Saturday, 30 November 2013

Blog Advent Calendar

Well it is that time of the year again and it is time for the 
House of Mouse Advent calendar.  

Back by Popular demand!
I will be donning new outfits for the latest offering, so I have to thank my Designer Anna (& Previously Naomi) for making such wonderful clothes.

In 2011 (for research Day 2012) there was a Christmas Theme and in 2012 (for Research Day 2013) we got to meet TeamG to raise awareness of the Research Days. 

As for the research Day 2014,  UCLP, who are organising it have been a bit slow to say the very least and lost the date they had...I wont't say why. In the meantime I have grown my santa beard.

I cannot even guess when the date the Research Day will be, but it is unlikely to be in the first quarter of 2014 or possibly first half of the year.

Anyway we have decided to do the Advent Calender and TeamG may have some more to say about Research 2014. 

This year I have decided to do MS labs of the UK and the World........Will you know them?

We do not generate money from the blog, our time is donated too, and typically do not advertise. However, as a thank you (Dank je wel) to Anna in Holland (and previously Naomi in UK) the creators of the MouseDoc and all the fun furry Characters.

Follow the link to the House of Mouse for those Stocking Fillers.
Anything on the Advent calendar and more!
Also have A Perfect Christmas (Vasco) in the US or UK

Beta-interferon in CIS 8-year follow-up

Early treatment delays cognitive progression. #MSBlog #MSResearch

"What do long-term extension studies tell us? They give us insights that are not necessarily obvious in the short 2-year pivotal trial. The one that stands out in this 8-year open-label extension study is that CISers treated immediately with IFNbeta had better cognitive outcomes at 8 years compared to MSers who had a delayed start on treatment. This is a very strong argument for early treatment. Treat early to delay the progression of cognitive impairment in MS. I have made the point in the past that in early MS cognitive impairment is the main driver of early disability in MSers; long before physical disability. If IFNbeta, which on average is only moderately effective, can have an impact on cognition if used early what impact will the more effective therapies have? Unfortunately, we don't have this data to hand, but all the efficacy data suggests they would have a major impact."
"Have you aligned all your ducks? 


Epub: Edan et al. Long-term impact of interferon beta-1b in patients with CIS: 8-year follow-up of BENEFIT. J Neurol Neurosurg Psychiatry. 2013 Nov 11. doi: 10.1136/jnnp-2013-306222.

OBJECTIVE: To examine the long-term impact of early treatment initiation of interferon beta-1b (IFNB1b, Betaferon/Betaseron) in CISers with a first event suggestive of MS.

METHODS: In the original placebo-controlled phase of BENEFIT, CISers were randomised to IFNB1b 250 μg or placebo subcutaneously every other day. After 2 years or diagnosis of clinically definite MS (CDMS), all CISers/MSers were offered open-label IFNB1b treatment for a maximum duration of 5 years. Thereafter, CISers/MSers were enrolled in an observational extension study for up to 8.7 years.

RESULTS: Of the initial 468 CISers, 284 (60.7%; IFNB1b: 178 (61.0% of the original arm), placebo: 106 (60.2% of original arm)) were enrolled in the extension study. 94.2% were receiving IFNB1b. CISers originally randomised to IFNB1b had a reduced risk of developing CDMS by 32.2% over the 8-year observation period (HR 0.678; 95% CI 0.525 to 0.875; p=0.0030), a longer median time to CDMS by 1345 days (95% CI 389 to 2301), and a lower annualised relapse rate (0.196 (95% CI 0.176 to 0.218) versus 0.255 (95% CI 0.226 to 0.287), p=0.0012), with differences mainly emerging in the first year of the study. Cognitive outcomes remained higher in the early treated CISers. EDSS remained low over time with a median of 1.5 in both arms.

CONCLUSIONS: These 8-year results provide further evidence supporting early initiation of treatment with IFNB1b in CISers with a first event suggestive of MS.

CoI: multiple

Survey results: MSology and eMedicine Portal

MSology survey results. There is support for a MS eMedicine portal. #MSBlog #MSResearch

"The results of this survey are self-explanatory. It is clear that most MSers who read this blog have access to healthcare professionals who specialise in MS. Things are clearly improving. I am reassured to hear that there is support for a eMedicine MS-specific portal, which I plan to set-up in the future. I have also posted some of the few comments left on the survey at the bottom of this post. Once again thank you for taking the time to complete this survey."


I am a big believer in e-medicine transforming healthcare delivery. The sooner it gets to MS the better.
I only got switched to a MSologist after I started DMTs, and only then because the PCT decided that all those on DMTs should be looked after by a specialist.

Having moved, I'm not entirely sure if the neuro I see is a MSologist or not, although they can prescribe DMTs, the actually prescription comes from a hospital in a different region (and it can be very hard to find out anything about an individual, especially if they don't work privately), though the MS Nurse is very good.

The NHS in general shouldn't get so uptight about using email, So many simple appointments could be avoided if medics were happy to send and receive email.

There are times I won't need a MSologist / MS nurse and a digital pathway determiner (an online way of helping push me down the right medical path) seems a sensible way of not wasting experts time while still accessing medical help

I realise I am lucky living in London with a fantastic GP, MS Nurse and a Neurologist specialising in MS less than 10 miles away. My Tysabri infusions are also given at the same hospital.

I live in Jerusalem. I could go to the MS center at ******* but believe that the center at ********** near Tel Aviv is better. I thus take two buses to get there because I do not drive. It's worth it. I can get emergency appointments when necessary. The level of care is excellent at all levels. Occasionally, I take a taxi. But it is expensive, so only do it when I feel sick or I need to be at the center very early in the morning. This does not happen very often. I strongly believe that is essential,to be treated by an MS specialist, particularly one who is located in a large multidisciplinary center. An added plus is to have a good doctor who listens, cares, and possesses a sense of humor. This is my situation.

I would prefer talking to a computer than my real neurologist. He's a smarmy git.

I think that neurologists should sub-specialise, it is confusing enough that the practice among MS specialists in the Uk is so varied, let alone having general neurologists also involved. There are practical problems in small hospitals though.

The Clinic Speak posts are a good start. I have found them very valuable.

I am very lucky, access to he MS team at Royal London monthly because of ASCEND trial.
I think access to someone who knows something about you, your diagnosis and history is essential. How else can you get good treatment? That is especially important if you are going to have remote treatment by phone or electronic method

Re e- medicine access to broadband/cable/satellite can be a significant problem for country people.

Fortunately, I live in Sydney, New South Wales, Australia, a large city with excellent health care facilities and services. I know I am very lucky to have this available to me.

Personally I have spinal stenosis and currently we are investigating hipbone necrosis .... So I know I am lucky to have ****** of Sheffield, Hallam hospital supporting me!!!!

It just gets so fuzzy ... The lines between which condition IS the CAUSE of my pain and inability to WEIGHT BEAR.

Re first question: at one time, I was seeing a neuro privately and had to wait 5 days to see him 'urgently'. Now, my next NHS appointment has been postponed from the 8 months specified by the neuro to 18 months (so far, anyway).

I am fortunate in that i live close to a large hospital with a specialist neurology centre. I was seen at my first visit by an ms specialist who told me at this visit that I probably had MS. Following brain MRI I was told at my next visit that I had ms and was offered dmd's and referred to an ms nurse. I appreciate that in this instance location location location was the thing that allowed me to be diagnosed so quickly. So yes I believe it is crucial to be seen by an ms consultant as quickly as possible. However it is also imperative that the gp considers this possible outcome and so refers you the correct person. However I concede that neurological manifestations come in all shapes and sizes so it is difficult for a gp to know when to refer and to whom.

