Monday, 16 October 2017

Barts MS at ECTRIMS 2017

In just over a week, MS researchers, Nurses and Clinicians will travel to Paris for the annual ECTRIMS conference. This is an important meeting where new research, trial results and treatment information is shared across the community. And we'd like some input from you, our readers!

Sunday, 15 October 2017

Saturday, 14 October 2017

Depletion of neutrophils after alemtuzumab

Neutrophils are your first line of defence against infection, but they express CD52 and therefore they are depleted by alemtuzumab. This will contribute to infections post treatment, but, whilst common, the level of depletion is rarely severe and long-lasting.  We have commented on this in a previous postbut you can now get a free copy of the paper.

Friday, 13 October 2017

Introducing MouseDoctor3

Hello, and thank you for reading my first post as MouseDoctor3.  Here's a brief introduction so you know my background...

Thursday, 12 October 2017

Anti-migration effect of DMF: alarms bells start ringing

This study looks at the influence of dimethyl fumarate (DMF) and its active breakdown product on control of the blood brain barrier

Wednesday, 11 October 2017

Advanced MS

Summary: Our position, as formerly stated, on more advanced (formerly know as progressive) MS. 

Is the term ‘progressive MS’ a misnomer? In general, progression means improvement, not worsening. We have made the case for using the term ‘advanced MS’, which we think captures the disability that comes with the later stages of MS.

Tuesday, 10 October 2017

Treating trigeminal neuralgia in MS

Clin Neurol Neurosurg. 2017 Sep 7;162:80-84. doi: 10.1016/j.clineuro.2017.09.004. [Epub ahead of print]

Stereotactic radio surgery and radio frequency rhizotomy for trigeminal neuralgia in multiple sclerosis: A single institution experience.

Holland MT, Teferi N, Noeller J, Swenson A, Smith M, Buatti J, Hitchon PW.



For patients with medically unresponsive trigeminal neuralgia (TN), surgical options include micro vascular decompression (MVD), radiofrequency rhizotomy (RF), and stereotactic radio surgery (SRS). Multiple sclerosis (MS) is a demyelinating condition that can be associated with TN, but is not amenable to treatment with MVD. We sought to identify the outcome differences of patients with TN in MS undergoing SRS or RFR in an attempt to identify factors that may influence outcomes. We also evaluated cost outcomes, both initially and over time, based on the index procedure. We performed a retrospective review of our experience with 17 cases.


A single institution retrospective chart review was performed. Since 1997, 17 patients with TN and MS have been treated at our institution. All patients underwent a preoperative MRI to rule out a compressive lesion. Patients either underwent SRS (n=7) or RFR (n=10) as their index procedure and were evaluated as a group based on this first procedure. Outcome measures included preoperative Expand Disability Status Score (EDSS) scores, pre- and postoperative facial pain and medication use, post-intervention facial numbness, need for subsequent procedures, and duration of follow-up. Charges for the index procedure, subsequent interventions, and total costs were tabulated and analyzed in 2017 US dollars, adjusting for inflation.

The median age of patients at first operation in each group was 58.5±10.9 and 63.5±7.5 for SRS and RFR respectively. There were no significant differences in basic demographics. Overall, 71% of these patients had an excellent or good initial pain outcome. Over time, 60% of RFR and 29% of SRS patients required additional procedures to obtain satisfactory pain relief. The patients who underwent RFR as their index procedure required a significantly higher number of procedures to achieve adequate pain relief (RFR=2.7 vs SRS=2.0 [p=0.04]). The average index procedure costs in US dollars were significantly different (SRS=53,300±5257 vs RFR=12,315±3387). The average subsequent costs (costs incurred following the initial intervention) (SRS=8320±17,842, RFR=36,002±46,767) and total costs (SRS=61,620±16,087, RFR=48,317±48,475) were not statistically significantly different.

TN in the setting of MS is highly difficult to treat medically with SRS and RFR being offered as options for these patients. Both can provide good initial pain relief. For patients who have RFR as their initial procedure, a larger number of procedures are required for relief compared to patients who initially underwent SRS. While there is a significant difference in the cost of the initial procedure, over time, with the cost of required subsequent interventions, there is no significant difference in total costs between the two groups.

Figure: Trigeminal nerve involvement in MS at root entry zone (white arrow points to an MS plaque, Mills et al. The British Journal of Radiology 2010)

Whoever said "if pain must come, may it come quickly" knew nothing about trigeminal neuralgia (TN). For those of you who have not come across TN, it is characterized by swift attacks of severe stabbing facial pain (normally affecting one side of the face), occurring anywhere between a few episodes/day to more than a couple/hour. It is not uncommon to discover sufferers have had whole sections of their teeth removed in an attempt to halt the pain! Thankfully, dentists are now more aware of this disorder and know to refer to a specialist.

