Author: Gavin Giovannoni

Cell lysis and anti-trafficking treatments in MS

My first presentation from Paris. A talk on DMTs that target cell trafficking and cell lysis mechanisms. 


ProfG    
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What can I do about my bladder?

Prof G, I was incontinent last week on the train and was very embarrassed. Can you help me please?

screenshot (100)
Clinical problem: I am 36 years of age and I have developed urinary frequency and urgency. Apart from this, I am well and active. I was incontinent last week on the train and was very embarrassed. It also happened several weeks ago on the way home from the pub. I had been out with friends and had had several glasses of wine. I had emptied my bladder before leaving the pub, but clearly, this was not enough to prevent wetting myself. What can I do?

Bladder dysfunction is the most common symptomatic problem I have to deal with in my MS clinic. More than half of MSers have bladder problems.

The following generic advice is what I would give MSers with different sorts of bladder symptoms:

I view bladder dysfunction in MSers as an integrator of damage and an early read-out of a poor prognosis. I would, therefore, take this symptom in any of patients very seriously. I would have a frank discussion with her about her prognosis and treatment and would assess her to see if she has possibly had a relapse and has other signs to localise the lesion causing her bladder problems. Most often it is due to spinal cord lesions and you may find other signs, for example, subtle weakness in the legs.

Over the years I have observed that MSers who develop bladder dysfunction tend to do worse than MSers who don’t have bladder symptoms. Why? The bladder is a complicated organ with several neurological components that can be affected by MS and hence is more sensitive to early damage.

Why is the bladder an integrator of MS damage? The descending nerve fibres that travel from the brain to the lower spinal segments are very long and hence have a greater chance of being affected by MS lesions in their path to the main bladder centre in the lower spinal cord. The same is true for motor fibres that control movement in the lower legs. The bladder, unlike the motor fibres to the leg, is more complicated because of the need to coordinate the different muscles. Therefore any progressive MS damage is more likely to manifest with bladder dysfunction early on. This is why I now include bladder problems high up on my list of poor prognostic factors in MS.

The bladder has two muscles that need to be coordinated. The (1) detrusor muscle, or balloon, and the (2) sphincter, or valve, muscle. When the bladder is filling up the detrusor muscle has to relax to allow the bladder to expand with urine and the sphincter has to contract to keep the urine in the bladder. The opposite occurs when you pass urine; the sphincter or valve opens and the detrusor contracts to empty the bladder. Simple?

What happens if the two muscles are not coordinated? This causes the symptom of hesitancy, i.e. when you try and pass urine the sphincter won’t open and you have to wait for the bladder to open; MSers find this very frustrating. The sphincter can also close as you passing urine, which breaks up the urine stream or prevents you from emptying your bladder completely. The latter also causes dribbling. The medical term for incoordination of the bladder muscles is dyssynergia or more correctly detrusor-sphincter-dyssynergia (DSD). The drug treatment for DSD includes the so-called alpha-blockers ( prazosin, indoramin, tamsulosin, alfuzosin, doxazosin and terazosin). Other strategies include small bladder stimulators or vibrators; these are placed over the pubic area and work by blocking signals that inhibit the sphincters. The vibrators work in some MSers and may help relax the sphincter. It is also important to try and relax when passing urine; this often helps improve hesitancy. The sound of running water, for example from a tap, may trigger the relaxation of the sphincter. This can be a problem in public toilets when opening a nearby tap may not be possible or inappropriate. Some MSers find pressing on the lower abdomen helps. If all else fails regarding hesitancy intermittent self-catheterisation (ISC) may be the only option.

In MS the commonest bladder problem is spasticity, or irritability, of the detrusor muscle. The detrusor can’t relax and this prevents the bladder filling to its maximum capacity. Frequent spasms of the detrusor muscle tell the brain that it is full and you need to go to the toilet. This causes frequency; i.e. the need to go to the toilet many times during the day and night. Frequency often goes with the symptom of urgency, the need to get to the toilet as quickly as possible to prevent yourself from being incontinent. Incontinence occurs as you often lose the ability to suppress or ignore the signals from the detrusor muscle and the sphincter relaxes or opens as part of spinal cord reflex. We treat this problem with the so-called anti-cholinergic drugs, for example, oxybutynin, solifenacin or tolterodine. The older generation anticholinergics such as oxybutynin cross the blood-brain-barrier and enter the brain where they can exacerbate cognitive problems in MSers. This is why I avoid using them. The commonest side-effect of anticholinergics is dryness of the mouth and they can make constipation worse. There is also a risk that they will relax the bladder too much and precipitate urinary retention. All MSers must be warned about this problem when starting anticholinergics; I have several MSers under my care go into retention on starting anticholinergics.