CCSVI November

MSResearch#; #CCSVI Trials maybe doomed to fail

Kazibudzki M, Latacz P, Ludyga T, Simka M. Efficacy and safety of cutting balloons for the treatment of obstructive lesions in the internal jugular veins. J Cardiovasc Surg (Torino). 2013 Oct 24. [Epub ahead of print]

Aim: In this technical note we present the results of endovascular treatment for chronic cerebrospinal venous insufficiency with the use of cutting balloons, with focus on feasibility and safety of these endovascular devices. 
Methods: We used cutting balloons during 70 procedures in 65 multiple sclerosis patients presenting with strictures of the internal jugular veins, primarily at the level of jugular valves. These devices were used only in selected cases, following unsuccessful standard balloon angioplasty, and on condition that commercially available devices could be applied (currently they are maximally 8 mm in diameter). 
Results: In all cases the perioperative course was uneventful, with no serious adverse events. Immediate technical success rate was 94.3%. In four cases (5.7%) cutting-balloon angioplasty alone was unsuccessful and stents were implanted. Primary, assisted primary and secondary patency rates after 6 months were: 94%, 98.5%, and 98.5%, respectively. Follow-up has revealed that out of the remaining 66 angioplasties four procedures failed (failure rate: 6.1%): in two patients stents were implanted, in one patient successful redo cutting-balloon angioplasty was performed, while in another case the treated segment of jugular vein totally occluded and was not feasible to reopen endovascularly. 
Conclusion: Cutting balloons can be safely used for the management of stenosed internal jugular veins. These devices can replace stents in the majority of cases, especially if standard balloon angioplasty is insufficient to restore proper outflow. However, the use of cutting balloons in this particular venous territory is limited by the fact that currently only small diameter devices are available.
A cutting balloon- It has a special balloon tip with small blades, that are activated when the balloon is inflated. Our advice is only to do this as part of a controlled trial until the process is of proven benefit.

Diaconu CI, Fox RJ, Grattan A, Rae-Grant A, Lu M, Gornik HL, Kim ES. Hydration status substantially affects chronic cerebrospinal venous insufficiency assessments. Neurol Clin Pract. 2013;3:386-391.

We sought to determine the effect of hydration on the criteria for chronic cerebrospinal venous insufficiency (CCSVI), a proposed hypothesis for the aetiology of multiple sclerosis (MS). Sixteen subjects (11 MS and 5 controls) were asked to fast overnight. The following morning, 2 CCSVI ultrasound examinations were performed: 1 in the mildly dehydrated state, and another 30-45 minutes after rehydrating with 1.5 L of Gatorade. Seven subjects fulfilled CCSVI criteria in the dehydrated state. Of these, 5 (71%) no longer fulfilled CCSVI criteria after rehydration. One additional subject met CCSVI criteria only after rehydration. Hydration status has a substantial effect on CCSVI criteria, suggesting that the sonographic findings of CCSVI may represent a physiologic rather than pathologic state.

Oops maybe having a drink of water or not can affect whether you have CCSVI or not.  So nt surprising that some people question the existence of this

BACKGROUND: Normally, chronic cerebrospinal venous insufficiency (CCSVI) has been studied using echo-colour Doppler (ECD). Subjects are examined in the supine and sitting positions, in accordance with a static protocol without rotation of the head. A dynamic approach, to assess venous sizes with different degrees of head rotation, has only been performed to improve jugular venous catheterisation. These echographic studies have suggested that head rotation to the contralateral side increases the cross-sectional area (CSA) of the internal jugular veins (IJVs) in supine subjects. Our goal was to evaluate the behaviour of CSA of the IJVs during supine head rotation in multiple sclerosis (MS) patients with CCSVI, compared to healthy controls (HCs).
METHODS: The IJVs of 313 MS patients with CCSVI (male 43.7%, male/female 137/176; mean age 45 years old, range 19--77 years) and 298 HCs, matched by gender (male 43.6%, male/female 130/168) and age (mean age 46 years old, range 20--79 years), were compared using ECD. Their CSAs were evaluated with the subjects seated in a tiltable chair, first in the supine position at the level of the cricoid cartilage, with the head in a neutral position, and then after contralateral rotation to 90[degree sign] from midline.
RESULTS: Significant differences between the jugular CSAs before and after head rotation were observed only in the MS patients for the IJVs with wall collapse (F[6,1215] = 6414.57, p < 0.001), showing on longitudinal scans a typical "hourglass" aspect that we defined as "miopragic". No significant difference was found in the distribution of these miopragic veins with regard to MS duration. There was a strong association between the CCSVI scores and the complexity of jugular morphological types (Chi2 [9, N = 313] = 75.183, p < 0.001). Wall miopragia was mainly observed in MS patients with SP (59.3%) and PP (70.0%) clinical forms, compared to RR (48.3%) forms (p = 0.015).
CONCLUSION: A dynamic ECD approach allowed us to detect IJVs with a significant increase in their CSAs during head rotation, but only in MS subjects. This feature, most likely the expression of congenital wall miopragia, could be secondary to dysregulation of collagen synthesis, but further histochemical studies will be needed to confirm this hypothesis.

Barkhof F, Wattjes MP. Multiple sclerosis: CCSVI deconstructed and discarded. Nat Rev Neurol. 2013 Nov 12. doi: 10.1038/nrneurol.2013.228. [Epub ahead of print]

Neurologists have had enough of this where are others may take a different tack see below

Alexander MD, McTaggart RA, Choudhri OA, Marcellus ML, Do HM. Percutaneous sclerotherapy with ethanolamine oleate for venous malformations of the head and neck. J Neurointerv Surg. 2013 Nov 14. doi: 10.1136/neurintsurg-2013-010924. [Epub ahead of print]

INTRODUCTIONVenous malformations frequently occur in the head and neck, and they can require treatment for a variety of reasons. Amongmultiple therapeutic approaches employed, percutaneous sclerotherapy has become one of the most commonly used treatments, with numerous sclerosants successfully utilized. Ethanolamine oleate has approval from the Food and Drug Administration for sclerosis of esophageal varices, and is used by some practitioners for the treatment of venous malformations. This study reports single center results of percutaneous sclerotherapy with ethanolamine oleate to treat venous malformations of the head and neck.
MATERIALS AND METHODS: Prospectively maintained procedural records were retrospectively reviewed to identify all patients with venous malformations who underwent percutaneous sclerotherapy. The Mulliken and Glowacki classification was used to diagnose venous malformations. Medical records and images were reviewed to record demographic information, lesion characteristics, treatment sessions, and clinical and imaging response. Quantitative volumetric analysis was conducted to augment commonly used poorly reproducible subjective outcome measures. Response was assessed after each session and completion of all percutaneous treatment. A χ2 analysis was performed to evaluate the effects of the above described characteristics on outcomes.
RESULTS: 52 interventions were performed for lesions in 26 patients. No complications occurred following any procedures. Response to individual sessions was categorized as excellent following two (3.8%) sessions, good following 45 (86.5%), and fair following four (7.7%) session. No sessions resulted in poor responses. Final results were excellent in two patients (7.7%), good in 22 (84.6%), and fair in two (7.7%). Average lesion volume reduction was 39% following each session, and 61% after treatment completion. Periorbital lesions were significantly less likely than lesions located elsewhere to have good or excellent outcomes. No other lesion or demographic features affected outcomes.
CONCLUSIONS: Percutaneous sclerotherapy with ethanolamine oleate appears to be safe and effective for the treatment of venous malformations and should be considered when treating these complex lesions. The efficacy of this agent appears to match or exceed that of other sclerosants used for such treatment, and further investigation in prospective controlled research is warranted