It is very rare in the general population (12 per 100,000), but is 20x commoner in MS. It is thought that central demyelination/MS plaques in the region of the trigeminal nerve root entry zone leads to the condition (see figure above). In a majority of cases the treatment is conservative using carbamazepine (an anti-epileptic) in the first instance, and three-quarters of cases respond to this. Those resistant to drugs, however, are offered surgical options:

  1. Radio frequency rhizotomy (RFR) is performed by first positioning the electrode correctly (see below), followed by lesioning at 10 ͒C increments from 50-90 ͒C ~ 1min. The electrode is adjusted intermittently to ensure that the lesioning covered the painful regions.
  2. Stereotactic radiosurgery (SRS) aka gamma knife/cyberknife is where radiation doses of 70-90 Gy is directed towards the root entry zone of the trigeminal nerve to lesion that region (see below).
In MS TN is difficult to treat both pharmacologically and surgically. Holland et al. in this paper studied both their success rates (i.e. the likelihood of recurrence) and the costs of both surgically treatments in those who have failed medical treatment.

They report that at point of intervention their cases were on average on 2 medications for their TN. Both rhizotomy and radiosurgery provided good initial relief of pain symptoms. However, there was a higher rate of recurrence in those who underwent rhizotomy; requiring more procedures. Radiosurgery also has the added advantage of being minimally invasive and had a lower rate of complications. The rate of facial numbness is 60% and 66% for radiosurgery and rhizotomy, respectively. However, a disadvantage of the radiosurgery is the delayed onset of action taking anywhere between 1-6 weeks before it takes effect. Whereas, rhizotomy, initially had a higher risk of complication and discomfort, the pain relief was immediate. Radiosurgery was initially more expensive, but when you considered subsequent procedures the total cost was equivalent over time for both procedures.

Overall, these findings are very promising and both procedures should be made available to patients, particularly when taking into account the debilitating nature of trigeminal neuralgia and the side effects of medical treatments.

Sunday, 8 October 2017

#ClinicSpeak & #ResearchSpeak: how close are we to pinning down EBV as being the cause of MS?

Causation theory is essential to frame the EBV problem in MS. #ClinicSpeak #ResearchSpeak

Summary: This post sets the scene for revisiting the Bradford-Hill criteria around EBV being the cause of MS. 

Are we any closer to proving EBV is the cause of MS? I have posted on this topic many times before, but one of the Bradford-Hill criteria we use for establishing causation is 'Coherence with Biological Background and Previous Knowledge'. We now have at least nine classes of DMTs that have been shown to work in MS. Over the last few months, we have been making the case that they work via B-cells in particular memory B-cells. It may be a coincidence that the memory B cell is the main cell where EBV resides in a latent state. The challenge now is how to work this knowledge into what we know about the pathogenesis of MS and the other factors that are in the causal pathway, for example, smoking, vD and UVB sunlight exposure, female sex and the genetic pathways identified from the whole genome association studies. We have so much to do and so little time. Regardless of this work, we need to start our proposed infectious mononucleosis and EBV vaccination studies sooner than later. Causation will only be proved when we show that preventing, or treating infectious mononucleosis or preventing EBV infection reduces the incidence of MS. 

The British Statistician, Sir Austin Bradford-Hill, has formulated more general and appropriate criteria of causation; the following are the Bradford-Hill criteria:










If you are interested in reading about these criteria I suggest the following references:

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1965; 58:295-300.

Bradford-Hills Criteria

Bradford-Hill's criteria have been modified to apply them to the problem of MS. I coauthored the following paper over 10 years ago. I think it is time to update it with new knowledge that has been acquired since then. The case now is more compelling than ever. 

Giovannoni et al. Infectious causes of multiple sclerosis.Lancet Neurol. 2006 Oct;5(10):887-94.

CoI: multiple and I am convinced EBV is the cause of MS.


Brain Drain Pipes: A waste removal system or the immune activating pathway

As you know I have been moaning about the Late Breaking abstracts selection at ECTRIMS2017, yep sour grapes:-( our paper wasn't selected for a talk:-(  

We will report on how and why cladribine works 

Luckily (for them) our cladribine poster on effects on lymphocytes is not next to the company sponsored poster. Wonder what they will say?  But as my alemtuzumab poster in next to it, I'll get hear:-).

But as for the rest of the late breakers we have many where the results are announced, so if you are pressed for time you can get home early.

1. We have the Fingolimod trial in children.....It worked (CLICK HERE)

2. We have anti retro virus trial...It failed at 6 months (CLICK HERE) but then it worked at 6 months (CLICK HERE)

3. The ozanimod (Fingolimod me-too) trial.... It worked (CLICK  HERE)
4. Are neurofilaments a biomarker for trials? My guess is Yes
5. We have pathogenic antibodies to MOG, which we are not sure if this is that important to all or only a subset of MS
6. Looking forward to the MS sprint progressive trial but no announcement from Medicinova...except that enrollment was completed in Sept and results expected 2018 (CLICK). But then they say "Dr. Fox will present the top line safety, tolerability and efficacy data of ibudilast in progressive MS".
7. Then there was the last one imaging lymphatics in primates, I thought who is interested in monkey brains?

