Monday, 31 October 2011

Cataract and glaucoma in MS'ers

Epub ahead of printBazelier et al. Risk of cataract and glaucoma in patients with multiple sclerosis. Mult Scler. 2011 Oct 24.

Background: The aim of the study was to evaluate whether MS is associated with risk of cataract or glaucoma (increased pressure in the eye). 

Methods: The investigators conducted a population-based cohort study utilizing the UK General Practice Research Database (1987-2009) linked to the national hospital registry of England (1997-2008). Incident MS patients (5576 cases) were identified and each was matched to six patients without MS (controls) by age, gender, and practice. 

Results: MS patients had no overall increased risk of cataract, adjusted (adj.) HR 1.15 (95% CI 0.94-1.41) or glaucoma, adj. HR 1.02 (95% CI 0.78-1.33). However the risk of cataract (adj. HR 2.45 (95% CI 1.56-3.86)) and glaucoma (adj. HR 1.70 (95% CI 1.01-2.86)) was significantly greater in patients < 50 years, particularly in men < 50 years: cataract, adj. HR 4.23 (95% CI 2.22-8.05) and glaucoma, adj. HR 2.76 (95% CI 1.28-5.93). 

Magnified view of cataract in human eye, seen on examination with a slit lamp

Conclusion: This is the first study which shows that the risk of cataract and glaucoma is elevated in MS patients younger than 50 years, particularly men.

"The results of this study are interesting and should inform clinical practice. In other words it is important for MS'ers to have regular eye checks and not assume that their visual problems are MS-related. Glaucoma and cataract are both treatable causes of visual loss. In the case of glaucoma the visual loss can be permanent."

MS presenting as a brain tumour

Kaeser et al. Tumefactive multiple sclerosis: an uncommon diagnostic challenge. J Chiropr Med. 2011 Mar;10(1):29-35. 

OBJECTIVE: A case report describes a rare presentation of MS that was initially diagnosed as a peripheral nerve lesion.

CLINICAL FEATURES: A 30-year-old woman presented with a complaint of a sudden right foot drop. MRI of the brain revealed a large mass in the left parietal lobe with additional white matter lesions. The mass and smaller lesions were consistent with a rare presentation of demyelinating disease, tumefactive* MS. 

* Tumefactive = presenting as a tumour

INTERVENTION AND OUTCOME: The patient was referred to a neurologist for further evaluation and treatment. Her short-term clinical course was punctuated by recurrent myospasms and neurologic deficits.

CONCLUSION: Tumefactive MS may mimic the clinical and MRI characteristics of glioma (brain tumour) or a cerebral abscess. 

"This case illustrates one of the atypical ways in which MS can present and why it is important for clinicians to always consider MS in the differential diagnosis. Other atypical presentations include first seizures, dementia, chronic fatigue and movement disorders."

Sunday, 30 October 2011

CSSVI News: Pro Data

Bastianello S, Romani A, Viselner G, Colli Tibaldi E, Giugni E, Altieri M, Cecconi P, Mendozzi L, Farina M, Mariani D, Galassi A, Quattrini C, Mancini M, Bresciamorra V, Lagace A, McDonald S, Bono G, Bergamaschi R. Chronic Cerebrospinal Venous Insufficiency in Multiple Sclerosis: Clinical Correlates from a Multicentre Study. BMC Neurol. 2011 Oct 26;11:132.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) has recently been reported to be associated with multiple sclerosis (MS). However, its actual prevalence, possible association with specific MS phenotypes, and potential pathophysiological role are debated.

METHOD: We analysed the clinical data of 710 MS patients attending six centres (five Italian and one Canadian). All were submitted to venous Doppler sonography and diagnosed as having or not having CCSVI according to the criteria of Zamboni et al.

RESULTS: Overall, CCSVI was diagnosed in 86% of the patients, but the frequency varied greatly between the centres. Even greater differences were found when considering singly the five diagnostic criteria proposed by Zamboni et al. Despite these differences, significant associations with clinical data were found, the most striking being age at disease onset (about five years greater in CCSVI-positive patients) and clinical severity (mean EDSS score about one point higher in CCSVI-positive patients). Patients with progressive MS were more likely to have CCSVI than those with relapsing-remitting MS.

CONCLUSION: The methods for diagnosing CCSVI need to be refined, as the between-centre differences, particularly in single criteria, were excessively high. Despite these discrepancies, the strong associations between CCSVI and MS phenotype suggest that the presence of CCSVI may favour a later development of MS in patients with a lower susceptibility to autoimmune diseases and may increase its severity.

You said
: Why are we wasting our time with this two bit theory? I come on this blog to learn about B cells, EBV, Vit D... CCSVI ruined another MS website I used to visit and I can see it happening here - the followers treat it as a religious cruscade. Let's take a decision not to give it any more time - there are plenty of other websites dedicated to CCSVI.

In the interests of balance it is important that we document positive as well as negative papers, concerning CCSVI. Furthermore, any silence on this subject matter would suggest that the venonous attacks and threats, by the crusaders, for negative posts have frightened us into submission. On face value given the data so far presented there appears to be little merit in this as a real concept.

However, we take the academic literature as an inspiration for the posts and as the CCSVIers have now got the MS Socieities investing heavily to investigate this, these posts will continue to crop up, as more an more papers appear in response to this investment. Based on what was presented at ECTRIMS these are looking likely to be negative, so perhaps a Very Expensive Damp Squib rather than a firework moment.

However, this will not distract us from posting on things that we believe are interesting. We do this as they appear in the literature, websites, financial markets or in response to your questions. I too have personally found this subject matter a bit tedious and maybe we should limit discussion to a round-up every now and again, in case something actually changes (I'll discuss this with Prof G when he returns).

Maybe I could replace it with "EAE-Cure of the Day" as this occurs generally daily/bidaily.........." of course mice don't get MS, who said they did?".

However, I am sure most of you are not interested in this either and unless they hit the media, or are earth shattering news, I think it is pointless spending the time to discuss this science fiction as so much of it becomes science fanasty that gets sucked into the black hole of scientific rubbish. What you want to know is science fact that is of relevance to you within a tangible amount of time..

As you may have noticed, we are not taking comments on these posts.......saves alot of aggrevation on both sides of the divide!

