Category: Archive

Are you about to have a lumbar puncture? If yes, what needle is your neurology team going to use to perform the lumbar puncture? If you want a simple guide to LPs please visit our LP web app.

One of the biggest successes we have had at Barts-MS is the derisking of lumbar punctures. This was driven by our PROXIMUS trial and subsequently informed our clinical practice. LPs are also becoming more important as CSF analysis is now center-stage with the new rendition of the McDonald diagnostic criteria. The presence of oligoclonal immunoglobulin bands, or OCBs, in the spinal fluid now confirm dissemination in time. So if you are having a lumbar puncture for diagnostic, or monitoring, purposes please ask your neurologist to make sure they use an atraumatic or non-cutting needle. This reduces the risk of post-LP headaches by an order of magnitude and if you do get a headache they tend to be mild and self-limiting.


What do we mean by monitoring LP? We are increasingly doing LPs to assess spinal fluid neurofilament levels. Neurofilaments are released in response to axonal and neuronal damage. If you have a raised neurofilament levels it means there is ongoing damage and something should be done about it. Knowing your spinal fluid neurofilament levels helps decision making about treatment initiation and switching.  It adds more information about your MS and prognosis and simply helps us get a better picture of your disease. 


I am confident that within a year, or two, almost all MSologists will be using spinal fluid and possibly blood neurofilament levels as part of their clinical decision making. This has been a long time coming. I have been working on neurofilaments for over 20 years. Who said research translates quickly into clinical practice? 

ProfG    
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One of our readers wants to make everyone aware of ‘An Instinct for Kindness‘, which was broadcast on BBC Radio 4.

….. This is a heartbreaking, but essential radio drama, about the bravery of suffering from MS and the true story of a woman who makes the decision to go to Dignitas in Switzerland to end her life. It is a tough listen, but you’ll be grateful you heard it. It is essential to hear this story for both sufferers and physicians working in MS…..

I have several patients who despite being JCV+ve insist on staying on natalizumab despite alternative treatment options? In fact, I have some patients who after switching to another DMT have opted to go back onto natalizumab. The reason given for the latter decision relates to the return of MS fatigue, or brain fog, after switching from natalizumab. Natalizumab is quite remarkable in this regard and is the only DMT in which an n=1 trial is sufficient to know that the therapy works. Patients come back and literally say to you ‘I feel well, my fatigue has gone and my thinking is clear’. This is why anything that decreases the risk of PML for patients on natalizumab is a good thing.

At present we have JC virus testing (negative and positive), level of JCV antibodies (antibody index), a rising antibody index, previous exposure to immunosuppression, and treatment duration to help guide us with regard to the PML risk assessment. We also have frequent MRI monitoring (3-4 monthly) to detect PML early and plasma exchange to remove natalizumab as a backup option if one of our patients develops PML. This is why it is so exciting to hear that extended interval dosing (EID) may be another option at hand to reduce the risk of PML.

The theory behind EID is that some cells are less sensitive to the effects of natalizumab and that if you delay the next natalizumab infusion by 1 or 2 weeks the saturation of their surface receptors drops below a threshold and allows these cells to traffic into the central nervous system. If these less natalizumab-sensitive cells are the antiviral CD8+ T-cells and/or the natural-killer cells that fight viruses then this could allow immune surveillance of the CNS to occur that will prevent PML from occurring. If you get the EID right the saturation of the immune cells causing MS, possibly the memory B cells, is sufficient not to allow MS to reactivate. It is clear that not all cells are made equal when it comes to the effect of natalizumab. Importantly, there several other adhesion molecules on cells that impact on adhesion (stickiness) of immune cells to the blood vessels in the CNS. It could also be a delicate balance between the availability of different accessory adhesion molecules that makes the difference.

These principles have been adopted by some neurologists in the USA and the data that is emerging from their centres suggests they are correct, i.e. despite being JCV+ve pwMS on natalizumab on EID have a much lower risk of developing PML.

When Biogen, who market natalizumab, saw these results that decided to interrogate their big databases on the use of natalizumab in the USA. They are fortunate to have the so-called TOUCH programme that is a mandatory database of all pwMS on natalizumab in the USA. The TOUCH database allowed the statisticians to find people who are on EID and to compare them to standard interval dosing (SID) for PML risk. Because the TOUCH programme is real-life data and is not a clinical trial database the periods of EID are variable. To deal with this the statisticians defined three different types of EID with increasing stringency. The remarkable finding that EID was found to reduce the risk of PML compared to SID and in the most stringently defined cohort of EID there were no cases, i.e. zero cases, of PML. These data are so important to pwMS on natalizumab and the MS community that I have asked Lana Zhovtis Ryerson, the senior author of the poster and presentation at ACTRIMS to do a guest post on this very important topic. Good news she has accepted.