Anyway we don't have to wait for ECTRIMS and glad to see that humans are imaged and so it is clear we have drainpipes from the brain. These will take stuff into the lymph glands.

Absinta M, Ha SK, Nair G, Sati P, Luciano NJ, Palisoc M, Louveau A, Zaghloul KA, Pittaluga S, Kipnis J, Reich DS. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017 Oct 3;6. pii: e29738. doi: 10.7554/eLife.29738

Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent (Gadofosveset binds reversibly to serum albumin, increasing its molecular weight from 0.9 to 67 kDa. Under physiological conditions, albumin has a low transcapillary exchange rate into the interstitial compartment, estimated to be on the order of 5% per hour, which explains the propensity of gadofosveset to remain within blood vessels). The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents. In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.
So we know that there is lymphatic type drainage in rodents and the presence of glymphatics and not it is evident that there are drainage pathways from the brain. It means that proteins can move from the brain to the node.
If you are interested in reading the brain drainage system has been known for some time, so you can even read about the glymphatics

However in the study they could not prove whether lymphatic vessels drain immune cells, CSF, or other substances from the brain to deep cervical lymph nodes, nor could we assess any link with the glymphatic system
There is a neat video if you follow the link to the paper, so the next question is where does the spinal cord drain to? I suppose I can ask this at ECTRIMS2017 in a couple of weeks
    The lymphatics  of the human brain

T cell Killing anothr Idea

Peeters LM, Vanheusden M, Somers V, Van Wijmeersch B, Stinissen P, Broux B, Hellings N. Cytotoxic CD4+ T Cells Drive Multiple Sclerosis Progression. Front Immunol. 2017 Sep 20;8:1160.

Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (P = 0.003, R2 = 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (P = 0.005, R2 = 0.29) and with EP and EDSS after 5 years (P = 0.008, R2 = 0.42 and P = 0.003, R2 = 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.

Yesterday, we had yet another post on the memory B cells and we had some cracking questions., some of which I could only give a "I don't really know yet" answer but we have been asking the same questions....but the answers need a bit more thought and a lot more reading.

But we need to ask questions and there is a killer punch we need to kill the idea and reformulate it we find the idea is wrong.

We need to listen to alternatives and here is another one. This study suggests that MS is cause by CD4 T cell that are killing machines and that they too occur in loads of different diseases.

You can read the paper as it is open access. They are expanded CD4+CD28null T cells are found in about 20% of both pwMS as well as healthy controls without obvious differences in numbers.
They are suggested to that these cells link to progression.

I would counter this by saying:

(a)  CD4 T cell depletion does not stop progression at least quickly
(b) CD4 deletion does not work in MS
(c) Histologically  there are few CD4 T cells in lesions, there are few in the nervous tissue
(d) Oligodendrocytes do not express MHC classs II, which is a recognition element targeted by CD4 T cells 
(e) Then we ask does the data  pass the "smack you in the eye test" and are the R2 values big enough, to me it says the effects cannot be explained by the CD4 T cells.

They do address the issue of CD4 monoclonal antibody and  intimate that the level of depletion wasn't big enough. We have also suggested that it may have been on the brink of not being enough based on animal studies, but alemtuzumab knocks CD4 and CD8 cells to pieces and this does not stop advanced MS. So the argument probably falls.

Saturday, 7 October 2017

How long are memory B cell depleted?. Can we learn from other conditions


We have been making the case that memory B cells are a central player in the treatment target for all drugs in MS. 

As we saw yesterday many people don't buy this idea (see below) or perhaps don't even know about this idea because they: (a) don't read the blog; (b) Don't read papers (c) cannot assimilate knowledge  or (d) all of the above:-) or (e) I'm wrong.

Yesterday I was sad, because it confirmed what I wrote above.

So I want to put more meat on the idea

I was talking about B cells and the fact there were are more than one type of cell that make up the CD19 population.

Some didn't like my slide

You (at least one of you) said I was talking "jibberish" and it is unrelated to people with MS and it was more relevant to scientists and doctors.

I said "nonsense" because, it is important in understanding the choices that you may need to make.

Is the level pitched wrongly...the answer will be yes and perhaps no...however virtually every part of the post has been explained in the past and so look at the education posts to help you get up to speed.

If you look at alemtuzumab, the CD19 B cell population (in green below) is back to normal levels within 3 months. But alemtuzumab is still working years it can't be the B cell? Can it?
This is the view if you see CD19 B cells as a single population as is usually portrayed. 

So can it be the B cell?

Yes it can, because that repopulation is occurring because of immature and then mature (also called naive B cells) cell subsets come rushing out of the bone marrow to fill the space vacated by the lymphocytes that are killed. This masks the fact that memory B cells are being depleted long-term.

See our picture from Baker et al. 2017 (below). This is the pattern you see with rituximab, and HSCT so there is nothing special going on.