There is a new class of drug that works on the so-called β₃ adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.  Mirabegron (Betmiga) is the first drug in this class and has the advantage over the other bladder drugs in that it does not have anticholinergic side effects. I am increasingly using mirabegron to prevent the unwanted anticholinergic side effects.

When urgency is a problem try some distraction techniques such as breathing exercises and mental tricks (for example, counting) to take your mind off the bladder; some MSers find this helpful. When urinary frequency is your main problem you may want to try and retrain your bladder by holding on for as long as you can each time before passing urine. The aim is to train the detrusor muscle to expand more so that it can hold on for longer when you need to go to the toilet. In my experience, these behavioural techniques rarely work for very long. As MS may be a progressive disease the bladder pathways may be affected by new MS lesions and hence get worse with time.

If you fail to respond to anticholinergics and behavioural techniques you need to have your bladder scanned to see if you have a raised residual volume. The residual volume is the amount of urine left behind after you have emptied your bladder. If the residual volume is greater than 80-100mL you may need to consider intermittent self-catheterisation or ISC. ISC serves two purposes; it increases your so-called functional residual bladder volume allowing more storage space for urine in the bladder; this reduces frequency and urgency. This is can help you if you have to take a long trip or to get through a social activity without having to pass urine. It also helps reduce nocturia or having to get up frequently at night to pass urine. You will be surprised how much better you feel if you get a good nights sleep. Reducing nocturia and improving sleep reduces daytime fatigue.

Another treatment that is becoming more common is botox of the detrusor muscle. This paralyses the muscle turning it into a flaccid bag for urine storage. Almost all MSers who have detrusor botox will have to use ISC as well. In the past, before botox was available, there were surgical techniques that could be used to denervate or remove the nerve supply to the bladder that had the same effect; these techniques are rarely used nowadays.

ISC also removes urine from the bladder. This is important if you are having recurrent bladder infections. The residual urine acts as a culture medium for bacteria and by flushing your bladder with urine you can prevent bladder infections. However, the opposite can occur. If you are don’t get the ISC technique correct you can introduce bacteria into the bladder that can then cause recurrent infections.

There is a potential link between bladder infections and disease progression. The more infections you have, in particular, severe infections, the more likely it is your MS will progress. Therefore if you have recurrent bladder infections you should try and prevent them occurring. How do you do this? By drinking lots of liquids; flushing the bladder reduces infection rates. Also alkalinising your urine by drinking cranberry juice or citric acid (citrasoda or lemonade) also helps. Increasing the frequency of ISC may also help. Finally using urinary antiseptics may help reduce infection rates. Urinary antiseptics are antibiotics that are concentrated in the urine; they are given in low concentrations which are meant to limit the impact on the rest of the body. I tend to cycle their use, every 3-4 months, to prevent the bacteria in the bladder becoming resistant. The agents I use currently are trimethoprim, cephalexin, nalidixic acid and nitrofurantoin.

If nocturia is your main problem using agents to concentrate the urine at night might help. There is a hormone called DDAVP that works on the kidney to reduce it making urine. You can take DDAVP as a nasal spray or tablets. DDAVP can only be taken once a day; if you use it continuously your kidneys will retain water and that can be very dangerous. The latter is called water intoxication; it presents as swelling of the feet and reduces the salt or sodium levels in your blood. If blood slay level become too low it can cause problems. This is why when you start using DDAVP you need to have your blood sodium levels checked about 4-6 weeks after starting therapy. I am not sure why, but some neurologists are reluctant to prescribe DDAVP. This is a shame as it is a very good drug and can make the difference between getting a good nights sleep or waking up feeling awful. You can also use DDAVP intermittently. If you use it the day, for example, when you need to go on a trip or to go out, you mustn’t use it again.

WARNING: You can only use DDAVP once a day.  The most common side effect of DDAVP is swelling of the feet; it happens in approximately a third of MSers and is more common in MSers who are less mobile.