Further studies are warrant then let the people do them 

Sternberg Z, Grewal P, Cen S, Debarge-Igoe F, Yu J, Arata M.
Blood pressure normalization post-jugular venous balloon angioplasty. Phlebology. 2013 Nov . [Epub ahead of print]

OBJECTIVE: This study is the first in a series investigating the relationship between autonomic nervous system (controls involuntary body activities) dysfunction and chronic cerebrospinal venous insufficiency in multiple sclerosis patients. We screened patients for the combined presence of the narrowing of the internal jugular veins and symptoms of autonomic nervous system dysfunction (fatigue, cognitive dysfunction, sleeping disorders, headache, thermal intolerance, bowel/bladder dysfunction) and determined systolic and diastolic blood pressure responses to balloon angioplasty.
METHODS: The criteria for eligibility for balloon angioplasty intervention included ≥50% narrowing in one or both internal jugular veins, as determined by the magnetic resonance venography, and ≥3 clinical symptoms of autonomic nervous system dysfunction. Blood pressure was measured at baseline and post-balloon angioplasty.
RESULTS: Among patients who were screened, 91% were identified as having internal jugular veins narrowing (with obstructing lesions) combined with the presence of three or more symptoms of autonomic nervous system dysfunction. Balloon angioplasty reduced the average systolic and diastolic blood pressure. However, blood pressure categorization showed a biphasic response to balloon angioplasty. The procedure increased blood pressure in multiple sclerosis patients who presented with baseline blood pressure within lower limits of normal ranges (systolic ≤105 mmHg, diastolic ≤70 mmHg) but decreased blood pressure in patients with baseline blood pressure above normal ranges (systolic ≥130 mmHg, diastolic ≥ 80 mmHg). In addition, gender differences in baseline blood pressure subcategories were observed.
DISCUSSION: The coexistence of internal jugular veins narrowing and symptoms of autonomic nervous system dysfunction suggests that the two phenomena may be related. Balloon angioplasty corrects blood pressure deviation in multiple sclerosis patients undergoing internal jugular vein dilation. Further studies should investigate the association between blood pressure deviation and internal jugular veins narrowing, and whether blood pressure normalization affects Patient's clinical outcomes.

What we want to know is, Is this treatment good for symptom control?

Tromba L, Blasi S, Vestri A, Kiltzanidi D, Tartaglia F, Redler A.Prevalence of chronic cerebrospinal venous insufficiency in multiple sclerosis: a blinded sonographic evaluation.Phlebology. 2013 Nov . [Epub ahead of print]

OBJECTIVES: To verify the prevalence of chronic cerebrospinal venous insufficiency in patients affected by different clinical forms of multiple sclerosis and in healthy subjects using the Zamboni ultrasound protocol combined with M-mode ultrasound examination.

MATERIALS AND METHODS: We enrolled 112 patients with multiple sclerosis and 67 healthy subjects from 20 to 67 years of age. All the patients underwent Duplex and color-Doppler sonography of the neck vessels, transcranial colour duplex sonography, M-mode study of the valve system and of venous abnormalities. Subjects were positive for chronic cerebrospinal venous insufficiency when at least two of five hemodynamic criteria of the Zamboni protocol were fulfilled. Chronic cerebrospinal venous insufficiency condition was further analyzed by a multivariate analysis including age, sex, disease duration, subtypes of multiple sclerosis and expanded disability status scale score as independent variables.
RESULTS: No healthy subjects was positive for chronic cerebrospinal venous insufficiency, while in the sample of patients affected by multiple sclerosis the diagnosis was made in 59.8% of cases (p < 0.0001). The first criterion was the most frequent in patients affected by multiple sclerosisand chronic cerebrospinal venous insufficiency (respectively 54.4% and 76.1%, p < 0.001). The second, third and fourth criteria were never present in healthy subjects but were detected in patients with multiple sclerosis. The positivity of the second criterion was associated with diagnosis of chronic cerebrospinal venous insufficiency in 100% of cases. The third criterion had a prevalence of 52.2% in the subgroup of chronic cerebrospinal venous insufficiency patients. It was positive in 36 multiple sclerosis patients and was associated with chronic cerebrospinal venous insufficiency diagnosis in all cases except one.The multivariate analysis showed that age, disease duration, sex, subtypes of multiple sclerosis and expanded disability status scale score were not considered predictors of this haemodynamic condition.
CONCLUSION: Chronic cerebrospinal venous insufficiency is a haemodynamic condition strongly associated with multiple sclerosis and is not found in normal controls. The addition of M-mode ultrasound to the diagnostic protocol allows improved observation of venous valve abnormalities.

The plot twists yet again some people agree with Zamboni  with a 100% v 0% in healthy controls, so now we look at other peoples experiences

Leone MA, Raymkulova O, Lucenti A, Stecco A, Bolamperti L, Coppo L, Liboni W, Rivadossi G, Zaccala G, Maggio M, Melis F, Giaccone C, Carriero A, Lochner P. A reliability study of colour-Doppler sonography for the diagnosis of chronic cerebrospinal venous insufficiency shows low inter-rater agreement. BMJ Open. 2013 Nov 15;3(11):e003508. doi: 10.1136/bmjopen-2013-003508.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been extremely variable, associated with multiple sclerosis in colour-Doppler sonographic studies. We aimed to evaluate inter-rater agreement in a colour-Doppler sonography venous examination.
PARTICIPANTS: 38 patients with multiple sclerosis and 55 age-matched (±5 years) controls.
INTERVENTION: Sonography was carried out in accordance with Zamboni's five criteria by eight sonographers with different expertise, blinded to the status of cases and controls. Each participant was evaluated by two operators.
RESULTS: The agreement was no higher than chance for criterion 2-reflux in the deep cerebral veins and criterion 4-flow not Doppler detectable in one or both the internal jugular veins (IJVs) or vertebral veins (VVs; -0.09). It was substantially low for criterion 1-reflux in the IJVs and/or VVs (0.29), criterion 3-IJV stenosis or malformations (0.23) and criterion 5-absence of IJV diameter increase when passing from the sitting to the supine position (0.22). The κ value for CCSVI as a whole was 0.20 (95% confidence limit -0.01 to 0.42). Intraclass correlation coefficients for the measure of cross-sectional area ranged from 0.05 to 0.25. Inter-rater agreement was low for CCSVI experts (κ=0.24; -0.11 to 0.59) and non-experts (0.20; -0.33 to 0.73); neurologists (0.21; -0.06 to 0.47) and non-neurologists (0.18; -0.20 to 0.56); cases (0.19; -0.14 to 0.52) and controls (0.21; -0.08 to 0.49). Zamboni-trained neurosonographers ascertained CCSVI more frequently than the non-trained neurosonographers.
CONCLUSIONS: Agreement was unsatisfactory for the diagnosis of CCSVI as a whole, for each of its five criteria and according to the different subgroups. Standardisation of the method is urgently needed prior to its further application in studies of patients with multiple sclerosis or other neurological diseases.