The blue (Total CD19+) is a composite response of the (green, pink and the baby blue). The antibody is given at 0 and 12 months and shows percentage change from baseline (-80 = 80% depletion)

This is the default pathway for B cell repopulation and will occur for all drugs that kill B cells. However, with HSCT and alemtuzumab, this occurs in the relative absence of effective T cell regulation by CD8 T cells and maybe CD4 T regs. The default pathway of T cells is the immediate repopulation comes from expansion of the memory cells, this is seen in humans and mice. There is nothing special going on. 

Friday, 6 October 2017

The new ideas of alemtuzumab

Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord. 2017;10:343-359

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, pre-existing disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

This is a review and we don't report of reviews but it is perhaps good that you can get an alternative view.  If you can get access to this.

However I have been spending the day getting my poster ready for ECTRIMS 2017 and so was happy to see the state of play, 

but....reading through this makes me feel that I am am living in an alternative universe:-(. 

Apparently there are "no new safety signals" emerging so best not give a plug for the ECTRIMS poster that shows alemtuzumab can stop working

P1231. C. Eggers, K. Akgün, T. Hofer, M. Egger, T. Ziemssen
Abrogation of the lymphocyte depleting action of Alemtuzumab by neutralizing antibodies - a case report. 

Apparently there is "recent evidence on the mechanism of action of alemtuzumab" so I thought great...our ideas are gaining some traction....but then the depression sets in. 

So in addition to the mechanism of inducing depletion and repopulation of T and B lymphocytes ,we get a result in a relative increase of cells with memory and regulatory phenotypes...yeah that's T cells. 

I guess memory B are not on the radar yet.

So  the 30,000 cells per millilitre going down to 2 is still an increase in the minds of my peers?. Maybe that the 2 Treg cells are now controlling the 1 surviving CD4 T cell is the relative cell increase we need.

The new mechanism is a expansion of NKCD56 high, so it works like daclizumab too?

Have a read of this and tell me what you think.

So if we do reviews, should we regurgitate a string of facts or try and tease mechanisms from the literature...I prefer the latter but maybe I am in a minority....too much speculation. 

What do you think?

Come back tomorrow. I'll have a go.

#PoliticalSpeak: should we move to a subscription model?

Are you prepared to pay for quality online MS-related content? #PoliticalSpeak

Do you think quality web content including medical education should be free? I note that the European Charcot Foundation is moving towards a subscription model. 

Is providing free content sustainable in the long term, i.e. does quality suffer? 

I think free quality content is sustainable provided it becomes opensource and the wider community engage, join-in and provide their time/content free of charge (e.g. Wikipedia). What do you think? 

Open-source content vs. Subscription-based content

CoI: multiple

Thursday, 5 October 2017

#ClinicSpeak: DOTS or no DOTS?

Should we trust our patients to take their oral cladribine tablets or should we make them come to the hospital to observe them doing it? #ClinicSpeak

Summary:  This post addresses the issue of adherence to oral cladribine tablets as prescribed. In addition, the post addresses some of the complexities of drug pricing. 

Wikipedia: DOTS (directly observed treatment, short-course), also known as TB-DOTS, is the name given to the tuberculosis control strategy recommended by the World Health Organization. According to WHO, "The most cost-effective way to stop the spread of TB in communities with a high incidence is by curing it.

The imminent UK launch of oral cladribine tablets (Mavenclad), at a list price of £2,047.24 per tablet, stimulated a debate amongst us at Barts-MS about whether, or not, we should trust our patients taking the tablets as prescribed or we should implement DOTS (directly observed treatment, short-course). One position is to trust our patients. Why? Firstly, if we allow them to collect their own prescriptions via a community pharmacy then the NHS does not have to pay VAT on the price (value-added tax). A DOTS programme will cost NHS England 20% more per tablet. Secondly, isn't our relationship with our patients based on trust? If we don't trust them to take their medication then we have failed as educators and as HCPs. The WHO DOTS programme was developed to solve the problem of poor long-term adherence to anti-TB drugs in resource-poor environments, which was selecting for drug-resistant TB strains. I, therefore, don't think we can compare the treatment of MS with the treatment of TB. 

What would happen if one of our patients drops and loses one of the tablets? I am sure Merck would be understanding and provide a replacement tablet. You need to remember that the manufacturing price of a cladribine tablet is unlikely to be very high and hence it would be relatively cheap for Merck to provide a replacement tablet or pack. The price of pharmaceuticals is really very complex and includes intangibles such as intellectual property, the cost of the preclinical R&D, the costs of the clinical development programme, regulatory, marketing, sales, life-cycle management and the whatever else Pharma does (including paying academics to sit on steering committees, participate in advisory boards, give talks, etc.). 