Results from the first trial of vitamin D for MS

A randomized trial of high-dose vitamin D2 in relapsing-remitting multiple sclerosis.

Stein et al, Neurology, October 25, 2011

OBJECTIVE: Higher latitude, lower ultraviolet exposure, and lower serum 25-hydroxyvitamin D (25OHD) correlate with higher multiple sclerosis (MS) prevalence, relapse rate, and mortality. We therefore evaluated the effects of high-dose vitamin D2 (D2) in MS.

METHODS: Adults with clinically active relapsing-remitting MS (RRMS) were randomized to 6 months' double-blind placebo-controlled high-dose vitamin D2, 6,000 IU capsules, dose adjusted empirically aiming for a serum 25OHD 130-175 nM. All received daily low-dose (1,000 IU) D2 to prevent deficiency. Brain MRIs were performed at baseline, 4, 5, and 6 months. Primary endpoints were the cumulative number of new gadolinium-enhancing lesions and change in the total volume of T2 lesions. Secondary endpoints were Expanded Disability Status Scale (EDSS) score and relapses.

RESULTS: Twenty-three people were randomized, of whom 19 were on established interferon or glatiramer acetate (Copaxone) treatment. Median 25OHD rose from 54 to 69 nM (low-dose D2) vs 59 to 120 nM (high-dose D2) (p = 0.002). No significant treatment differences were detected in the primary MRI endpoints. Exit EDSS, after adjustment for entry EDSS, was higher following high-dose D2 than following low-dose D2 (p = 0.05). There were 4 relapses with high-dose D2 vs none with low-dose D2 (p = 0.04).

CONCLUSION: We did not find a therapeutic advantage in RRMS for high-dose D2 over low-dose D2 supplementation. Classification of evidence: This study provides Class I evidence that high-dose vitamin D2 (targeting 25OHD 130-175 nM), compared to low-dose supplementation (1,000 IU/d), was not effective in reducing MRI lesions in patients with RRMS.

"This study is the first published randomised double blind controlled trial of vitamin D supplementation in MS. Disappointingly it did not show that taking higher doses of vitamin D can protect against MS disease activity. However, several features of this study mean that further work is still needed to test whether vitamin D is an effective treatment or not. This study was very small (20 patients- as compared to trials such as Alemtuzumab using 500- the more patients you have the more likely you are able to see whether a treatment works); both groups of patients were taking more vitamin D than the UK Government recommend per day (6000IU of vitamin D a day versus 1000IU) so the control group may have had some protection as well; the study was run for 6 months which is thought to be too short to really say whether there is a meaningful effect of treatment, and the investigators used vitamin D2 instead of the more active D3. All of this being said, the study raises the question of whether vitamin D deficiency is only involved in triggering MS and not in how the disease progresses; but we need to test this appropriately."

Saturday, 29 October 2011

Research: Antibiotics and MS

Background: A 2006 study from the United Kingdom (163 cases) found that penicillin use may decrease the risk of multiple sclerosis (MS).

Methods: To confirm this finding, the authors conducted a nationwide case-control study in Denmark, using the Danish Multiple Sclerosis Registry to identify 3,259 patients with MS onset from 1996 to 2008, and selected 10 population controls per case (n = 32,590), matched on sex and age. Through the National Prescription Database, prescriptions for antibiotics redeemed from 1995 to 2008 and before the date of first MS symptom/index date were identified.

Results: Conditional logistic regression analysis was used to compute odds ratios associating antibiotic use with MS occurrence. In total, 1,922 patients (59%) redeemed penicillin prescriptions before the index date and 2,292 (70%) redeemed any type of antibiotic prescription. Penicillin use was associated with an increased risk of MS (odds ratio = 1.21, 95% confidence interval: 1.10, 1.27). Use of any type ofantibiotic was similarly associated with an increased risk of MS (odds ratio = 1.41, 95% confidence interval: 1.29, 1.53). The odds ratios for different types of antibiotics ranged between 1.08 and 1.83.

Conclusions: Thus, this study found that penicillin use and use of other antibiotics were similarly associated with increased risk of MS, suggesting that the underlying infections may be causally associated with MS.

Following suggestions that gut flora can influence disease, Based on studies on animals that indicate that gut flora can enhance or inhibit autoimmunity . This perhaps suggests that the answer will not be black and white

Minocycline is a traditional antibiotic with profound anti-inflammatory and neuroprotective effects and good tolerance for long-term use. Rather than an adverse effect, monocycline has some encouraging results from the animal model and clinical experiments on minocycline make it an interesting candidate for MS treatment, whether used alone or combined with other drugs. TThis is being investigated.

Science News: Microbes in the Gut Trigger MS?

At ECTRIMS last week, there were a few Docs talking about digging in Pooh, looking for the Gold (Gut Flora) that teaches Us about the Trigger of MS, others were adding parasites to influence disease.

Now in a Top Science Mag, scientitists bring us the new idea (or is it?) about the role of Gut Flora (Nothing to do with Margarine, but the bacteria that live in the Gut) and the development in MS. Story hitting the News stands near you!

Active multiple sclerosis lesions show inflammatory changes suggestive of a combined attack by T and B lymphocytes against brain white matter. These pathogenic immune cells derive from progenitors that are normal, innocuous components of the healthy immune repertoire but become autoaggressive upon pathological activation. The stimuli triggering this autoimmune conversion have been commonly attributed to environmental factors, in particular microbial infection. However, using the relapsing-remitting mouse model of spontaneously developing experimental autoimmune encephalomyelitis, here we show that the commensal gut flora-in the absence of pathogenic agents-is essential in triggering immune processes, leading to a relapsing-remitting autoimmune disease driven by myelin-reactive white blood cells. We show further that recruitment and activation of autoantibody-producing B cells from the endogenous immune repertoire depends on availability of the target autoantigen and commensal microbiota. Our observations identify a sequence of events triggering organ-specific autoimmune disease and these processes may offer novel therapeutic targets".

They say "Thus, the disease is caused by changes in the immune system and not by disturbances in the functioning of the nervous system. “Multiple sclerosis research has long been preoccupied with this question of cause and effect. Our findings would suggest that the immune system is the driving force here,” says Hartmut Wekerle, Director at the Max Planck Institute in Martinsried.