There is not agreement between individuals, so the specificity of the test is very low. This is failing the smack you in the eye test i.e if you cant obviously see the difference is it really there. However the post below is even more damming

Van den Berg PJ, Visser LH The Fluctuating Natural Course of CCSVI in MS Patients and Controls, a Prospective Follow-Up. PLoS One. 2013 Nov ;8(11):e78166.

OBJECTIVES: A new treatable venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis. The natural course of CCSVI has not been examined yet. This is crucial given the fact that surgical procedures are increasingly offered to MS patients to treat venous stenosis.

METHODS: To document the natural course of venous haemodynamics we performed extra- and transcranial echo colour Doppler (ECD) in 52 multiple sclerosis patients and 28 healthy controls (HC) and re-examined this group after a median period of 16 weeks. The reexamination was done being blinded to the initial findings and the patients did not undergo any intervention.
RESULTS: The ECD examination at baseline showed CCSVI in 5 (9.6%) of the 52 multiple sclerosis patients and 0 HC (P = 0.26). At follow-up the diagnosis CCSVI could not be reconfirmed in 3 out of 5 patients at follow-up, while 2 new CCSVI-positive multiple sclerosis patients were detected.
CONCLUSIONS: ECD examination shows a fluctuating natural course of the extracranial venous haemodynamics, which makes determination of CCSVI by ECD examination unreliable.

Oh Dear this suggests that clinical trials will be meaningless because if CCSVI is here one minute and gone the next then how can you do proper can't.

Ciciarello F, Mandolesi S, Galeandro AI, Marceca A, Rossi M, Fedele F, Gesualdo M, Cortese F, Zito A, Federico F, Livrea P, Trojano M, Scicchitano P, Ciccone MM. Age-Related Vascular Differences Among Patients Suffering from Multiple Sclerosis. Curr Neurovasc Res. 2013 Nov 24. [Epub ahead of print]

The aim of our study was to analyze morphological and functional aspects of cerebral veins by mean of eco-color-Doppler in young (i.e., ≤30 years old) and older (i.e., >30 years old) patients suffering from multiple sclerosis. 552 multiple sclerosis patients were evaluated by mean of a dedicated Echo-Color-Doppler support (MyLab Vinco echo-color Doppler System, Esaote), in both supine and sitting positions. 458 (83%) showed alterations in their morphological and functional structures of cerebral veins and were divided in two different groups: 1) ≤30 (110 patients) and 2) >30 years old (348 patients). Young patients showed a statistically significant higher number of both haemodinamically (44% vs 35%, p<0.01) and non-haemodinamically (51% vs 45%, p<0.05) significant stenosis in the internal jugular veins. A lower percentage of young patients showed blocked outflow in the cervical veins (50% vs 65%, p<0.01) as compared to older. Patients >30 years old outlined a significant higher disability degree (Expanded Disability Status Scale score: 5 vs 3, p<0.01) as well as higher disease duration (12 vs 5 months, p<0.01) than younger. No differences could be outlined about multiple sclerosis clinical form of the disease. Young and adult groups are different kind of patients, the former showing much more cerebral veins stenosis and blocked flow in internal jugular veins and vertebral veins than the latter. Duration of disease could explain such differences: the higher the diseases duration, the higher the degree of vascular alterations and, therefore, the disability degree. This could be due to the complex venous hemodynamic impairments induced by the alterations in vascular walls: the blocked or difficult blood flow through stenosis could increase the hydrostatic pressure in the skull and this could induce cerebral cells damages that could lead to the genesis of more advanced morphological abnormalities. Furthermore, the vessels' alterations could impair venous endothelial functions which could turn in a possible alteration of the controls of cerebral vein return which could worsen the cerebral vascular outflow. 

ShiftMS: Peoples Hot Topic - Repurposing of Drugs

Can we repurpose drugs? #MSBlog #MSResearch

Our annual MS Research Day is facing delays; will a series of Google hangouts be an appropriate substitute? #MSResearch #MSBlog

"Finally my first hangout in collaboration with ShiftMS. We are planning to do these more often in the New Year. You may be aware that the scheduling of the 2014 UCLP MS Research Day will be delayed and will only happen towards the middle of next year. To fill the gap before the event we will be hosting a series of Google Hangouts to update you on our research programme. We will try and get you a provisional programme in the next few weeks. If you have any suggestions or requests for topics you would like covered please let us know."

Friday, 29 November 2013

21st European Charcot Meeting, Baveno, Italy

What a fight? MRI vs. clinical outcomes. Who won? #MSBlog #MSResearch

"The following is my presentation from this morning at the European Charcot Meeting in Baveno, Italy. I covered laboratory measures of disease variability and prognosis. My talk was benign compared to the sparring bout, or some would argue fist-fight, between George Ebers and the MRI lobby. It made for entertaining viewing. Who won? Neither. Both clinical and MRI metrics are important to capture the impact of MS. One thing that was a positive is that George Ebers admitted and presented data to show that relapses on treatment are predictive of long-term disabilty compared to relapses in natural history studies. This means that there is now consensus that having relapses on DMTs is predictive of a poor response. This is one of the fundamentals that underpins our campaign for zero tolerance and treat-2-target of NEDA (no evidence of disease activity)."

ProfB in the Media

Faculti does short interviews about science stuff:

See Prof B talk about cannabis and symptom control:

Animal testing to get even more expensive?

Nathoo N, Yong VW, Dunn JF. Using magnetic resonance imaging in animal models to guide drug development in multiple sclerosis.Mult Scler. 2013 Nov 21. [Epub ahead of print]
Major advances are taking place in the development of therapeutics for multiple sclerosis (MS), with a move past traditional immunomodulatory/immunosuppressive therapies toward medications aimed at promoting remyelination or neuroprotection. With an increase in diversity of MS therapies comes the need to assess the effectiveness of such therapies. Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the effectiveness of MS therapeutics in clinical trials. As all new therapeutics for MS are tested in animal models first, it is logical that MRI be incorporated into preclinical studies assessing therapeutics. 

There has been a failure to translate many animal studies into human benefit. Some of these failures may have because the MRI outcomes measures used in trials were either sensitive enough, they did not detect pathologically/clinically meaningful outcomes as anticipated. For example in the Lamotrigine trial the outcome measure was CNS atrophy and the drug treatment appeared to make atrophy occur at a faster rate than the placebo. Was this because it made the MSers lose more nerves?. However once treatment stopped the size of the CNS became bigger so it was hardly nerves re growing. Maybe there was swelling due to MS and the drug had anti-inflammatory effects and got rid of the swelling? We cannot know what really happened because we could not view the tissues. In animal studies one could and maybe work out what MRI outcomes are really measuring. The problem is the degree of resolution as the CNS of animals is much smaller than a human brain, but with even more powerful MRI machines amazing images are achievable. It would be great to perform imaging in all animal studies, but it will mean that millions have to be found to purchase and maintain the scanners if this was uniformly used. Also it is important that scanners can image the spinal cord, which is more difficult, because of breathing making the spinal cord move, and not just the brain, because in most cases the neurological deficits are because of spinal cord involvement.

Don't Forget Digesting Science

Our American readers will have been just digested their Thanksgiving Turkey, so don't to forget to Digest some Science. 

                             A site for children of People with MS

For the Brits they will be thinking about their Turkey, as we come into the final hurdle and run into Christmas.

