. This tremor reduction tends to be associated with improved quality of life and function in those who respond. MSer reported outcome measures may not correlate with physician rated clinical outcome such as tremor scoring systems and more subtle assessment of these MSers is required.

Other posts on tremor:

24 Aug 2013
"Are there any anatomists out there? The following is for you. A particular type of cerebellar tremor is one that affects the nerve fibres that leave the cerebellum in the so called superior cerebellar peduncles and pass through ...
29 Jul 2012
OBJECTIVES: Cerebellar tremor is a very disabling sign of MS, and various kinds of treatments have been proposed with different results. Primidone is one of the medications, mostly advised for essential tremor. The aim of ...
09 Jul 2012
The 3 main outcomes were the median changes in Bain tremor rating scores for tremor severity, writing, and drawing an Archimedes spiral from baseline to 6 and 12 weeks after treatment with botulinum toxin type A compared ...
19 Jan 2012
Background and purpose: Severe multiple sclerosis (MS) tremor causes disability poorly responsive to medication. Deep brain stimulation (DBS) or thalamotomy can suppress tremor, but long-term outcomes are unclear.

20 Jul 2011
The following NMSS video explains the types of tremors MS'ers may get. The one that is the most disabling is called a cerebellar outflow tremor (aka rubral tremor); this is a course flapping tremor that when severe prevents the ...
22 Jul 2011
Re: "The fewer medicines you take, the better off you'll be." No not really; it is always a trade off between symptoms and their impact on your functioning (activities of daily living, social and occupational) and how effective they ...
24 Jul 2011
What does it mean if a MS symptom (intention tremor) improves in the first few months and then becomes worse than before treatment started? “The expectation of Natalizumab therapy is to prevent future attacks; it does little to ...
02 Jan 2013
People with cerebellar dysfunction have poor balance and co-ordination, slurred speech, jumping eyes or nystagmus and a tremor." Objective: In this study the investigators correlated the anatomical abnormalities in RRMSers ...

CD8 killers

Sauer BM, Schmalstieg WF, Howe CL. Axons are injured by antigen-specific CD8+ T cells through a MHC class I - and granzyme B-dependent mechanism. Neurobiol Dis. 2013 Jul 27. doi:pii: S0969-9961(13)00204-0. 10.1016/j.nbd.2013.07.010. [Epub ahead of print]

Axon injury is a central determinant of irreversible neurological deficit and disease progression in patients with multiple sclerosis (MS). CD8+lymphocytes (CTLs) within inflammatory demyelinated MS lesions correlate with acute axon injury and neurological deficits. The mechanisms of these correlations are unknown. We interrogated CTL-mediated axon injury using the transgenic OT-I antigen-specific CTL model system in conjunction with a chambered cortical neuron culture platform that permitted the isolated manipulation of axons independent of neuron cell bodies and glia. Interferon gamma upregulated, through a dose dependent mechanism, the axonal expression of functional major histocompatibility complex class I (MHC I) molecules competent to present immunologically-relevant antigens derived from endogenously expressed proteins. Antigen-specific CTLs formed cytotoxic immune synapses with and directly injured axons expressing antigen-loaded MHC I molecules. CTL-mediated axon injury was mechanistically dependent upon axonal MHC I antigen presentation, T cell receptor specificity and axoplasmic granzyme B activity. Despite extensive distal CTL-mediated axon injury, acute neuron cell body apoptosis was not observed. These findings present a novel model of immune-mediated axon injury and offer anti-axonal CTLs and granzyme B as targets for the therapeutic protection of axons and prevention of neurological deficits in MS patients.

In the past few weeks we have been talking about function of CD8 postivie T cells they can be supressor cells this study shows they may be damaging

What do YOU call a Neurologist?

I am currently doing yet another poll on the description of someone with MS and maybe will use this at ECTRIMS. 

The question is....How do you prefer to be labelled/described?. 

Some of the the terms you think are OK and some you think are pretty poor. I will talk about this soon.

However, as an exercise in reverse. I ask you ....What we should call someone who treats a person with MS?

Please be imaginative. Some of the responses could be quite formal but I also want some of the answers to be tongue-in-cheek, so I can use them in a talk in the near future. 

I can come up with quite a few but let's have fun together.  
Let's get it off your chest.