"The scientists are certain that the intestinal flora can also trigger an overreaction of the immune system against the myelin layer in persons with a genetic predisposition for multiple sclerosis. Therefore, nutrition may play a central role in the disease, as diet largely determines the bacteria that colonise the intestines. “Changing eating habits could explain, for example, why the incidence of multiple sclerosis has increased in Asian countries in recent years,” explains Hartmut Wekerle.

Precisely which bacteria are involved in the emergence of multiple sclerosis remains unclear. Possible candidates are clostridiums, which can have direct contact with the intestinal wall. They are also a natural component of healthy intestinal flora but could possibly activate the T cells in persons with a genetic predisposition. The scientists would now like to analyse the entire microbial genome of patients with multiple sclerosis and thereby identify the differences in the intestinal flora of healthy people and multiple sclerosis patients.

(The Guys in Boston are already doing this.. so the race is on!)

We all know that we are what we eat, but before we become antibiotic junkies, the Scots dump the Haggis, we all start to eat ManFood (MS is increasing in Women) and South African (Has low incidence of MS, Genetics of the Brits) let's look at the story.

When you make mice, whose white blood cells are all made to react to the brain, then you have a time bomb waiting to explode and cause disease. This happens once enough white blood cells, namely T cells, are triggered to circulate around the blood stream looking for their target (prey). Once they enter the brain, they trigger the attack the brain cells. It has been known for years that the level of cleaniness of animals, which represents the number of infections/bacteria/viruses they harbour, will influence this. In some cases of autoimmunity, this is inhibitory but in the case of the type of mouse model used in the new study, the more bacteria the more rapidly the disease occurs. The gut has often been a site for problems in mice have genetically engineered immune systems.

In this new study the wheel was re-invented or perhaps refined, using new tools to track events, and the finger is now pointed firmly at gut flora as a trigger for autoimmunity. It was shown that germ-free mice do not develop spontaneous disease compared to mice with a normal gut flora. Such disease returned when the gut flora was re-colonised, where they activated the T cells (white blood cells).

It was shown many years ago that expansion and activation of T cells is the critical part in this process, which allows T cells to circulate round the blood and then enter the tissues. This enter of cells into the brain, is the important process that determines whether disease will develop of not. In normal animals this expansion and maturation of such damaging T cells has not happened. However in the genetically engineered mice they are full of such cells, waiting for a stimulus such as a bacterial protein, to trigger them into activation. This stimulus could be part of our normal gut flora. Therefore, in the scenario it is obvious that the immune system, rather than the nervous system, is the problem and may be more akin to triggering further disease episodes, where the immune system has been activated, rather than starting disease from scratch.

In this new report, they suggest that the T cells help generate myelin-acting B cells, the white blood cells that produce antibodies and that together they conspire to work in a co-ordinated fashion to trigger disease, as has been shown before in this, and other models. This new study elegantly shows this sequence of events.

However, there are other studies that demonstrate that disease in mice can develop in the complete absence of B cells, in contrast to the new report, so this pathway is not necessarily the only route to generate lesions that could occur in MS. As such there are other alternative hypothesises such as via immunity triggered by molecular mimicry, response to heat shock responses or that is secondary to a primary damaging event or that MS is not autoimmune (but response to therapy tells us at least some elements of MS are due to the immune response).

It is being suggested that MS is just an "Outside-In" Disease (Autoimmunity entering and attacking the brain) rather than the Inside-Out (Brain problem leading to development of (auto)immunity) as suggested by some people actually looking at MS, rather than animal models that we know are outside-In diseases. However, we know that elements of MS don't not respond to immunosuppression, so in my view we still need to keep an open mind about "driving forces"

Modification of immune responsiveness by our internal and external environments appears to be sensible and this study adds to the jigsaw. Spare a thought for the scientist hunting through the stools (now that's a shit job) to find the trigger, but let's find it/them before we have a new dietary regime.

Currently it appears that B cells contribute to the damage in MS by producing damaging antibodies, but perhaps more importantly they can also act a antigen presenting cells to stimulate the damaging immune response. Thus inhibition of this function would be beneficial in relapsing MS, as has been shown with ocrelizumab and rituximab, which are anti CD20 B cell depleting antibodies

However, there is also data that B cells can be bad and B cells can be good and importantly the gut flora can influence the development of regulatory B cells responses that control autoimmunity. Therefore, the situation is going to be complex, and the inhibition of their function can make autoimmunity worse as well as better.

This can happen in MS and it is clear that inhibiting every B cell target is not always beneficial in MS, so over to Prof G to describe Atacicept activity and worsening of MS from ECTRIMS News 2011.

Friday, 28 October 2011

Cortical lesions in MS

Sormani et al. Modeling the distribution of new MRI cortical lesions in multiple sclerosis longitudinal studies. PLoS One. 2011;6(10):e26712. Epub 2011 Oct 20.

OBJECTIVE: Recent studies have shown the relevance of the cerebral grey matter involvement in MS. The number of new cortical lesions (CLs), detected by specific MRI sequences, has the potential to become a new research outcome in longitudinal MS studies. 

AIM: To define the statistical model better describing the distribution of new CLs developed over 12 and 24 months in patients with RRMS.

METHODS: Four different models were tested on a group of 191 RRMS patients untreated or treated with 3 different disease modifying therapies. Sample size for clinical trials based on this new outcome measure were estimated by a bootstrap resampling technique.

RESULTS: The zero-inflated Poisson model gave the best fit for new CLs developed over 12 and 24 months both in each treatment group and in the whole RRMS patients group adjusting for treatment effect.

CONCLUSIONS: The sample size calculations based on the zero-inflated Poisson model indicate that randomized clinical trials using this new MRI marker as an outcome are feasible.

"Why is this study important? Because it focuses on an area of the disease that until recently has been hidden from view and which contributes a lot to the burden of the disease. We simply need therapies that protect the gray matter; gray matter is the part of the brain that use to think - it makes us who we are. MS disease in gray matter results in cognitive impairment and contributes to fatigue. By stopping gray matter pathology we may be able to protect MS'ers from developing cognitive impairment."

"Again progressive MS'ers seem to have been forgotten in this study. I will write to Professor Sormani to ask her if she has a data set to look at this issue in people with SP and PP MS."