Thursday, 28 November 2013

Blocking LINGO1 in fish promotes myelination

Yin W, Hu B Knockdown of Lingo1b protein promotes myelination and oligodendrocyte differentiation in zebrafish. Exp Neurol. 2013 Nov. doi:pii: S0014-4886(13)00336-1.10.1016/j.expneurol.2013.11.012. [Epub ahead of print]

Demyelinating diseases include multiple sclerosis, which is a neurodegenerative disease characterized by immune attacks on the central nervous system (CNS), resulting in myelin sheath damage and axonal loss. Leucine-rich repeat and immunoglobulin domain-containing neurite outgrowth inhibitory protein (Nogo) receptor-interacting protein-1 (LINGO-1) has been identified as a negative regulator of oligodendrocytes differentiation. Targeted LINGO-1 inhibition promotes neuron survival, axon regeneration, oligodendrocyte differentiation, and remyelination in diverse animal models. Although studies in rodent models have extended our understanding of LINGO-1, its roles in neural development and myelination in zebrafish (Danio rerio) are not yet clear. In this study, we cloned the zebrafish homolog of the human LINGO-1 and found that lingo1b regulated myelination and oligodendrocyte differentiation. The expression of lingo1b started 1 (mRNA) and 2 (protein) days post-fertilization (dpf) in the CNS. Morpholino oligonucleotide knockdown of lingo1b resulted in developmental abnormalities, including less dark pigment, small eyes, and a curly spinal cord. The lack of lingo1b enhanced myelination and oligodendrocyte differentiation during embryogenesis. Furthermore, immunohistochemistry and movement analysis showed that lingo1b was involved in the axon development of primary motor neurons. These results suggested that Lingo1b protein functions as a negative regulator of myelination and oligodendrocyte differentiation during zebrafish development.
The Zebrafish has clear young and you can genetically manipulate the fish so you can see myelination happening. In this study they look at the effect of blocking LINGO1 and this caused more myelin to form and also helped nerves grow,so if it is important in myelin formation in fish and rodents, there is a good chance it is important in humans too. Pharma thinks so and there are studies to deliver a LINGO-1 blocking molecule. I only hope enough of it can get into the CNS to do its stuff.

Exercise is GOOD:-)

J Neurol. 2013 Nov. [Epub ahead of print]

Multiple sclerosis (MS) is an incurable disease, and despite current pharmacologic treatment being effective in reducing relapse rates and lesion burden, there is little evidence that these treatments work as effectively in preventing disability progression. In such cases, non-pharmacologic techniques such as exercise therapy with rehabilitation purposes may play an important role. This systematic review of randomised controlled trials (RCTs) aims at investigating the effects of exercise therapy in MS patients. The electronic database PubMed was searched for studies indexed between February 2004 and June 2012. Studies eligibility criteria included: clinical diagnosis of MS free of exacerbation; and intervention with exercise therapy, measured as activities of daily living (ADL). Two reviewers independently screened the titles and abstracts of the references retrieved. The methodological quality of the RCTs was assessed using the Physiotherapy Evidence Database scale (PEDro scale). The PubMed search resulted in a total of 72 articles, 11 of which were included in this review. The analysis included 591 participants, of which 358 (60.6 %) were women. Patients had a mean age between 37.1 and 54.6 years. Duration of MS since diagnosis was reported in nine of the 11 studies and varied between 5.2 and 15.9 years. According to PEDro scale, nine of the 11 included studies were considered to be of high methodological quality, with scores ranging from 7 to 10. In eight of the 11 included studies, the effectiveness of exercise therapy was compared to standard care, in two it was compared to those on a waiting list, and in one, to control treatment. The results of this review suggest that exercise therapy may have a beneficial effect in patients with MS, and therefore may be recommended for the rehabilitation of these patients.
Well as we all know exercise is GOOD :-). This systematic review says so to but what is is noticeable is that that so many of the studies that were looked at  failed to to make the the cut. So many studies of non pharmaceutical treatments just do have enough power to make any compelling case such that some uniform advice abut which and what exercises is the best, however if you are seeing a physio I am sure they now best.

Wednesday, 27 November 2013

Coming Soon!

#MS Research Christmas Cheer/Cheese is coming

As people in the US prepare for Thanksgiving, It is nearly time for Xmas fever as the holiday season is upon us, Guess what's coming!

Big Brother: modeling MS using electronic health records

We are watching every step you take; using Big Brother to study the impact of MS. #MSBlog #MSResearch

"Big Brother, are you ready for him? The use of data collected for other reasons can be very useful for imputing the impact of MS on quality of life and physical functioning. This study shows how by trawling electronic health records (EHR) you can assess the severity of MS and it correlated reasonably well with measured outcome, i.e. the EDSS and  its derivative the MS severity score (MSSS) and the MRI metric of brain volume. EHR are just the beginning. What about your bank or credit card statements? It can tell us how much your are earning and spending; employment is a good indicator of health. We may be able to see if, when and how much you are spending on MS-related healthcare services. We can also see if your spending pattern changes over time; less spending on leisure activities, for example movies, restaurants, golf, holidays, etc. could indicate reduced quality of life and an advance in your MS. What about your smart phone? How you use it and where it goes by  tracking it will tell us something about your MS. The less mobile you are the more disabled."

"Are you ready for the Orwellian world of Big Brother? Could I convince you that this type of data will help health economists assess the real impact of MS on peoples lives and it can then be used to assess whether or not DMTs or MS services are making an impact on MS at a population level."

"To explore this issue further I would appreciate it if you could complete this short survey. Thank you."

Xia et al. Modeling disease severity in multiple sclerosis using electronic health records. PLoS One. 2013 Nov 11;8(11):e78927. doi: 10.1371/journal.pone.0078927.

OBJECTIVE: To optimally leverage the scalability and unique features of the electronic health records (EHR) for research that would ultimately improve patient care, we need to accurately identify patients and extract clinically meaningful measures. Using multiple sclerosis (MS) as a proof of principle, we showcased how to leverage routinely collected EHR data to identify patients with a complex neurological disorder and derive an important surrogate measure of disease severity heretofore only available in research settings.

METHODS: In a cross-sectional observational study, 5,495 MS patients were identified from the EHR systems of two major referral hospitals using an algorithm that includes codified and narrative information extracted using natural language processing. In the subset of patients who receive neurological care at a MS Center where disease measures have been collected, we used routinely collected EHR data to extract two aggregate indicators of MS severity of clinical relevance multiple sclerosis severity score (MSSS) and brain parenchymal fraction (BPF, a measure of whole brain volume).

RESULTS: The EHR algorithm that identifies MS patients has an area under the curve of 0.958, 83% sensitivity, 92% positive predictive value, and 89% negative predictive value when a 95% specificity threshold is used. The correlation between EHR-derived and true MSSS has a mean R(2) = 0.38±0.05, and that between EHR-derived and true BPF has a mean R(2) = 0.22±0.08. To illustrate its clinical relevance, derived MSSS captures the expected difference in disease severity between relapsing-remitting and progressive MS patients after adjusting for sex, age of symptom onset and disease duration (p = 1.56×10(-12)). 

CONCLUSION: Incorporation of sophisticated codified and narrative EHR data accurately identifies MS patients and provides estimation of a well-accepted indicator of MS severity that is widely used in research settings but not part of the routine medical records. Similar approaches could be applied to other complex neurological disorders.