Oral cladribine tablets have many advantages one of which is taking tablets, albeit for only 16-20 days over a 2 year period with the potential for the treatment effect to last years. Why would we then want patients to come to the hospital so that we can directly observe them taking their tablets? One person suggested that patients may be tempted to sell their tablets on eBay to the highest bidder? Do you think the prescribing of oral cladribine tablets will result in a secondary market? I suspect not in the UK, but I may yet be proved wrong. A potential solution to the latter is to use smart tablets, i.e. each tablet is labelled with a RIF (radio frequency identification) tag that is tracked by a wearable device, linked to your phone, to make sure each tablet is taken as prescribed. Or we can simply trust our patients. What do you think? 

CoI: multiple

A solution to MERCK pills

ProfG has been contemplating how to deliver maven clad at £2 grand a pill its more precious than gold

When DrK and I attempted to do a trial in USA & Mexico of generic cladribine, which the US funders (PECORI) and UK funders (MRC) were not interested in:-(. Rather than spend a few million on their neighbours in the South, who had organised a multi centre trial and were going to put human resource into the project, they were happy to fund two trials doing the same thing for $23,000,000 :-(.

Anyway, we discussed the issue of dosing that profG is discussing and how to get the drug delivered. 

We thought that the most sensible thing would have been to take the drug to the person, rather than the person to the drug. 

If it costs VAT (sales tax) of 20% to deliver a DOT, at £400 a pill I would drive round to deliver them. So maybe we can have a new business

 or we could have the Merck Mobile going round the community as a driving advert,and as a mobile clinic to provide the pills or a motor bike paramedic. Food for thought

Wednesday, 4 October 2017

Natalizumab (Tysabri) and PML risk: an update

Progressive Multifocal Leukoencephalopathy is a life-threatening, progressive demyelinating disease affecting the white matter tracts of the brain. It is caused by reactivation of the John Cunningham (JC) virus. Although JC virus infects 80 – 90% of the world’s population, PML is exceptionally rare and almost exclusively occurs in people who are immunosuppressed, either due to a disease such as HIV/AIDS or due to medication.

In the MS world, cases of PML have been linked to the use of natalizumab, a highly-effective disease-modifying drug which prevents entry of immune cells into the central nervous system. PML was thought to occur in around 0.5% of people treated with natalizumab. Given that there is no effective treatment for PML, it is crucial that we have a method for working out who is at risk of developing PML and who can be safely treated with natalizumab.

We knew already that the three risk factors for PML in people getting natalizumab are:
1. The presence of antibodies against the JC virus (implying prior infection)
2. Previous immunosuppressive treatment
3. Duration of natalizumab therapy

To clarify how an individual’s risk of PML depends on these factors, Chang et al did some excellent digging: they collected data from participants treated with natalizumab in 4 big studies (STRATA, STRATIFY-2,  TOP, and TYGRIS). Altogether this produced a cohort of 37,249 people treated with natalizumab.

They found that 0.4% of the cohort were diagnosed with PML. Of these people, 120 had antibody results available. 119/120 (99%) of these people tested positive for anti-JCV antibodies in the 6 months preceding PML diagnosis.  Out of 13,996 people who were negative for anti-JCV antibodies, only 1 developed PML within 6 months of the test. This shows that the presence of antibodies against JC virus is extremely sensitive for detecting PML risk. I.e. if you don’t have antibodies against the JC virus, you’re incredibly unlikely to get PML.

Among people with anti-JCV antibodies, the cumulative probability of developing PML over 6 years was 2.7% if they had had prior immunosuppression, and 1.7% if they had not. The cumulative risk was relatively stable throughout the first 2 years of treatment, but increased after year 2. This confirms what we knew, i.e. that immunosuppression and a longer duration of treatment increase the risk of PML.

Lastly, they found that the amount of anti-JCV antibody correlated with the risk of developing PML in people who had not had immunosuppression. Interestingly, the amount of anti-JCV antibody did not correlate clearly with PML risk in people who had had immunosuppression (see figure). This implies that antibody titres are not a reliable guide to PML risk in people who have been previously immunosuppressed. A possible explanation for this is that immunosuppressive drugs may ‘clear up’ antibodies in the blood but not touch antibodies in the CNS.

This study is excellent – it extends and confirms what we understood about the factors that predispose people to PML. It also provides pwMS and clinicians with a way of calculating an individual’s risk. This kind of evidence is invaluable when people are deciding with their neurologist whether to pursue treatment with natalizumab or switch to another DMT.

Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).
Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort.
156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00–0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8–4·0) in patients with previous immunosuppressant use and 1·7% (1·4–2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00–0·03) in year 1 (1–12 infusions) to 0·6 (0·0–1·5) in year 6 (61–72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0–0·2) in year 1 to 3·0 (0·2–5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0–0·5) in year 1 to 10·0 (5·6–14·4) in year 6 for those with an index of more than 1·5.
Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit–risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants.

Antibodies to MOG is this the answer to autoimmunity

Khare P, Challa DK, Devanaboyina SC, Velmurugan R, Hughes S, Greenberg BM, Ober RJ, Ward ES. Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model. J Autoimmun. 2017. pii: S0896-8411(17)30155-5.
Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. 