Other advice I give to MSers is that if you are a smoker you may want to consider stopping. Stopping smoking may significantly improve your bladder symptoms, as nicotine irritates the bladder. Similarly, reducing alcohol and caffeine consumption may also help; both these agents affect the kidney and cause it to make more urine. Medically this is referred to as diuresis and these agents are mild diuretics. Try to anticipate times when urinary frequency and urgency are likely to be most inconvenient; reducing the amount that you drink beforehand may help. For example, when you go out, don’t drink much for 2-3 hours before you go out. However, do not reduce your total fluid intake to less than 2.0 litres each day. After you have finished passing urine, go back to the toilet again after a few minutes to try to pass some more urine. This is called the double micturition technique, which aims to make sure the bladder is emptied completely.

Finally, if all else fails some MSers may need to be catheterised. This can be done via the urethra or the lower abdominal wall. The latter is called a suprapubic catheter. Being permanently catheterised sounds awful but in some MSers, this drastically improves their quality of life. I have several MSers who have let bladder dysfunction control their lives; as a result, they have become socially isolated. They are typically anxious about being incontinent in public. To avoid this possibility they choose to stay at home. This is clearly unnecessary and with the strategies highlighted above. Adequate bladder control should be the norm in MS. In my experience, the biggest hurdle to achieving adequate bladder control is MSers accepting their bladder symptoms as being part of the disease and living with them.

If you have bladder problems tell your nurse or neurologist; they will be able to help you. Don’t suffer in silence.

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.

The neuroaxonal loss – the underlying element of ‘advanced MS’ – is there from the beginning. This means the neurodegenerative phase of MS is present from the beginning before pwMS become physically disabled. Do you agree?

MS is one disease and not two or three diseases. As we have said before, the division of MS into several diseases is not backed up by science. This false division of MS into several diseases has become counter-productive to the field of MS. The division of MS into multiple diseases was Pharma-led to get MS defined as an orphan disease. This helped in that it allowed interferon-beta-1b to get a licence based on the results of one pivotal phase 3 study.

Similarly, we believe the division between SPMS and PPMS is false. There are no pathological, genetic, imaging or other data that suggests these are different entities. We, therefore, propose doing trials in both populations simultaneously.

To slay the dogma that more advanced MS has reduced inflammation, or is non-inflammatory. There are clinical, imaging and pathological data that shows inflammation plays a part in advanced MS. Therefore not to target more advanced MS with an anti-inflammatory is folly.

Reserve capacity in particular systems plays an important part in how MS worsens. Neuronal systems with reserve are more likely to be able to recover function and hence show a treatment effect compared to neuronal systems in which reserve capacity is exhausted. In the latter systems, it will simply take longer to show a treatment effect; we have referred to this as therapeutic-lag. These observations are explained by MS being a length-dependent axonopath. i.e. the longer nerve fibres, (to the legs) are more likely to be affected than shorter fibres, (those to the hands and arms). This means that we will need to focus more on arm-&-hand function as a primary outcome measure in clinical trials, in particular in pwMS who have lost too much function in their lower limbs (EDSS>=6.0). 



We need to challenge the current view that once someone has lost lower limb function and is a wheelchair user that their disease is not modifiable. We have good data that DMTs can slow the worsening of upper limb function despite subjects being wheelchair-bound. We feel very strongly about this point and are very keen that future trials in advanced MS include wheelchair users. Why should we write-off people with MS who have lost leg function? What keeps pwMS independent and functioning in society is arm and hand function. We as a community have to think about that very carefully. We have rehearsed these arguments many times as part of our #ThinkHand campaign and plans to a trial in wheelchairs users (#Chariot-MS).

I think we also have to accept that we will need to use combination therapies to make a real difference to more advanced MS. I am not necessarily talking about two anti-inflammatories, but an anti-inflammatory targeting adaptive immune responses in combination with a neuroprotective or remyelination therapy. I agree there is a good argument for combining an anti-inflammatory that targets innate immune mechanisms – for example, laquinimod which targets hot microglia – with a classic anti-inflammatory against targeting adaptive immune mechanisms.

Is it time to ditch the EDSS. The whole MS community, or almost, knows that the EDSS is not fit for purpose in more advanced MS. We need to get the regulators to accept this. We also need to work on a set of outcome measures that capture the whole impact of MS on someone with MS. We are getting there with the new rendition of the MS functional composite. But in my opinion, this is not enough. We need more patient-related outcome measures in the battery, in particular, a better hand-and-arm function PROM. We are aware that there are several out there and some are in development; these need to be validated and used in clinical trials.