Genetic changes in brain areas before the immune cells accumulate

Huynh JL, Garg P, Thin TH, Yoo S, Dutta R, Trapp BD, Haroutunian V, Zhu J, Donovan MJ, Sharp AJ, Casaccia P. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci. 2013 Nov 24. doi: 10.1038/nn.3588. [Epub ahead of print]

Using the Illumina 450K array and a stringent statistical analysis with age and gender correction, we report genome-wide differences in DNA methylation between pathology-free regions derived from human multiple sclerosis-affected and control brains. Differences were subtle, but widespread and reproducible in an independent validation cohort. The transcriptional consequences of differential DNA methylation were further defined by genome-wide RNA-sequencing analysis and validated in two independent cohorts. Genes regulating oligodendrocyte survival, such as BCL2L2 and NDRG1, were hypermethylated and expressed at lower levels in multiple sclerosis-affected brains than in controls, while genes related to proteolytic processing were hypomethylated and expressed at higher levels. These results were not due to differences in cellular composition between multiple sclerosis and controls. Thus, epigenomic changes in genes affecting oligodendrocyte susceptibility to damage are detected in pathology-free areas of multiple sclerosis-affected brains.
This study indicates that there are factors in the so called normal appearing white matter that are modifying the genes, which may influence what proteins cells they may make. What is causing this cytokines produced from some distance away or maybe the virus triggering MS 

PERKing up myelin repair

Lin Y, Huang G, Jamison S, Li J, Harding HP, Ron D, Lin W. PERK Activation Preserves the Viability and Function of Remyelinating Oligodendrocytes in Immune-Mediated Demyelinating Diseases.Am J Pathol. 2013 Nov doi:pii: S0002-9440(13)00721-9. 10.1016/j.ajpath.2013.10.009. [Epub ahead of print]

Remyelination occurs in multiple sclerosis (MS) lesions but is generally considered to be insufficient. One of the major challenges in MS research is to understand the causes of remyelination failure and to identify therapeutic targets that promote remyelination. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum stress modulates cell viability and function under stressful conditions. There is evidence that PERK is activated in remyelinating oligodendrocytes in demyelinated lesions in both MS and its animal model, experimental autoimmune encephalomyelitis (EAE). In this study, we sought to determine the role of PERK signaling in remyelinating oligodendrocytes in MS and EAE using transgenic mice that allow temporally controlled activation of PERK signaling specifically in oligodendrocytes. We demonstrated that persistent PERK activation was not deleterious to myelinating oligodendrocytes in young, developing mice or to remyelinating oligodendrocytes in cuprizone-induced demyelinated lesions. We found that enhancing PERK activation, specifically in (re)myelinating oligodendrocytes, protected the cells and myelin against the detrimental effects of interferon-γ, a key proinflammatory cytokine in MS and EAE. More important, we showed that enhancing PERK activation in remyelinating oligodendrocytes at the recovery stage of EAE promoted cell survival and remyelination in EAE demyelinated lesions. Thus, our data provide direct evidence that PERK activation cell-autonomously enhances the survival and preserves function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases.
I am sure we have commented earlier in the year on PERK earlier this year but the search feature has conked-out (Lin W et al. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci. 2013 ;33(14):5980-91). PERK is a signalling molecule that can enhance remyelination. Can we find activators of PERK that are tolerated?

Tuesday, 26 November 2013

Is EBV-infection under the control of Vitamin-D?

Ramien C, Pachnio A, Sisay S, Begum J, Leese A, Disanto G, Kuhle J, Giovannoni G, Rickinson A, Ramagopalan SV, Moss P, Meier UC.Hypovitaminosis-D and EBV: no interdependence between two MS risk factors in a healthy young UK autumn cohort. Mult Scler. 2013 Nov 5. [Epub ahead of print]

Late Epstein-Barr virus infection and hypovitaminosis-D as environmental risk factors in the pathogenesis of multiple sclerosis are gaining great interest. We, therefore, tested for in-vivo interdependence between Epstein-Barr-virus (EBV)-status and 25-hydroxyvitamin D3 (25(OH)D3) -level in healthy young individuals from a United Kingdom (UK) autumn cohort. EBV-load was measured by quantitative polymerase chain reaction and 25(OH)D3 levels by isotope-dilution liquid chromatography-tandem mass spectrometry. This young, healthy UK autumn cohort showed surprisingly low levels of 25(OH)D3 (mean value: 40.5 nmol/L ± 5.02). Furthermore, we found that low 25(OH)D3 levels did not impact on EBV load and anti-EBV nuclear antigen-1 (EBNA-1) titers. However, we observed a correlation between EBV load and EBNA-1 titers. These observations should be of value in the study of the potential relationship between hypovitaminosis-D and EBV-status in the pathophysiology of multiple sclerosis
“As EBV-status and suboptimal Vitamin-D levels are potential risk factors for MS, we wanted to test whether they acted in concert or independently. In collaboration with Birmingham’s CMV/EBV teams, we measured EBV-status and Vitamin-D levels in young, healthy medical students.

What did we find? To our surprise, the majority of students had insufficient Vitamin-D levels. Interestingly, the samples were obtained in 2007 after one of the wettest UK summers. We did not see an effect on the control of EBV-infection at these suboptimal vitamin-D levels.

There are now two potential scenarios: vitamin-D and EBV-status act independently as risk factors in MS or optimal vitamin-D levels may be needed to exert an effect on EBV-infection.”

Several studies have monitored anti-EBV responses and vitamin-D levels in MSers:

Epstein-Barr virus antibodies and vitamin D in prospective multiple sclerosis biobank samples. Salzer J, Nyström M, Hallmans G, Stenlund H, Wadell G, Sundström P. Mult Scler. 2013 Oct;19(12):1587-91. 2013 Apr 2.

Vitamin D supplementation and antibodies against the Epstein-Barr virus in multiple sclerosis patients. Disanto G, Handel AE, Damoiseaux J, Hupperts R, Giovannoni G, Smolders J, Ramagopalan SV. Mult Scler. 2013 Oct;19(12):1679-80.

Review on EBV and VitD: Vitamin D: a link between Epstein-Barr virus and multiple sclerosis development? Disanto G, Meier U, Giovannoni G, Ramagopalan SV.  Expert Rev Neurother. 2011 Sep;11(9):1221-4.

“Furthermore, given my past area of work, I am very interested in the literature on Hepatitis-C/ Hepatitis-B/HIV-infection. They are testing similar ideas on persistent virus infections and Vitamin-D at the moment to see whether vitamin-D supplementation has an effect on anti-viral immune responses, immunopathology and the response to treatment.”

Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Farnik H, Bojunga J, Berger A, Allwinn R, Waidmann O, Kronenberger B, Keppler OT, Zeuzem S, Sarrazin C, Lange CM. Hepatology. 2013 Oct;58(4):1270-6. doi: 10.1002/hep.26488. Epub 2013 Aug 7.

Vitamin D deficiency is associated with severity of liver disease in HIV/HCV coinfected patients. Guzmán-Fulgencio M, García-Álvarez M, Berenguer J, Jiménez-Sousa MA, Cosín J, Pineda-Tenor D, Carrero A, Aldámiz T, Alvarez E, López JC, Resino S. J Infect. 2013 Nov 1. S0163-4453(13)00326-5. 10.1016/j.jinf.2013.10.011. [Epub ahead of print]

“So far we conclude that rainy UK summers may impact on your health and you may want to consider vitamin-D supplementation in the UK or spending your summer holidays somewhere sunny.”