In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in 'humanized' mice that transgenically express human FcγRs (hFcγRs). 

Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

Does this work change your mind. I have been challenging DrLove to say what causes the oligodendrocyte damage in MS. 

Her response was that it was MOG (myelin oligodendrocyte glycoprotein) specific antibodies and I have said that I don't buy this. 

There is no question that antibody to MOG can cause damage in rodents. We showed this years ago, but we weren't the first to do it. It was shown that antibody that could activate complement could kill oligodendrocytes, if it could get in the brain. 

In this study they have used a genetically engineered mouse so that the antibody can more easily interact with the macrophages and other cells that have the Fc receptor that can bind to bottom end of an antibody. They say this is more important than the complement activation and so counteract numerous other studies. 

This contradiction does not worry me as we also showed that the complement fixation element was not an absolute requirement. Also mice can have defective complement systems and even they can have defective Fc receptors like the strain of mouse we work with. They find that antibodies can have greater activity via certain Fc types. This is fine but the question is how common is this activity is this the norm or the isolated case?. 

That the antibodies come from MS, says that this damaging approach can and probably does occur, so yet more evidence that autoimmunity occurs in MS. However a MOG-reactive antibodies are associated with the development of a neuromyelitis optica-like demyelinating syndrome not MS. 

So is this the cause of MS...I'll be talking with Dr Love, but people have looked for anti-MOG responses in MS and it has not been consistently found, so I may come back and try to convince you that it is the answer.

On thing that animals tell us is that each individual reacts to a different set of antigens.

If we say memory B cells are the issue, again the problem is where does the specificity for the CNS come into the equation? 

What does an EBV infected B cell see or do to trigger relapses. 

Is it alpha B crystallin? 

We know oligodendrocytes express this, 

I dont know but I am pretty convinced it is not the blood vessels...

#NeuroSpeak & #ClinicSpeak: natalizumab and lymphomas

PML is not the only complication associated with natalizumab therapy. #NeuroSpeak #ClinicSpeak

Summary: Albeit rare, natalizumab is increasingly being associated with CNS lymphoma. This is probably due to reduced immune surveillance as a result of natalizumab blocking lymphocyte trafficking into the CNS. 

Evolution designed the immune system to fight infections and to clear pre-malignant cells from the body before they cause a problem. To do this the immune system has developed surveillance systems that depends on trafficking of cells from the blood into the tissues. If you block trafficking of cells into the CNS (central nervous system) with drugs, such as natalizumab, then you increase the chances of developing malignancies in the target organ. It is therefore no surprise that we are beginning to see an increasing number of case reports of primary CNS lymphomas in pwMS on long-term natalizumab. This potential complication was predicted more than a decade ago by several insightful people in the field. Please be aware that to the best of my knowledge this complication is rare, but acts as a reminder to pwMS on natalizumab that you need to be vigilant of new symptoms that could herald CNS complications. PML is definitely not the only severe complication associated with natalizumab therapy. 

Na et al. Central nervous system lymphoma associated with natalizumab.
J Clin Neurosci. 2014 Jun;21(6):1068-70.

Patients with primary central nervous system lymphoma (PCNSL) after treatment with natalizumab have been considered co-incidental. We report another case of PCNSL in a patient where the explosive onset suggests a causal link.

Nixon et al. Natalizumab Associated Primary Central Nervous System Lymphoma. World Neurosurg. 2017 Sep 26. pii: S1878-8750(17)31647-9.

Natalizumab, a selective adhesion molecule inhibitor binding to α-4 subunit of integrin, has emerged to be an effective immuno-modulator especially in the treatment of relapsing-remitting Multiple Sclerosis and Crohn's disease. Literature documenting the development of progressive multifocal leukoencephalopathy from its use is widely available. However, only handful of reports cites the development of a more concerning pathology, primary CNS lymphoma (PCNSL) from its administration, thereby triggering a debate on a possible causal association. Considering paucity of literature and the prognostic severity of PCNSL, we herein report its development in a young woman with Crohn's disease that was previously administered Natalizumab. Additionally, we provide a comprehensive review of literature on cases of lymphoma development following Natalizumab use to re-emphasize the drug association with PCNSL, if at all.

CoI: multiple

Tuesday, 3 October 2017

#ClinicSpeak: Will MS Self-Rx become a reality?

Will I have enough hours in my day to curate the MS Tube map? #ClinicSpeak

Summary: A tentative start to curate the #ClinicSpeak posts into an MS self-management website.

I have been promising to launch a curation tool to help pwMS self-manage (self-Rx) their MS. It has been on my ToDo list for over 2-years. It comes up each year in my appraisal and gets moved to next year's ToDo list. My next appraisal is in a few week's time.