We at Barts-MS have acted on this already and have offered EID to a few of our patients at risk of PML on natalizumab. The question that needs to be answered is whether or not EID will be associated with some loss of efficacy of natalizumab. However, it may be possible to walk a tightrope and get the dosing just right to prevent MS and to keep the MS shredder at bay. We as an MS community will now have to do trials to find the sweet spot for EID. This may not be simple in that we may have to dose each patient differently to get the right level of VLA-4 saturation to treat MS, and intermittent VLA-4 desaturation to allow selective anti-viral cell trafficking to prevent PML. I predict that personalised dosing will come to pwMS on natalizumab; this will be based on body size and intermittent analysis of VLA-expression levels on cells to optimise the exact dose and duration between infusions.

I am personally thrilled by these results, Why? Anything that derisks PML for pwMS on natalizumab is a good thing and it increases the chances of us getting our natalizumab #BrainAttack trial off the ground (Biogen employees, I hope you are reading this post) and it also breathes new life into natalizumab possibly for people with more advanced MS. The latter is important because natalizumab is one of the DMTs that is effective in more advanced MS, particularly on slowing down or preventing worsening of hand and arm function. If Biogen were brave they would consider doing some of their EID saturation and mechanistic studies in SPMS as part of an ASCEND II+ trial; the + refers to extending the cohort into wheelchair users. If Roche is prepared to test ocrelizumab in PPMSers who are in wheelchairs, why wouldn’t you test natalizumab in SPMSers in wheelchairs? The unmet need in SPMS in terms of numbers is much larger than the PPMS population; the business case is a no-brainer (it writes itself).

ProfG    
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My speech from our #ThinkHand Awareness event on Thursday night. 

We are hosting our #ThinkHand Awareness event tonight. The good news is that Shift.ms will be there to help promote the campaign. The following are some YouTube clips, from their reporters, explaining the campaign and how you can help. 

Thank you Shift.ms for helping and spreading hope for the million-plus people who have MS and are using a wheelchair.

What is the #ThinkHand campaign?

What treatments are available to improve upper limb function?

We are hosting our #ThinkHand awareness event tomorrow night. We were hoping to get Theresa May to attend and endorse the event. At least she responded. JK Rowling didn’t even acknowledge our invitation. Very poor form? 

We, Barts-MS, and the NHS needs your help to try and prevent Listeriosis after alemtuzumab treatment. We are raising money to produce a Listeriosis Prevention Pack. 

Barts-MS Listeria Prevention Pack Prototype

Barts MS Listeriosis Prevention Pack

We need to raise £7,000 which will be used to manufacture a large number of listeriosis prevention packs. The packs contain a food choice and hygiene manual, food stickers, fridge magnet, wallet card and thermometer. This pack, which has been designed by the Barts-MS advisory group, will engage both people with MS and healthcare professionals to take a pro-active approach to listeria prevention.

Why a listeria pack?

Currently, all we have is a single advice sheet with only basic information. We hope that we can fully prevent any unnecessary infections and enable patients, their family and friends to dramatically reduce the risk of infection.

The Barts MS team have developed the information in the pack with a cross-disciplinary team involving a listeriosis expert, people with MS, designers and healthcare professionals who will deliver it.

Why do we still need a pack? 


The reported incidence of Listeriosis post-alemtuzumab is reported as being 0.25%. In other words, 1 person in every 400 people treated with alemtuzumab gets Listeriosis. We are aware of at least one person who died as a result of this complication. 


What are we doing about it?


One solution is to provide prophylactic antibiotics. We use a drug called cotrimoxazole, a broad-spectrum antibiotic. The problem with this drug is that some people can’t  take it because they are allergic to the drug and others refuse because they are really worried about the effects of broad-spectrum antibiotics have on their microbiome. The microbiome refers to the trillions of bacteria that live in and on our bodies. 


An excellent, and currently best-selling, book ‘The Diet Myth: The Real Science Behind What We Eat‘, by Professor Tim Spector, details the impact of broad-spectrum antibiotics on our health. As a result of this book, I have had two patients turn down the option of Listeria antibiotic prophylaxis as part of our Alemtuzumab treatment protocol. One said: ‘No thank you; I don’t want my microbiome bazooka-ed’. I seem to recall this term being used in the book. We, therefore, have to also rely on diet to prevent Listeriosis a potentially life-threatening complication of alemtuzumab treatment. 

A few weeks ago I was invited to give a lecture at the annual Swiss MS Society meeting on ‘The Charcot Project’ and the rationale behind using anti-viral drugs to treat MS.

As promised my slides from the meeting; they should be self-explanatory:

ProfG    
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The following update on PML risk on fingolimod was released to us by Novartis. 

ProfG    
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