CI: Ute-Christiane Meier reports no conflict of interest

Cardiac safety of fingolmod in the real world

Fingolimod has a reasonable cardiac safety profile. in terms of the first-dose effect, in the real world. #MSBlog #MSResearch

"This study, in a large number, of MSers starting fingolimod show that the cardiac events associated with fingolimod are uncommon and relatively benign. These results should reassure MSers considering starting fingolimod and mirror our experience of the drug at the Royal London Hospital. Extra vigilance, however, is required for MSers with  pre-existing cardiac conditions or baseline cardiac findings, and those receiving beta blockers and/or calcium channel blockers. The latter drugs are typically used to treat hypertension."

Epub: Gold et al. Assessment of cardiac safety during fingolimod treatment initiation in a real-world relapsing multiple sclerosis population: a phase 3b, open-label study. J Neurol. 2013 Nov.

Objective: The aim of this study was to evaluate short-term safety and tolerability of fingolimod in a real-world population with relapsing multiple sclerosis, focusing on cardiac safety during treatment initiation. 

Methods: MSers received fingolimod 0.5 mg once daily for four months. MSers excluded from the pivotal studies with certain pre-existing cardiac conditions or baseline cardiac findings, and those receiving beta blockers and/or calcium channel blockers, were eligible. Heart rate and electrical conduction events were monitored using ambulatory electrocardiography for at least 6 h after the first dose. 

Results: Of 2,417 enrolled MSers , 2,282 (94.4 %) completed the study. Fingolimod initiation was associated with a transient, mostly asymptomatic decrease in heart rate. Bradycardia adverse events occurred in 0.6 % of MSers and were more frequent in individuals receiving beta blockers and/or calcium channel blockers (3.3 %) than in other MSer subgroups (0.5-1.4 %); most events were asymptomatic, and all MSers recovered without pharmacological intervention. In the 6 h post-dose, the incidences of Mobitz type I second-degree atrioventricular block and 2:1  atrioventricular blockwere higher in patients with pre-existing cardiac conditions or baseline cardiac findings (4.1 and 2.0 %, respectively) than in those without (0.9 and 0.3 %, respectively); at pre-dose screening, patients with pre-existing cardiac conditions or baseline cardiac findings had the same incidence of Mobitz type I second-degree atrioventricular block (4.1 %) and a slightly lower incidence of 2:1 atrioventricular block (0.7 %) than 6 h post-dose. All recorded conduction abnormalities were asymptomatic. 

Conclusion: This study adds to the evidence showing that cardiac effects during fingolimod initiation remain consistent with those known from previous, controlled studies, even if patients with pre-existing cardiac conditions or baseline cardiac findings are included.

CoI: multiple

Plasticity another road to repair in addition to Remyelination

Mori F, Kusayanagi H, Nicoletti CG, Weiss S, Marciani MG, Centonze D. Cortical plasticity predicts recovery from relapse in multiple sclerosis.Mult Scler. 2013 Nov 21. [Epub ahead of print]

BACKGROUND:Relapsing-remitting multiple sclerosis (RRMS) is characterized by the occurrence of clinical relapses, followed by remitting phases of a neurological deficit. Clinical remission after a relapse can be complete, with a return to baseline function that was present before, but is sometimes only partial or absent. Remyelination and repair of the neuronal damage do contribute to recovery, but they are usually incomplete.

OBJECTIVE: We tested the hypothesis that synaptic plasticity, namely long-term potentiation (LTP), may represent an additional substrate for compensating the clinical defect that results from the incomplete repair of neuronal damage.

METHODS:We evaluated the correlation between a measure of LTP, named paired associative stimulation (PAS), at the time of relapse and symptom recovery, in a cohort of 22 newly-diagnosed MS patients.

RESULTS: PAS-induced LTP was normal in patients with complete recovery, and reduced in patients showing incomplete or absent recovery, 12 weeks after the relapse onset. A multivariate regression model showed that PAS-induced LTP and age may contribute to predict null, partial or complete symptom recovery after a relapse.

CONCLUSION:Synaptic plasticity may contribute to symptom recovery after a relapse in MS; and PAS, measured during a relapse, may be used as a predictor of recovery.

Recovery from relapse results from loss of conduction block (inhibition of nerve transmission), remyelination to repair the myelin and so aid transmission and also plasticity, which results from the formation of new synapses (joints between nerves) and the creation of new nerve pathways. This can be seen using functional MRI where brain areas light up due to activity and following some neurological insult different areas of the brain light up completing the same tasks. So the brain rewires and makes new nerve circuits. This is a bit like the internet there are many pathways through which the information can flow and if one pathway gets blocked another pathway is used. Making new synapses helps in this process and the formation of synapses can be influenced by drug treatments. Is new synapse critical for recovery, this study suggests that is is important and that the older we get the less we make synapses, however synapse supporting drugs may be useful.

Monday, 25 November 2013

Trauma and the risk of MS

Does trauma cause MS? Did you have a head injury prior to the onset of your MS? #MSBlog #MSResearch

"This is meta-analysis, i.e. the combing of many studies on the same issue, suggests that head injury and other traumas in childhood, increases your chance of developing MS. The increased risk is relatively small  (~40%). Whether this is an association or causation needs further study. One of the issues that always raises its head with these sorts of studies is ascertainment bias; if you have a disease you are more likely to recall events that if you don't have a disease. The other issue is could early or asymptomatic MS predispose you to trauma rather than trauma to MS? It is clear that MS may have a long presymptomatic phase that lasts years. It is conceivable that presymptomatic MS may affect neural pathways that reduce your reflexes and reactions time that leads to an increased risk of MS. All this would need to be studied in more detail. This study raises more questions than it answers, but is of interest nevertheless. My big concern is the medicolegal profession will take this as evidence to laucnh a new tranche of legal cases claiming that trauma causes MS and expecting insurance companies to pay out a lot of money. The legal burden of proof - beyond reasonable doubt - is way below the burden of proof required by scientists."

"If head trauma does trigger MS how does it do it? Does it cause the release of brain proteins or antigens that trigger an autoimmune reaction? Does it open or damage the blood brain barrier allowing autoimmune cells to enter the brain and spinal cord? Does it activate the so called innate immune system in the brain and spinal cord that then triggers the development of autoimmune disease? Questions, questions and more questions."

Epub: Lunny et al. Physical trauma and risk of multiple sclerosis: A systematic review and meta-analysis of observational studies. J Neurol Sci. 2013.

BACKGROUND: We aimed to examine physical trauma as a risk factor for the subsequent diagnosis of MS.

METHODS: We searched for observational studies that evaluated the risk for developing MS after physical trauma that occurred in childhood (≤20years) or "premorbid" (>20years). We performed a meta-analysis using a random effects model.

RESULTS: We identified 1362 individual studies, of which 36 case-control studies and 4 cohort studies met the inclusion criteria for the review. In high quality case-control studies, there were statistically significant associations between those sustaining head trauma in childhood (OR=1.27; 95% CI, 1.12-1.44; p<0.001), premorbid head trauma (OR=1.40; 95% CI, 1.08-1.81; p=0.01), and other traumas during childhood (OR=2.31; 95% CI, 1.06-5.04; p=0.04) and the risk of being diagnosed with MS. In lesser quality studies, there was a statistical association between "other traumas" premorbid and spinal injury premorbid. No association was found between spinal injury during childhood, or fractures and burns at any age and the diagnosis of MS. The pooled OR of four cohort studies looking at premorbid head trauma was not statistically significant.