CCSVI: Un-supportive Data

Doepp F, Würfel JT, Pfueller CF, Valdueza JM, Petersen D, Paul F, Schreiber SJ.
Venous drainage in multiple sclerosis: A combined MRI and ultrasound study.
Neurology. 2011 Oct 26. [Epub ahead of print]

"Our Data Contradictic the 100% prevalence of CCSVI criteria in MS"........
Another paper going with the tide! Will the Idea Drown?

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was proposed as the causal trigger for developing multiple sclerosis (MS). However, current data are contradictory and a gold standard for venous flow assessment is missing.


To compare structural magnetic resonance venography (MRV) and dynamic extracranial color-coded duplex sonography (ECCS) in a cohort of patients with MS.

METHODS:We enrolled 40 patients (44 ± 10 years). All underwent contrast-enhanced MRV for assessment of internal jugular vein (IJV) and azygos vein (AV) narrowing, graded into 3 groups: 0%-50%, 51%-80%, and >80%. ECCS analysis of blood flow direction, cross-sectional area (CSA), and blood volume flow (BVF) in both IJV and vertebral veins (VV) occurred in the supine and upright body position.

RESULTS: MRV identified 1 AV narrowing. IJV analysis yielded 12 patients for group 1 (30%), 19 patients for group 2 (48%), and 9 patients for group 3 (22%). By ECCS criteria, 4 patients (10%) presented with venous drainage abnormalities. Jugular BVF was different only between groups 1 and 3 (616 ± 133 vs 381 ± 213 mL/min, p = 0.02). No other parameters in supine position and none of the parameters in the upright body position, apart from the IJV-BVF decrease in groups 1 and 3 (479 ± 172 vs 231 ± 144 mL/min, p = 0.01), were different.

CONCLUSIONS:Our ECCS data contradict the postulated 100% prevalence of CCSVI criteria in MS. MRV seems more sensitive to detect IJV narrowing compared to ECCS. A measurable hemodynamic effect only exists in vessel narrowings >80%. Our combined data argue against a causal relationship of venous narrowing and MS, favouring the rejection of the CCSVI hypothesis.

Thursday, 27 October 2011

Biogen-Idec announces results from the 2nd BG12 phase 3 trial

Biogen-Idec have announced positive top-line results from CONFIRM, the second of two pivotal phase 3 clinical trials designed to evaluate the effectiveness of the oral compound BG-12 (dimethyl fumarate) in RRMS's. 

BG-12 met the CONFIRM study's primary endpoint by significantly reducing annualized relapse rate (ARR) by:
  • 44% for twice daily (BID) dosing (p< 0.0001) and by 51% for three time daily (TID) dosing (p< 0.0001) versus placebo at two years. The CONFIRM study's reference comparator, glatiramer acetate (GA; 20 mg subcutaneous daily injection), reduced the ARR by 29% (p< 0.02) compared with placebo at two years.
In addition to significantly reducing ARR, BG-12 met all secondary relapse and MRI endpoints for both dose regimens. Results for the BG-12 and GA treatment groups at two years compared with placebo included:
  • BG-12 reduced the number of new or newly enlarging T2-hyperintense lesions by 71% for BID (p<0.0001) and by 73 percent for TID (p<0.0001), while GA provided a 54 percent (p<0.0001) reduction.
  • BG-12 reduced new T1-hypointense lesions by 57 percent for BID (p<0.0001) and by 65 percent for TID (p<0.0001), while GA provided a 41 percent (p<0.003) reduction.
  • BG-12 reduced the proportion of patients who relapsed by 34 percent for BID (p<0.003) and by 45 percent for TID (p<0.0001), while GA provided a 29 percent (p<0.01) reduction.
  • Initial results showed that BG-12 reduced 12-week confirmed disability progression as measured by the Expanded Disability Status Scale (EDSS) by 21% for BID and 24% for TID at two years compared to placebo, and GA reduced confirmed disability progression by 7%. These results were not statistically significant, they may be attributable to the unexpectedly low rate of disease progression in the placebo group, which was approximately half of what has been seen in other clinical trials of approved and experimental multiple sclerosis (MS) therapies.
Both dose regimens of BG-12 showed favorable safety and tolerability profiles, which were similar to those seen in the first phase 3 or DEFINE study. Overall, the incidence of adverse events (AEs), serious adverse events (SAEs) including serious infections, and discontinuations due to AEs were similar across all study groups, including placebo. The incidence of hepatic and renal events was also comparable among all study groups. The most common AEs in the BG-12 groups were flushing and GI events. There were no malignancies in the BG-12 groups.

"This is very good news for people with RRMS. What is now needed is a trial of BG12 in progressive MS. Hopefully Biogen-Idec will prioritise this ASAP."

"I am surprised that glatiramer acetate (Copaxone) did so poorly in this study; it has a history of doing well in head-2-head studies."

Source: Biogen-Idec Press Release 26th Oct 2011

CoI: Multiple

Wednesday, 26 October 2011

Team G News: Prof G Talking about Injectable Drug in the Pipeline

If you want another opertunity to see & meet members of Team G.
The folks at Shift MS offer up Prof G. Talking about new injectable drugs

If you don't want to see, don't press the link

Tuesday, 25 October 2011

The Big Knit comes home to Barts and The London

Barts and The London is very pleased to exhibit “Multiple Sclerosis: the big knit” from the 7- 11th November 2011.

Multiple Sclerosis: the big knit” is a collaborative science project where knitters from around the UK created three tableaux of MS. At the start of this year 150 knitters created over 300 objects to contribute to the woolly artwork. The project was created by the British Society for Immunology for a science talk at Cheltenham Science Festival. 

Please see the invite to The Blizard exhibition and the opening event with drinks reception on Monday the 7th November. There will be talks from our team from 5.30 – 6pm on the 7th November.

People with MS, friends, family and children and members of the public with an interest in MS are all welcome to attend. 

The talks will be educational and targeted at the public.