The idea is to curate all the #ClinicSpeak posts from the blog onto an easy to navigate website that can be read as you would a book and to hyperlink it to the MS Tube map with each stop on the line being linked to a particular web page or online resource. If I start now and do 2 or 3 links per day it will be completed within a few months (or years). Before proceeding can you please let me know your thoughts on this initiative? It is a very big project and I don't want to spend months doing it unless it will be used. As the map builds the stops will turn blue indicating that the stop is now linked to a completed web page.

CoI: multiple

Why CSF is still relevant in MS

Int J Mol Sci. 2017 Sep 27;18(10). pii: E2061. doi: 10.3390/ijms18102061.

Clinically Isolated Syndrome According to McDonald 2010: Intrathecal IgG Synthesis Still Predictive for Conversion to Multiple Sclerosis.

Schwenkenbecher P, Sarikidi A, Bönig L, Wurster U, Bronzlik P, Sühs KW, Pul R, Stangel M, Skripuletz T.


While the revised McDonald criteria of 2010 allow for the diagnosis of multiple sclerosis (MS) in an earlier stage, there is still a need to identify the risk factors for conversion to MS in patients with clinically isolated syndrome (CIS). Since the latest McDonald criteria were established, the prognostic role of cerebrospinal fluid (CSF) and visual evoked potentials (VEP) in CIS patients is still poorly defined. We conducted a monocentric investigation including patients with CIS in the time from 2010 to 2015. Follow-ups of 120 patients revealed that 42% converted to MS. CIS patients with positive oligoclonal bands (OCB) were more than twice as likely to convert to MS as OCB negative patients (hazard ratio = 2.6). The probability to develop MS was even higher when a quantitative intrathecal IgG synthesis was detected (hazard ratio = 3.8). In patients with OCB, VEP did not add further information concerning the conversion rate to MS. In patients with optic neuritis and negative OCB, a significantly higher rate converted to MS when VEP were delayed. In conclusion, the detection of an intrathecal IgG synthesis increases the conversion probability to MS. Pathological VEP can help to predict the conversion rate to MS in patients with optic neuritis without an intrathecal IgG synthesis.

I've often asked myself the question if Ian McDonald (of the McDonald criteria) hadn't been who he was (undoubtedly a leader in the field of MS) or an MRI aficionado, where would the diagnostic criteria for MS be now? This is not in any way a criticism of a great mind and visionary - I met Ian McDonald in Queen Square during my PhD, and he had an aura that simply shimmered.

Prominent leaders inspire great change; often for the betterment of society as a whole, but how many of these decisions are directly or indirectly based on intrinsic satisfaction? 

One of the earlier derivations of the MS diagnostic criteria was the Poser criteria (see above), introduced in 1983 and had 94% sensitivity for MS versus post-mortem analysis. The criteria took into consideration the oligoclonal band (OCB) test and other paraclinical measures, which were subsequently dropped in the McDonald 2010 criteria. This decision to move forward with MRI as the sole deciding factor in MS diagnosis also has had some unforeseen knock on effects on MS research; for instance, research on MS histology and the CSF largely stagnated, as a result.

"Even in the presence of many lesions (> 10 or > 8), magnetic resonance imaging could not accurately rule multiple sclerosis in (likelihood ratio of a positive test result 3.0 and 2.0, respectively)" - Whiting P

Fast-forward more than a decade, and researchers such as Schwenkenbecher are re-evaluating this stance. They found that in those presenting with the initial demyelinating event (CIS), OCB and VEP both contributed separately to increasing the likelihood of recurrent demyelinating events. The usefulness of OCB test is demonstrated pictographically below. Conversion to MS was higher in those who were OCB+ (55%) than those who were OCB- (21%), and OCB+ individuals were twice as likely to convert to MS. Similarly, IgG synthesis (i.e. presence of antibodies) in the CSF was found in 66% of those who went on to develop MS. Now, if you look at the presence of immune cell activity in the CSF, it was present in 59% who later developed MS. Moreover, if you combined both baseline MRI and OCB findings together the sensitivity of the pick up for the future development of  MS increased to 65%. When it comes to abnormal findings on VEP following optic neuritis, in the absence of OCB positivity there was still an additional predictive value of VEP as far as conversion to MS at a future date was concerned.

We therefore stand a decade on, expectantly for those who develop the MS diagnostic criteria to take note of this and similar findings. In reality, I'm yet to see this happen. In the US, lumbar punctures are hardly preformed and yet we face a new era of B cell therapies - ocrelizumab, in particular, selected cases based on OCB positivity. The irony of this is that those who designed the study understood the value of having a positive OCB result.

Monday, 2 October 2017

#ClinicSpeak: Does PPI increase social capital?

The impact of reducing social isolation cannot be under-estimated. It may prevent the need for assisted suicide. #ClinicSpeak

My wife was travelling back from a conference in Bath yesterday and she listened to the following programme about a man with PPMS who had made a decision to end his life at a clinic in Switzerland, I assume Dignitas. However, a fellow MSer decided to befriend him and try and help. As a result of her intervention, Colin went from being socially isolated to having a friend and being welcomed into her family. In short, he had someone who cared about him. As a result of their friendship, he has postponed suicide as an option to dealing with his life with primary progressive MS. 