We need to think creatively about our trial design. I am not an expert here, but some in the community are pushing for adaptive trials, i.e. a multi-arm phase 2 trial with a seamless design allowing it to be converted into a phase 3 study. Pharma don’t like adaptive designs nor do the regulators. We need to include two phases in trials of more advanced MS. For example, the standard head-to-head phase with a robust primary outcome, say the 9-HPT, followed by an open-label extension where the study subjects remain blinded to their original treatment allocation. This will allow us to capture therapeutic lag. If we had done this we would have had licensed treatments for more advanced MS decades ago. The logic behind this trial design is explained in detail in our length-dependent axonopathy paper (see below).

We also need more sensitive biomarkers to get proof-of-concept trials done more quickly. I know I am biased, but I really think neurofilament level monitoring in the CSF and/or blood will provide us with this tool. This means we will be able to do phase 2 studies a lot quicker and more cheaply than we have done them in the past. We are in the final stages of the PROXIMUS trial and we have learnt a lot in the process. The PROXIMUS trial is an add-on neuroprotective trial in which we add oxcarbazepine, a sodium channel blocker, on top of an existing DMT in subjects with ‘early SPMS’.

We also need to push for political change. We need true incentives for the repurposing of off-patent drugs. We have discussed this on this blog before and have written a paper on the so called ‘Big Pharma Alternative’ in which we propose potential solutions.

Regulatory changes are also required. We need to get the FDA and EMA to accept wheelchair users in trials. Some of my colleagues think this is a big issue. I don’t. If we do a trial and provide compelling data that a specific drug in combination with another drug delays, or stops, worsening disability in upper limb function in pwMS in wheelchairs they would be obliged to license the combination, provided it was safe. What we need from them, however, is to accept the need for combination therapies. MS is a complex disease and hence will need a complex solution to tackle it, i.e. combination therapies. This is not rocket science and happens all the time in other disease areas, like cancer.

More detailed cost-effective models that focus on loss of upper-limb function and bulbar function (swallowing and speech) are needed. It is clear from the recent EU health economic study that costs soar as pwMS lose arm function. Are you surprised? When you lose arm function you lose your independence.

We also need to tackle ageing and its impact on worsening MS. I think the evidence that early, or premature, ageing from reduced brain, and cognitive, reserve drives worsening MS in older pwMS, is beyond doubt. What we need is some way of dissecting-out premature ageing from MS-specific mechanisms. Another issue with ageing is the emergence of comorbidities as a driver of worsening MS, in particular smoking, hypertension, hypercholesterolaemia, metabolic syndrome, diabetes and a sedentary lifestyle. I sit on many trial steering committees and we deal with this problem by simply putting an age cap on the trial population. This is the main reason why trials in advanced MS usually have a ceiling of say 55, or 60, years of age. This is ageist and we must develop better tools for dealing with this issue.

We need to manage expectations. PwMS are expecting an effective treatment to restore function or return them to normal. The latter is not going to happen. The best we can expect is to slow down the rate of worsening disability, or flat-line their disability, with anti-inflammatory and neuroprotective strategies. I say this knowing that in pathways with reserve capacity there is a possibility of improvement in function, but not enough improvement for me to falsely raise their hopes . To get substantial and meaningful improvements in disability we need new treatment strategies, possibly remyelination therapies that work, but we will almost certainly need treatments that promote recovery mechanism (axonal sprouting, synaptogenesis and plasticity) to restore function.


As you can see at Barts0MS we are passionate about tackling more advanced MS. I personally think we have thrown-out many babies (DMTs) with the bathwater. Why? We haven’t thought deeply enough about some of the issues highlighted above. We need to start a serious debate about these issues and get on with the job of protecting arm and hand function in pwMS. 

Giovannoni et al. Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses. Mult Scler Relat Disord. 2017 Feb;12:70-78.

P.S. DrK (@KlausSchmierer) is looking for a large donation to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the NIHR costs down to under £2.5M to have any chance of getting this trial funded. Thank you. 

ProfG    
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#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:

1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS

2. STRENGTH OF ASSOCIATION

3. TEMPORAL SEQUENCE

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)

5. SPECIFICITY

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE

7. BIOLOGICAL PLAUSIBILITY

8. REASONING BY ANALOGY

9. EXPERIMENTAL EVIDENCE

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.    

ProfG    
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#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

#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

#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

#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

#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