I'll explain later

Wednesday, 28 August 2013

ai-Chi and balance

Bayraktar D, Guclu-Gunduz A, Yazici G, Lambeck J, Batur-Caglayan HZ, Irkec C, Nazliel B. Effects of Ai-Chi on balance, functional mobility, strength and fatigue in patients with multiple sclerosis: A pilot study. NeuroRehabilitation. 2013 Aug 7. [Epub ahead of print]

Multiple Sclerosis (MS) patients are often referred to aquatic physical therapy, but unfortunately, researches on the effects of aquatic therapy in MS patients are limited.
The purpose of this study was to investigate the effects of Ai-Chi on balance, functional mobility, strength and fatigue in ambulatory patients with MS.
METHODS: Twenty-three ambulatory female patients were divided into two groups as experimental (n = 15) or control (n = 8) for 8-week treatment program. The experimental group underwent Ai-Chi exercises in a swimming pool and the control group performed active arm and leg exercises combined with abdominal breathing exercises at home. Static standing balance was measured with duration of one-leg stance, functional mobility was evaluated with Timed-up and Go test and 6 minute walk test, upper and lower muscle strength was assessed with hand-held dynamometer and fatigue was evaluated with Fatigue Severity Scale.
RESULTS:Improvements were observed in static standing balance, functional mobility, upper and lower extremity muscle strength and fatigue in the Ai-Chi group (p < 0.05), but no significant differences in any outcome measures were observed in the control group (p > 0.05) after the intervention.
CONCLUSIONS: According to these findings Ai-Chi may improve balance, functional mobility, upper and lower extremity muscle strength and fatigue in patients with MS.

Ai Chi is a water movement and relaxation program that has been created to help aquatic practitioners and people enjoy the water in a flowing yet powerful progression.  It is an efficient exercise program that increases oxygen and caloric consumption simply with correct form and positioning in the water, it is a perfect relaxation technique for highly stressed, over-challenged clients, and it is ideal for creating improved range of motion, balance and mobility. Ai Chi, created by combining Tai-Chi concepts with Shiatsu and QiGong techniques, is performed standing in shoulder depth water using a combination of deep breathing and slow, broad movements of the arms, legs, and torso. It is an aquatic technique that can be used with groups or one-on-one. Ai Chi has been successfully used with pain management, arthritis, fibromyalgia, COPD, diabetes, MS, amputee, paraplegic, etc. and with neurological and orthopedic diagnoses and balance deficits.

Exercise is good for you even if it is water

Fingolimod and infections

Fingolimod is not associated with an increased rate of infections. #MSBlog #MSResearch

"Because fingolimod causes a low lymphocyte count, and there have been a few deaths due to viral infections in people with MS on the drug, it is assumed that fingolimod is a potent immunosuppressive agent. The study below challenges this assumption. You also have to remember that the number of deaths due to infections is very small relative to the number of MSers treated; 3 herpesviral infection related deaths with over 70,000 treated MSers and two of these deaths occurred on a higher dose of fingolimod that subsequently was not licensed, i.e. the 1.25mg dose. The 0.5mg dose is the one that has been licensed."

"There is little doubt that fingolimod reduces the peripheral lymphocyte counts. However, you need to know about what type of lymphocytes are affected and what happens to those lymphocytes? Firstly, fingolimod is not a depleting agent; it simply traps lymphocytes in peripheral lymph nodes by removing one of the signals that lymphocytes use to migrate from lymph nodes. If you stop fingolimod and wait for it to wash-out of the system the vast majority of MSers will see their lymphocyte counts return to normal. This is reassuring. In addition, fingolimod does not affect all lymphocytes in the same way; it does not trap the so called effector cells. These cells are primed and ready for action when being exposed to an infection the immune system has already seen. This is good news if you get exposed to infectious agents you have seen in the past. What is not good news is if you come into contact with a new virus or infection, or so called exotic infections, that your immune system has not encountered in the past. Animals and people on fingolimod have a blunted response to new infections. Please note this is a blunted response, which means they can still respond to the agent but not as quickly, or briskly, as someone not on fingolimod."

"What about opportunistic infections? Opportunistic infections are defined as infections that rarely occur in humans unless they are immunocompromised. For example people with HIV or AIDs, with cancer, with malnutrition, or on immunosuppressive drugs to prevent transplant rejection tend to get opportunistic infections. Examples include fungal infections and infections related to tuberculosis. The study below reassuringly shows that fingolimod is not associated with opportunistic infections. This is very good news and indicates that fingolimod is not a potent immunosuppressive agent."