CONCLUSIONS: The result of the meta-analyses of high quality case-control studies suggests a statistically significant association between premorbid head trauma and the risk for developing MS. However, cohort studies did not. Future prospective studies that define trauma based on validated instruments, and include frequency of traumas per study participant, are needed.

Bee Stings in Animals

Karimi A, Ahmadi F, Parivar K, Nabiuni M, Haghighi S, Imani S, Afrouzi H.Effect of honey bee venom on lewis rats with experimental allergic encephalomyelitis, a model formultiple sclerosis.Iran J Pharm Res. 2012 Spring;11(2):671-8.

Multiple sclerosis (MS) is a progressive and autoimmune neurodegenerative disease of the central nervous system (CNS). This disease is recognized through symptoms like inflammation, demyelination and the destruction of neurological actions. Experimental allergic encephalomyelitis (EAE) is a widely accepted animal model for MS. EAE is created in animals by injecting the tissue of myelin basic protein (MBP), CNS, or myelin oligodendrocyte glycoprotein (MOG) along with the adjuvant. EAE and MS are similar diseases. Honey Bee venom (Apis mellifera) contains a variety of low and high molecular weight peptides and proteins, including melittin, apamin, adolapin, mast cell degranulating peptide and phospholipase A2. Bee venom (BV) could exert anti-inflammatory and antinociceptive effects on the inflammatory reactions. The guinea pig spinal cord homogenate (GPSCH) is with the Complete Freund's Adjuvant (CFA), consisting of 1 mg/mL Mycobacterium tuberculosis. It was used for inducing EAE in Lewis rats for creating the MS model. The haematoxylin and eosin and luxol fast blue methods were used respectively in analyses of inflammation and detection of demyelination in the central nervous system. In this study, we indicated that the treatment of EAE with Bee venom decreased the symptoms of clinical disorder, pathological changes, inflammatory cell infiltration, demyelination in the central nervous system.

Beesting therapy is another one of those alternative therapies without much evidence either way. It has been suggested that they may have anti-inflammatory properties. This study suggest that Bee sting venon may have anti-inflammatory effects in EAE. Remember if you are allergic to bee stings such an treatment could have very serious consequences

Whats a virus like particle

You asked what is a virus like particle. A virus high-jacks cell machinery to reproduce itself  and may bud of to make new infective virus particles, sometimes they can be seen as membrane blebbing.
They look like virus and sometimes can be seen blebbing on the cell surface but you may need to find the viralRNA/DNA and show infection to confirm it is a live virus
Many years ago I made a B cell line. We fused a B cell with a B cell plasmocytoma (A plasma cell tumour) to do some antigen binding assays. We called it BCTL-1 (Big Chief Team Leader 1 at the suggestion of someone in the lab...someone elses was once called FUJA..won't say why).  I was quite excited about it and please with myself by then I did some electron microscopy of the line. We saw virus like particles budding from the cell. Were they virus? I was not going to find out. Were they a health risk producing something that could infect a human? We then froze them down and they are sat in secure freezer storage at about -200 degrees centigrade. 

However I then checked many of the standard cell (tumour) lines from rodents, such as those used to make monoclonal antibodies (NS1), T cell hybridomas, macrophage lines etc, etc. These all contained virus-like particles. Maybe the virus was the cause of the cell becoming a tumour or may be a consequence of rapid division. Mice like humans harbour many endogenous retro virus is one of them important in MS

Sunday, 24 November 2013

Clinic Speak: occurance of joint contractures is common

Do you have a joint contracture? Time to check and get active. #MSBlog #MSResearch #ClinicSpeak

"When you become disabled and immobile due to limited walking or being wheelchair or bed bound, you tend not put your joints through a full range of movement. Therefore the muscles and tendons shorten around the joint and this reduces the range of motion of the joint. These process results in the development of contractures. Contractures prevent MSers regaining mobility. Contractures are also associated with a large number of other problems, for  example spasticity, pain, bladder and bowel problems, pressure sores, dependency oedema (swelling of the legs), deep vein thromboses or DVTs and sleep problems to highlight the obvious ones. Therefore it is important to try and prevent them from developing by frequent exercises that put your joints through a full range of movement and results in adequate and full stretching of the muscles and ligaments.  The best person to help with this problem is a physiotherapist. Some contractures are reversible when detected and treated early. Once a contractures becomes fixed it may need other interventions to correct it, for example botox injections to weaken the muscle, optimisation of anti-spastic medication and occasionally surgical procedures to release or lengthen the tendons. Very rarely the joints may fuse and then the contracture becomes fixed; the latter is very rare in MSers and usually occurs in people with joint disease, for example rheumatoid arthritis."

"In MSers with severe disability, who are typically bed-bound, get spasms of the muscles that cross the legs, which result in scissoring of the legs and hip contractures. These contractures make it very difficult to maintain proper hygiene below and is often the trigger for the use of more interventional treatments for example intrathecal phenol and the insertion of suprapubic catheters. Phenol works by destroying the nerves to and from the spinal cord and break the reflex arcs that drive the muscles spasms and spasticity. Phenol converts the legs from being stiff and difficult to move into being flaccid and easy to move. Intrathecal phenol can only be used when MSers have lost both their bladder and bowel function and is in general an irreversible treatment. When phenol is used in well selected MSers it can make a big difference to their nursing requirements and improve their quality of life."

"If you are worried about having contractures bring it to the attention of your nurse, neurologist, or physiotherapist so that you be advised on a necessary treatment programme to reverse them. It will make a big difference to the quality of your life in the long-run."

Epub: Hoang et al. Prevalence of joint contractures and muscle weakness in people with multiple sclerosis.Disabil Rehabil. 2013 Nov 18.

Objectives: To investigate the prevalence of joint contracture (limited passive range of joint motion) and muscle weakness in a population with multiple sclerosis (MS). A secondary aim was to establish normative data of functional tests of mobility and balance of people with MS who are still ambulant. 

Design: Cross-sectional study. 

Setting: People with MS living in metropolitan Sydney, Australia. 

Participants: 330 people with MS living in metropolitan Sydney, Australia were randomly sampled on 23 July 2009 from the MS Australia register and invited to participate. 

Main outcome measures: Passive range of motion of large joints of the limbs and muscle strength. Tests of walking and balance were also conducted. 

Results: 156 people (109 females, 47 males; mean age 54.2 years; mean time since diagnosis 14.9 years) agreed to participate and were assessed. Fifty-six per cent (56%) of participants had contracture in at least one major joint of upper or lower limb. The most common site of contracture was the ankle (43.9%). Seventy per cent (70%) of participants had muscle weakness in one or more muscle groups. As muscle weakness, joint contractures were present at early stage of MS and the prevalence was associated with the progression of the disease. 

Conclusions: These data show that in addition to muscle weakness joint contractures are highly prevalent among people with MS, especially in the ankle joint. This implicates that prevention of contracture is crucial in providing rehabilitation to people with MS. Implications for Rehabilitation Joint contractures are highly prevalent of people with MS, especially in the lower limb, even at an early stage. While many interventions such as stretching and serial casting have been implemented to reduce contractures, there is not yet strong evidence for their effectiveness.