If you can make it please RSVP to Alison Thomson who started this initiative:

ECTRIMS 2011: Barts and The London

If you are interested the following is a list of our contribution to ECTRIMS this year:

Epstein-Barr virus and MS 8
G. Giovannoni (London, UK)

Identification of Epstein-Barr Virus associated epigenetic changes and association with multiple sclerosis
S. Ramagopalan, G. Ebers, U. Meier, G. Giovannoni (Oxford, London, UK)

VSN16R a novel agent for the control of spasticity P 561
D. Baker, G. Pryce, C. Visintin, R.G. Pertwee, C. Tanner, R. Ross, A. Irving, S. Sisay, S.J. Jackson, G. Giovannoni, D.L. Selwood (London, Aberdeen, Dundee, UK)

Fingolimod (FTY720) modulates microglial activation to augment markers of remyelination P 494
S. Jackson, G. Giovannoni, D. Baker (London, UK)

Do siblings have markers of multiple sclerosis risk? P 230
R. Dobson, U.C. Meier, K. Schmierer, G. Giovannoni (London, UK)

Selective targeting of spasticity by CNS-excluded cannabinoids P 570
G. Pryce, C. Visintin, B. Lutz, G. Marsicano, G. Giovannoni, D.L. Selwood, D. Baker (London, UK; Mainz, DE; Bordeaux, FR)

Selective targeting of neuroprotection to MS lesions: sodium channel blockers in experimental autoimmune encephalomyelitis P 493
S. Al-Izki, G. Pryce, S. Amor, W. Gerritsen, J. Garthwaite, G. Giovannoni, D.L. Selwood, D. Baker (London, UK; Amsterdam, NL)

Wrist and ankle activity monitoring correlates with clinical outcome measures in subjects with multiple sclerosis P 507
M. Espasandin, T. Barber, M. Calado-Marta, A. Johnston, G. Giovannoni (London, UK)

Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial 95
R. Gold, L. Kappos, A. Bar-Or, D. Arnold, G. Giovannoni, K. Selmaj, M. Yang, K. Dawson (Bochum, DE; Basel, CH; Montreal, CA; London, UK; Lodz, PL; Cambridge, US)

Fatty acid amide hydrolase as a target for neuroprotection P 955
R.S. Graves, G. Pryce, A. Cabranes, J. Fernández-Ruiz, T. Bisogno, V. Di Marzo, B.F. Cravatt, G.J. Michael, G. Giovannoni, M.R. Elphick, D. Baker (London, UK; Madrid, ES; Naples, IT; La Jolla, US)

BG-12 effects on patient-reported outcomes in relapsing-remitting multiple sclerosis: results from the DEFINE study P 1071
L. Kappos, R. Gold, D. Arnold, A. Bar-Or, G. Giovannoni, K. Selmaj, C. Tompkins, S. Agarwal, K. Dawson (Basel, CH; Bochum, DE; Montreal, CA; London, UK; Lodz, PL; Cambridge, US)

Mitigating severe lymphopenia: post hoc analysis of data from the 96-week CLARITY study P 1000
G. Giovannoni, P. Soelberg Sørensen, H. Butzkueven, G. Comi, S. Cook, K. Rammohan, P. Rieckmann, P. Vermersch, D. Bock, J. Weiner, N. Kurukulasuriya, D. Mikol (London, UK; Copenhagen, DK; Melbourne, AU; Milan, IT; Newark, Miami, US; Bamberg, DE; Lille, FR; Rockland, US; Geneva, CH)

Relapses and lymphocyte counts before and after rescue therapy in the phase III, 96-week, double-blind, placebo-controlled CLARITY study of cladribine tablets for relapsing-remitting multiple sclerosis P 917
P. Soelberg Sørensen, G. Giovannoni, P. Rieckmann, G. Comi, S. Cook, K. Rammohan, P. Vermersch, N. Kurukulasuriya, A. Hamlett, A. Galazka (Copenhagen, DK; London, UK; Bamberg, DE; Milan, IT;

Efficacy on MRI endpoints of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial P 831
D. Arnold, R. Gold, A. Bar-Or, L. Kappos, G. Giovannoni, K. Selmaj, R. Zhang, K. Dawson (Montreal, CA; Bochum, DE; Basel, CH; London, UK; Lodz, PL; Weston, US)

Innate immune activation is associated with latent Epstein-Barr virus infection in active MS lesions P 789
J.S. Tzartos, G Khan, M. Cruz-Sadaba, A. Vossenkamper, S. Lonardi, E. Sefia, A. Meager, J. Middledorp, P. Farrell, G. Giovannoni, U.-C. Meier (Athens, GR; Al Ain, AE; Madrid, ES; London, UK; Brescia, IT; Potters Bar, UK; Amsterdam, NL)

Safety and tolerability of BG-12 in the phase 3 DEFINE trial in patients with relapsing-remitting multiple sclerosis P 994
K. Selmaj, R. Gold, L. Kappos, A. Bar-Or, D. Arnold, G. Giovannoni, M. Sweetser, M. Novas, K. Raghupathi, K. Dawson (Lodz, PL; Bochum, DE; Basel, CH; Montreal, CA; London, UK; Weston, US)

Analysing and redesigning the outpatient experience for people with multiple sclerosis P 1066
A. Thomson, M. Espasandin, T. Denholm, G. Giovannoni (London, UK)
15:30 - 17:00 Neuroprotection 2

Neuroprotection in a novel optic neuritis model P 963
K. Lidster, S. Jackson, P. Coffey, M. Baker, J. Garthwaite, D. Selwood, G. Giovannoni, D. Baker (London, UK)

A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis: primary results of the SELECT trial 149
G. Giovannoni, R. Gold, K. Selmaj, E. Havrdova, X. Montalban, E.W. Radue, D. Stefoski, R. Robinson, K. Riester, J. Elkins, G. O'Neill (London, UK; Bochum, DE; Lodz, PL; Prague, CZ; Barcelona, ES; Basel, CH; Chicago, Redwood City, Cambridge, US)

Efficacy and safety results from CARE-MS I: a phase 3 study comparing alemtuzumab and interferon-beta-1a 151
A. Coles, V. Brinar, D.L. Arnold, J. Cohen, C. Confavreaux, E.J. Fox, H.-P. Hartung, E. Havrdova, K. Selmaj, H. Weiner, G. Giovannoni, S.L. Lake, D.H. Margolin, M. Panzara, D.A.S. Compston (Cambridge, UK; Zagreb, HR; Montreal, CA; Cleveland, US; Lyon, FR; Round Rock, US; Düsseldorf, DE; Prague, CZ; Lodz, PL; Boston, US; London, UK; Cambridge, US)

High-field imaging and improved cortical visualisation 69
K. Schmierer (London, UK)