This is social capital at work. If you increase your social capital, i.e your network of friends and family, then your life becomes worthwhile. 

It has recently come to my attention that our patients with MS who engage with our patient and public involvement initiatives (PPI) seem to be doing much better than those who don't. Engagers are better informed, have improved quality of life and seem to have a renewed purpose. They get more out of meeting other people with MS and sharing experiences than they do out of the actual PPI activity. This could all be an association, i.e. the kind of pwMS who engage with PPI projects are self-selecting and will do better than those who don't engage. 

I hypothesise that it is causal, i.e. PPI is acting as a catalyst and is increasing their social capital and hence their outcomes. I am not sure if anyone has studied or documented this observation, but it would be great to have the evidence at hand. 

BBC RADIO 4. Hardeep's Sunday Lunch, Series 6. Sunday 1st October 2017 - 13:30.

In the first programme of this series, Hardeep is in his native Scotland to cook lunch for Inverness based friends Colin Campbell and Rona Tynan. Colin has lived with primary progressive multiple sclerosis since his 30s and at the age of 56 made the decision to end his life at a Swiss Clinic rather than face an unbearable, lonely decline. Hearing his plight, fellow MS patient Rona Tynan felt compelled to get in touch with him. The former London Met police officer has lived with MS for 12 years and she felt distressed that Colin wanted to end his life, especially when he was more able than her. In June this year, when Hardeep turned up at Rona's door to make the pair of them a haggis curry, Colin still had an appointment for the Swiss Clinic in his diary.

Producer: Helen Lee.

#GuestSpeak: reflections on the MS Society walk

Can the MS Society better communicate the plight of people with more advanced MS? #GuestSpeak

Some of you will have read Patrick's older blog posts already. The following is his third post in a series about empowering people with more advanced MS to enable them to raise money for the MS Society.

Previous posts in this series: 

  1. Taking the MS Society to task - 24-July-17
  2. Taking the MS Society to task (2) - 13-Sept-17

MS Society. Together we walk

On Sunday, 24 September I went to Battersea Park in London to take part in the MS society walk. I left the house at an 8:45, caught the train to Euston and arrived at the start just after 11. I had hoped to be there earlier. Getting to Battersea Park from Euston station by public transport is not easy.

It was a lovely sunny day The MS society walk started at the bandstand in Battersea Park. Maybe I'm not very good at finding things, I had to ask several people how to get there. By the time I arrived everyone else had started their walk. There was a Zumba session at the beginning which I missed and might have made the day more exciting. I only had myself to blame.

I had never been to Battersea Park before. It was full of people and their children enjoying the sunshine and fresh air. There were people running, walking or cycling on tricycles and bicycles. Many people were wearing smart and possibly expensive exercise outfits. I felt stunningly underdressed but I was on my mobility scooter.

By the time I arrived everyone had set off on their walk. Nonetheless, I was issued with a bright orange MS society T-shirt which I put on, given some water, emergency rations and a map for the 6K walk.

When I reached the end of the walk back at the bandstand I must admit I felt slightly depressed. I saw no signs of the 'fantastic post-event celebration in Battersea Park'. There was a steel band playing when I arrived but no party atmosphere.

Over 600 people took part that day. I couldn't help but feel that the wrong message was being given to the public. The message on the T-shirt said 'let's stop MS together'. I did not see any interaction between the MS society and the participants with the general public. I saw people finish the walk and leave the park on foot.

The public must assume everyone with MS can walk and does not suffer any physical disability. I asked one of the volunteers at an entrance to Battersea Park how many mobility scooters had they seen that day. They told me they had seen about five.

MS sufferers, their family and friends know how crippling this disease can be. It took me 46 minutes to walk 1 km at the beginning of September. The public at the Battersea Park did not see the real world of MS. I suspect many of the walkers were friends or family of people with MS who were unable to participate.

Why didn't the society arrange walks of 500 m or 1 km for people like me who are unable to walk and have to use a Rollator? It's not difficult at Battersea Park, plenty of smooth flat road to walk on. The general public would then see the real world of MS.

I think The MS society should consider arranging their next walk using the facilities provided by Parallel London in the Olympic Park. There are distances from 100 m to 10 K. I'm sure they could have their own tent there. It is completely accessible with good car parking and excellent public transport links. Westfield shopping centre is only a stone's throw away with shops and plenty of places to eat.

I am Patrick Burke, I was diagnosed with RRMS in 1995 but I believe the symptoms started in 1972.The disease turned into SPMS in about 1999/2000. I took medical retirement in 2012 and set up the website Aid4Disabled in the same year. The website is the story of my MS since retirement and it also identifies a wide range of objects that are readily available and can improve quality of life. I am also a member of the Barts MS Advisory Group.

CoI: None