"Can the manufacturers therefore claim that fingolimod is not immunosuppressive, but rather an immunomodulatory agent? Immunomodulatory in this context implies that it modulates the immune system without causing immunosuppression. I say no. Why? Well it is known that fingolimod reduces your lymphocyte count, it also blunts, but not abolishes, your response to vaccines and it blunts the immune response to novel, or new not previously seen, infections. Fingolimod was also tested as an anti-rejection agent in people having kidney or renal transplants and it worked reasonably well. All this points to fingolimod being immunosuppressive. Fingolimod must  therefore be, at least, mildly immunosuppressive to have these effects."

"You will note from reading the study below that fingolimod was not associated with an increase in infections in the studies analysed. So that take home message is that fingolimod is mildly immunosuppressive and is not associated with an increased rate of infections nor rate of opportunistic infections. MSers who choose to go onto fingolimod will find this very reassuring. However, they must stay vigilant to infections and if they get infections they should seek medical attention to have them treated promptly; why take a chance if you don't need to. The other thing is MSers will not be able to have live vaccines whilst on fingolimod."

"It is a great pity that the EMA has given fingolimod a second-line license in Europe, when it is used first-line in many other countries, for example Switzerland, USA and Australia. Fingolimod is one of the highly-effective agents, is an oral tablet, and MSers in Europe are being forced to wait until they have failed one of the so called 1st-line treatments to access the drug. Hopefully, now that the EMA has recommended Alemtuzumab for active MS they will change their stance on fingolimod, and for that matter natalizumab in JCV-seronegative MSers. Time is brain and the sooner MSers have a choice to go onto highly-effective treatments the better. I personally don't think regulators should be making the these decisions for MSers. What do you think?"

Epub: Francis et al. Temporal profile of lymphocyte counts and relationship with infections with fingolimod therapy. Mult Scler. 2013 Aug 15.

BACKGROUND: Reduction in peripheral blood lymphocytes is an expected pharmacodynamic outcome of fingolimod therapy.

OBJECTIVE: The objective of this article is to evaluate lymphocyte dynamics during and after fingolimod therapy and assess the relationship between lymphocyte counts and infections.

METHODS: Lymphocyte counts and their relationship with infections were evaluated in three multiple sclerosis (MS) populations: (Group A) FREEDOMS phase 3 core study group (n = 1272); (Group B) All Studies group (one phase 2 and two phase 3 studies, plus their extensions; n = 2315); and (Group C) Follow-up group (after fingolimod discontinuation; n = 538).

RESULTS: Administration of fingolimod 0.5 mg led to reductions in lymphocyte counts to a steady-state of 24%-30% of baseline values within two weeks, which remained stable while on therapy. Following fingolimod discontinuation, average counts exceeded the lower limit of normal range within six to eight weeks, and were 80% of baseline values by three months. In Group A, infection rates per patient-year were 1.4 with placebo and 1.0 in fingolimod-treated patients who had the lowest lymphocyte counts (< 0.2 × 109/l). No evidence was seen for an increase in serious or opportunistic infections.

CONCLUSIONS: Fingolimod induces a rapid and reversible reduction in lymphocyte counts without an increase in infections relative to placebo. Because fingolimod reduces blood lymphocyte counts via redistribution in secondary lymphoid organs, peripheral blood lymphocyte counts cannot be utilized to evaluate the lymphocyte subset status of a MSer.

CoI: multiple

Genetics and T cells

Thessen Hedreul M, Möller S, Stridh P, Gupta Y, Gillett A, Beyeen AD, Ockinger J, Flytzani S, Diez M, Olsson T, Jagodic M Combining genetic mapping with genome-wide expression in experimental autoimmune encephalomyelitis highlights a gene network enriched for T cell functions and candidate genes regulating autoimmunity. Hum Mol Genet. 2013 [Epub ahead of print]

The experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the central nervous system commonly used to study multiple sclerosis (MS). We combined clinical EAE phenotypes with genome-wide expression profiling in spleens from 150 backcross rats between susceptible DA and resistant PVG rat strains during the chronic EAE phase. This enabled correlation of transcripts with genotypes, other transcripts and clinical EAE phenotypes and implicated potential genetic causes and pathways in EAE. We detected 2285 expression quantitative trait loci (eQTLs). Sixty out of 599 cis-eQTLs overlapped well-known EAE QTLs and constitute positional candidate genes, including Ifit1 (Eae7), Atg7 (Eae20-22), Klrc3 (eEae22) and Mfsd4 (Eae17). A trans-eQTL that overlaps Eae23a regulated a large number of small RNAs and implicates a master regulator of transcription.We defined several disease-correlated networks enriched for pathways involved in cell-mediated immunity. They include C-type lectins, G protein coupled receptors, mitogen-activated protein kinases, transmembrane proteins, suppressors of transcription (Jundp2 and Nr1d1) and STAT transcription factors (Stat4) involved in interferon signaling. The most significant network was enriched for T cell functions, similar to genetic findings in MS, and revealed both established and novel gene interactions. Transcripts in the network have been associated with T cell proliferation and differentiation, the TCR signaling and regulation of regulatory T cells. A number of network genes and their family members have been associated with MS and/or other autoimmune diseases. Combining disease and genome-wide expression phenotypes provides a link between disease risk genes and distinct molecular pathways that are dysregulated during chronic autoimmune inflammation..

This study shows how genetical complex event a simple model is. MS adds another level of complexity

Tuesday, 27 August 2013

Powering trials for childhood MS

Childhood MS. Do we need placebo-controlled trials? #MSBlog #MSResearch

"As you know MS is relatively rare in children. Therefore it is not feasible to do large phase 3 clinical trials to show that a DMT is effective in children as we do in adults. What we tend to do is extrapolate the results of adult trials to children. This is not correct. Children may respond or not respond to a DMT for a whole lot of reasons. Legislation has been enacted in both the US and EU that forces pharma companies to do clinical trials in the paediatric population within a certain number of years of them being granted a license for an adult indication. This is good and bad. Good in that it forces us to get data on a specific DMT in children. Bad in that the regulators often want a placebo-controlled data to show that drug is working. Is this ethical when we know how damaging untreated MS can be and we already know that this drug is effective in the adult population? Would you let your child be randomised into a placebo-controlled trial, and run the risk of them being allocated placebo or dummy drug, when the drug in question has already been shown to be effective in adult-MS?"

Epub: Verhey et al. Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials. Neurology. 2013 Aug 21.

OBJECTIVE: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints.

METHODS: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters.

RESULTS: Assuming a 50% reduction in new T2 lesions over 6 months, 90 MSers/arm are required, whereas 165 MSers/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 MSers/arm (using ARR) to 105 MSers/arm (TTFR) for a 50% reduction in relapses, and 230 MSers/arm (ARR) to 365 MSers/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 MSers/arm (60 MSers/arm for TTFR) for a 50% reduction in relapses and 145 MSers/arm (200 MSers/arm for TTFR) for a 30% reduction.

CONCLUSION: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration.

Other posts on childhood MS:

12 Apr 2013
BACKGROUND: Obesity in late adolescence has been associated with an increased risk of multiple sclerosis (MS); however, it is not known if body size in childhood is associated with MS risk. METHODS: Using a prospective ...
27 Mar 2013
"This report is timely can confirms the MS communities commitment to children with MS and the need to get DMTs approved for treating childhood MS. Hopefully, parents of children with MS will find this initiative a move in the ...
05 Feb 2013
Langer Gould A, Brara SM, Beaber BE, Koebnick C: (epub) Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome Neurology 2013. OBJECTIVE:To determine whether childhood obesity is a ...
29 Jan 2013
#MSBlog: Childhood and adult MS looks the same on MRI. Are you surprised? Donohue et al. No Regional Gray Matter Atrophy Differences between Pediatric- and Adult-Onset Relapsing-Remitting Multiple Sclerosis.

30 Jun 2012
Research: childhood-onset vs. adult-onset MS. Epub: Pichler et al. Differences and similarities in the evolution of morphologic brain abnormalities between paediatric and adult-onset multiple sclerosis. Mult Scler. 2012 Jun 19.
14 Mar 2012
Objective:To investigate the association between childhood trauma and multiple sclerosis (MS) by comparing histories of child abuse and neglect between patients with MS and adults from the general population in a ...

26 May 2013
"No surprises here; the profile of interferon-beta in childhood-onset MS appears similar to that in adults. I wonder what the new generation drugs will be like, in particular the more efficacious ones. Will they prevent the ...
23 Jan 2013
I did not have a particularly 'sterile' childhood, spent a lot of time at the stables and generally outside, certainly nothing like the overkill you hear of theses days. However, even my experience was probably fairly sterile ...