In multiple sclerosis´ protein phosphorylation competes with the free proton binding capacity in post-mortem brain tissue P 1102
K. Schmierer, D. Tozer, A. Petzold (London, UK; Amsterdam, NL)

Autoimmunity to astrocytes in multiple sclerosis and EAE P 310
S. Amor, L. Qiu, F. Puentes, B. van der Star, J. Palace, W. Gerritsen, P. van der Valk, D. Baker (Amsterdam, NL; London, UK; Oxford, UK)

Autoimmunity to axonal proteins in multiple sclerosis P 742
F. Puentes, B. van der Star, R. Huizinga, W. Gerritsen, P. van der Valk, D. Baker, S. Amor (London, UK; Amsterdam, NL)

B. van der Star, R. Huizinga, R. Jong, W. Gerritsen, F. Puentes, P. van der Valk, S. AmorP254

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis (Amsterdam, Rotterdam NL, London UK)

CCSVI: Pro-Data

Epub: Zivadinov R, Poloni GU, Marr K, Schirda CV, Magnano CR, Carl E, Bergsland N, Hojnacki D, Kennedy C, Beggs CB, Dwyer MG, Weinstock-Guttman B. Decreased brain venous vasculature visibility on susceptibility-weighted imaging venography in patients with multiple sclerosis is related to chronic cerebrospinal venous insufficiency. BMC Neurol. 2011 ;11(1):128.

"Good News for CCSVIers? ...A paper going against the tide!"

BACKGROUND: The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC).

METHODS: 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: <.3 mm, .3-.6 mm, .6-.9 mm and >.9 mm.

RESULTS: CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p<.0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter <.3mm, and increased DFV compared to HC (all p<.0001). Subjects diagnosed with CCSVI had significantly increased DFV (p<.0001), decreased overall ATVV and ATVV of veins with a diameter <.3mm (p<.003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p<.0001) on pre- and post-contrast SWI, but not in HC.

CONCLUSIONS: MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS.

Monday, 24 October 2011

ECTRIMS: Alemtuzumab phase 3 results

Coles et al. Efficacy and safety results from CARE-MS I: a phase 3 study comparing alemtuzumab and interferon-beta-1a.

Objective: Presentation of top line clinical efficacy and safety results from phase 3 pivotal study: Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I)

Background: Alemtuzumab is an anti-CD52 humanized monoclonal antibody that alters the circulating lymphocyte pool. Alemtuzumab was significantly more effective than subcutaneous interferon-beta-1a (SC IFNB-1a) in a phase 2 trial (CAMMS223) with relapsing-remitting multiple sclerosis (RRMS) patients. CARE-MS I is a phase 3 trial designed to confirm the efficacy and safety of alemtuzumab versus SC INFB-1a.

Methods: CARE-MS I is a 2-year, randomised, rater-blinded, active-comparator, global trial comparing the safety and efficacy of alemtuzumab to IFNB-1a in active, treatment-naïve RRMS patients. Patients received 2 annual short cycles (5 days and 3 days) of 12 mg/day intravenous alemtuzumab or 44 mcg SC IFNB-1a 3 x weekly for 24 months. Entry criteria included: age 18-50 years; MS symptom onset <= 5 years; baseline Expanded Disability Status Score (EDSS) <=3; 2 or more relapses in the 24 months prior to study entry; and at least 1 attack in the 12 months prior to study entry. The primary efficacy endpoints are relapse rate and time to sustained accumulation of disability (SAD). SAD is defined as an >=1 point increase in EDSS lasting >=6 months (or >=1.5 point increase if baseline EDSS <1). Blinded raters assessed EDSS quarterly, and relapses as needed. Safety was assessed continuously. The protocol included a safety education and monitoring program for early detection of identified secondary autoimmune disorders as part of a proactive risk mitigation strategy.


Alemtuzumab reduced the annualised relapse rate compared to 
IFNβ-1a by 55% (P<0.0001). 8% alemtuzumab and 11% IFNβ-1a treated subjects showed disability progression (confirmed at 6 months). This was not statistically significant (P=0.22) due to the unexpected low rate of sustained disability in IFNβ-1a treated arm. There was a significant slowing in brain atrophy on alemtuzumab vs. IFNβ-1a ; brain volume change -1.5% IFNβ-1a vs -0.8% alemtuzumab.

Headline adverse events:
No alemtuzumab treatment discontinuations occurred due to adverse events. 18% of subjects developed autoimmune thyroid disease with alemtuzumab compared to 6% on IFNβ-1a. 0.8% of subjects treated with alemtuzumab developed autoimmune thrombocytopenia (3 cases). 67% of subjects developed infections (1.9% serious) on alemtuzumab compared to 46% (1.1% serious) on IFNβ-1a. There were 2 cases of thyroid carcinoma with alemtuzumab.

Conclusions: CARE-MS confirmed alemtuzumab's ability to reduce relapses compared to IFNβ-1a. It did not slow the progression of diability compared to IFNβ-1a due to low event rate.

"Some people felt let down by these results after the hype of the phase 2 results. Not me. I still think Alemtuzumab is the most effective treatment in late stage development, but it comes with risks that for some will be worth taking. The fact that the trial did not show an impact on disability progression is not important; the subjects in this study were very early in the course of the disease."

"More worrying was the reporting of two thyroid cancers in Alemtuzumab treated subjects. It seems likely that one of the cancers pre-dated the trial as the subject had a thyroid nodule documented before entering the study. Fortunately, both were detected early and excised."

"After my experience with Cladribine and the regulatory decisions concerning the cancer risk associated with this drug I sincerely hope the regulators don't take the same view in relation to these cancers!"

CoI: Multiple

Sunday, 23 October 2011

ECTRIMS: BG12 results

Gold et al. Clinical efficacy of BG-12, an oral therapy, in relapsing-remitting multiple sclerosis: data from the phase 3 DEFINE trial.

Background: BG-12 (dimethyl fumarate) is an experimental oral treatment for relapsing-remitting multiple sclerosis (RRMS) that may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway. In a Phase 2b trial, BG-12 reduced inflammatory activity in patients with RRMS. 

Objective: To report the effects of BG-12 on clinical efficacy endpoints in the Phase 3 DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS) study. 

Methods: DEFINE was a randomised, double-blind, placebo-controlled, multicentre clinical trial that evaluated the efficacy and safety of BG-12 over 2 years in patients with RRMS. Patients aged 18-55 years with McDonald criteria diagnosis of RRMS and an Expanded Disability Status Scale (EDSS) score of 0.0-5.0 (inclusive) were randomly assigned on a 1:1:1 basis to placebo, BG-12 240 mg PO twice daily (BID), or BG-12 240 mg three times daily (TID). All subjects underwent clinical assessments at screening, baseline, and every 4 weeks for up to 2 years. The primary endpoint was proportion of patients relapsing at 2 years, with relapses confirmed by an independent neurology evaluation committee to ensure consistent and accurate reporting across sites. Secondary clinical efficacy endpoints at 2 years were annualised relapse rate (ARR) and disability progression using EDSS. Efficacy analyses were conducted on the intention-to-treat population. 

Results: A total of 1234 patients were dosed with placebo (n=408), BG-12 BID (n=410), or BG-12 TID (n=416), with similar demographic and clinical characteristics across treatment groups. All primary and secondary endpoints of the study were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo (P<0.0001) at 2 years. ARR was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID (P<0.001). The risk of confirmed 12-week disability progression was reduced by 38% with BG-12 BID (P<0.01) and by approximately 34% with BG-12 TID (P<0.05). The overall incidence of adverse and serious adverse events was similar among the placebo group and both BG-12 treatment groups. 

Conclusions: The results from this large Phase 3 study support the potential of BG-12 as an effective oral treatment for patients with RRMS that has a novel mechanism of action.

"Although this is old news these results were one of the highlights of the meeting. BG12 is based on a drug that has been used for several years in psoriasis with a good side effect profile. In other words it seems to be safer than other drugs with this level of efficacy. Another positive attribute is that BG12 may have neuroprotective effects based on its mechanism of action; this makes it a great candidate for testing in progressive MS."

CoI: Multiple

Saturday, 22 October 2011

ECTRIMS: Daclizumab results

Giovannoni et al. A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis: primary results of the SELECT trial. 

Background: Daclizumab HYP (DAC HYP) is a humanized monoclonal antibody specific for the alpha subunit (CD25) of the human IL-2 receptor. DAC HYP modulates IL-2 signaling in-vivo and causes an expansion of CD56^bright natural killer cells. 

Objective: To evaluate the safety and efficacy of DAC HYP monotherapy in patients with relapsing-remitting MS (RRMS). 

Methods: We randomly assigned 600 patients with clinically definite RRMS and at least one MS relapse in the prior 12 months or one new Gd+ lesion in the prior 6 weeks to receive either DAC HYP 150 mg or DAC HYP 300 mg or placebo as a subcutaneous injection once every 4 weeks for 52 weeks. The primary endpoint was the annualized relapse rate (ARR). 

Results: A total of 559 patients (93%) completed the treatment period. Among patients randomized to DAC HYP (150mg, 300mg) versus placebo, there was a significantly lower ARR (0.21, 0.23 vs. 0.46; p<0.001), a higher proportion of relapse free patients (81%, 80% vs. 64%; p<0.001); and a trend towards improvement in the MSIS-29 physical score (p<0.001, p=0.12 vs. placebo). There were significant reductions in the mean number of new or newly enlarging T2 lesions at 1-year (2.4, 1.7 vs. 8.1) and the mean number of new Gd+ lesions between weeks 8-24 in a monthly MRI substudy (n=309) (1.5, 1.0 vs. 4.8) in the DAC HYP 150mg and 300mg groups vs. placebo (p<0.001 for all comparisons). The risk of 3-month sustained disability progression at 1-year, a tertiary study endpoint, was reduced by 57% (p=0.02) in the DAC HYP 150mg group and by 43% (p=0.09) in the DAC HYP 300mg group. Serious adverse events, excluding MS relapses, occurred in 5% in the placebo group, 6% in the DAC HYP 150mg group, and 8% in the DAC HYP 300mg group. One DAC HYP treated patient who was recovering from a serious rash died due to a complication of a psoas abscess. Serious adverse events in DAC HYP treated patients, included an increase in serious infections (2%), serious cutaneous events (1%) and elevations in liver function tests (ALT/AST) >5x ULN (4%). 

Conclusions: Monthly, subcutaneous DAC HYP monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression. These benefits and risks warrant further evaluation.

"These results are very interesting and surprising. Firstly, DAC works in an interesting way by targeting a messenger in the immune system called IL2, it blocks in binding to its high affinity receptor. Secondly, DAC had an impact on disability in a 52 week study; this is very unusual finding in a one year study that is traditionally too short to see an impact on disability. The latter suggests DAC may be a very effective therapy in relapsing MS."

CoI: Multiple.

Friday, 21 October 2011


"Some food for thought; a selection of abstracts on CCSVI from the ECTRIMS/ACTRIMS/LACTRIMS meeting in Amsterdam."

P633: Haug et al. Intracranial venous pressure in MS is normal: ophthalmodynamometry data
Conclusions: Our data give no evidence however of an increase in intracranial venous pressure. Venous congestion in MS patients is implausible.

P631: Cavalla et al. CCSVI prevalence in a northern Italian population of MS patients and controls
Conclusions: In our population, CCSVI assessed by ECD appears to be more frequent in MS patients than in controls; however, CCSVI is found in more than one third of normal controls. These data are similar to those obtained with a similar protocol in a larger North American population. The issue of anomalous venous drainage in MS needs to be further clarified, also evaluating patients affected by other neurological diseases. The high frequency of CCSVI also in healthy controls suggests poor specificity of the current CCSVI criteria.

Conclusions: We found no evidence to suggest that MS patients have excess of CCSVI. In addition we failed to observe a typical venous flow pattern in MS patients. Until carefully designed controlled studies to investigate CCVSI have been completed, invasive and potentially dangerous endovascular procedures as therapy for MS should be discouraged.

Conclusion: Doppler sonography is a suitable method for the investigation of IJV. We have not found any hemodynamically significant stenosis. No correlation was found between Tr and VF suggesting that reflux is not an indicator of venous insufficiency. Reflux was not observed in the proximal part but was observed in the distal part, where lumen area is substantially larger and venous valves are found, suggesting that the turbulence due to lumen dilation and valve movements is the real cause of the reflux. We have not found any significant difference in hemodynamics that might support the idea of CCSVI in MS patients. Based on these results catheter-dilatation does not seem to be a rational and acceptable approach in the treatment of MS.

P531:  Bonaventura et al. Femoral venous thrombosis and pulmonary massive embolism as a rare and major complication related to endovascular treatment of jugular veins in multiple sclerosis patient. 
Conclusion: This case should advice attention on this serious side effect, with venous deep thrombosis and pulmonary embolism, because in many cases patients have interventions in another far country and they need to travel long distances quickly in the post surgery. Regardless of the efficacy of these procedures in MS, we advise that it is necessary to consider and prevent this serious adverse event. 

Conclusions: This study shows that CCSVI is definitely not the cause of MS nor is it a late secondary phenomenon of MS, as it is not associated with disability. Therefore, there are no bases for “decongestant” procedures in MS patients. We strongly recommend extreme caution in interpreting an ultrasound-based diagnosis of CCSVI as absolute evidence of a pathological process involving the brain and the spinal cord, which in our opinion requires confirmation by VGF.

P1125: Burton et al. A systematic review of the association between chronic cerebral spinal venous insufficiency (CCSVI) and multiple sclerosis.
Conclusion: A meta-analysis of 8 studies found greater odds of CCSVI in MS patients compared to HC that was statistically significant, while such a relationship between CCSVI in MS patients vs. OND patients was not significant. However, limitations including uncertainty regarding blinding and its success and the marked heterogeneity of the results do not allow definitive conclusions to be reached. These early results raise the possibility that CCSVI may not be MS-specific, and it may follow, not precede the onset of disease. Further high quality controlled studies are needed to definitively determine if CCSVI is truly associated with MS. 

P1128: Dolic et al. Risk factors for chronic cerebrospinal venous insufficiency (CCSVI) in a large cohort of volunteers. 
Conclusions: Risk factors for CCSVI differ from established risk factors for peripheral venous diseases. Vascular, infectious and inflammatory factors were associated with higher CCSVI frequency.

P1105: Chambers et al. Chronic cerebrospinal venous insufficiency is not associated with clinically isolated syndrome or mild multiple sclerosis.
Conclusions: Our findings indicate that CCSVI, as defined by the Zamboni ultrasound criteria, is not seen in CIS and mild RRMS (EDSS <= 2), and provide further evidence that CCSVI does not have a causal role in the pathogenesis for the onset of MS.

P1104: Fox et al. Ultrasound assessment of chronic cerebrospinal venous insufficiency.
Conclusion: Initial pooled results found that 30% of subjects met criteria for CCSVI. A high proportion of subjects (45%) had valvular or intraluminal abnormalities on B-mode. Surprisingly, no subjects were found to have reverted postural control. Identification of deep cerebral vein reflux depended upon the ultrasound technique: QDP found reflux in half of subjects, but traditional Doppler found reflux in none. This observation highlights the importance of ultrasound methodology in performing and interpreting deep cerebral vein assessments. Ongoing studies will help clarify the potential relationship between CCSVI and MS.

P1108: Barreto et al. Prospective case-control study of CCSVI with imaging-blinded assessment: progress report focused on neurosonography.
Conclusion: At this stage, our studies suggest that NS findings described as CCSVI are much less prevalent than previously reported and do not distinguish MS from other subjects. We will now focus on whether NS can be complemented or supplanted by MRV and/or TV.

P134: Diaconu et al. Anatomical and histological analysis of venous structures associated with chronic cerebro-spinal venous insufficiency.  
Conclusion: Post mortem examination of the IJV and AZY veins of MS patients and non-MS controls demonstrated a variety of structural abnormalities and anatomic variations. Vein wall stenosis occurred at similar frequency in MS and non-MS controls. However, the frequency of intraluminal abnormalities with possible hemodynamic consequences was higher in MS patients compared to healthy controls, although the current sample size is limited. These results suggest that MRV (which predominantly evaluates vein wall stenoses) may be less effective than ultrasound in identifying venous abnormalities in CCSVI. In addition, examining only wall circumference in CCSVI ultrasound studies may miss some intraluminal abnormalities.

Thursday, 20 October 2011

Epub ahead of printSyc et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain. 2011 Oct 17. 

In post-mortem eyes there is loss of cells in the retina in MS'ers.

Mini glossary:
  • Post-mortem = after death
  • Ganglion cells = specialised cells in the retina that integrate signals from the light sensing rods and cones
  • Retina  = layer at the back of the eye responsible for vision

The objective of this study was to ascertain whether patients with MS or the MS mimic euromyelitis optica (NMO) develop retinal neuronal layer damage following acute optic neuritis, and to characterise changes over time. 

Retinal nerve fibre layer thickness, was measured using a technique called optical coherence tomography or OCT, which has been proposed as an outcome measure in studies of neuroprotective agents in MS. 

OCT was performed serially in 20 participants during the acute phase of optic neuritis, and again 3 and 6 months later. OCT was also performed cross-sectionally in 98 MS'ers participants, 22 subjects with NMO and 72 healthy controls. 

Results: Neuronal thinning was observed in the ganglion cell layer of eyes affected by acute optic neuritis 3 and 6 months after onset (P < 0.001). Ganglion cell layer thickness was lower in both participants with MS and participants with NMO, with and without a history of optic neuritis, when compared with healthy controls (P < 0.001) and correlated with visual function. 

Of all patient groups investigated, those with NMO and a history of optic neuritis exhibited the greatest reduction in ganglion cell layer thickness. 

Results from the longitudinal study demonstrate retinal neuronal layer thinning following acute optic neuritis, corroborating the hypothesis that axonal injury may cause neuronal pathology in MS. 

Further, these data provide evidence of subclinical or asymptomatic disease activity, in both participants with MS and with NMO without a history of optic neuritis, a disease in which subclinical disease activity has not been widely appreciated. 

The subsequent thinning of the retinal ganglion cell layer following acute optic neuritis, in the absence of evidence of baseline swelling, suggests the potential utility of quantitative OCT retinal layer segmentation to monitor neuroprotective effects of novel agents in therapeutic trials.

"This study is very useful and adds to the data supporting the use of OCT as an outcome measure for screening putative neuroprotective compounds in MS."

"In fact we have a trial that is about to start to test phenytoin using OCT as the outcome measure. The trial design was developed as part of our PROMISE 2010 programme."