Symptoms and treatments – Page 4 – Prof G's MS Blog Archive

Social prescribing survey

I have been taken to task and chastised for neglecting the blog and my patients. I realise that the blog is part of our #ThinkSocial campaign. To help understand the need for social prescribing I would appreciate it if you could please complete the following survey.

Thank you.

Social Medicine and Social Prescribing

We are launching a new campaign called #ThinkSocial. Why?

About a year ago Barts-MS was criticised for pandering to the informed rich. More than half the patients we treat are out-of-area and when it comes to our alemtuzumab-treated patients more than two-thirds are out-of-area; i.e. in an ideal world they should be treated and managed by their local team. The problem we have is that informed patients seek out and find centres who offer them highly-effective treatments.

The implications of this stinging criticism are that we are neglecting the patients on our own patch to look after these other patients. In response to this, we did an audit and showed that our patients (Tower Hamlets, Hackney and Newham) are as likely to be on high-efficacy second-line therapies as patients from other boroughs. Our patients are not being disadvantaged. At about the same time as this criticism, I became aware of the massive variance in the NHS when it comes to DMT prescribing and access to MS services, which prompted us to hold our Variance meeting last month.

In addition to this Barts-MS has been very proactive in promoting their off-label essential DMT list to address under treated MS in resource-poor environments. This has subsequently led to the MS International Federation (MSIF) taking up the challenge and leading on an application to the WHO to get a few highly selected DMTs on the Essential Medicines List (EML).

Independent of this I noticed that patients engaging with our PPI (patient-public involvement) programme seemed to do better than patients who didn’t engage. I suspect this is because PPI increases social capital, i.e. support networks, that helps people with MS. Social capital is well studied in other disease areas, but not MS. As a result of this, we have started to explore social capital as a treatment for MS and are actively studying it. The concept of social prescribing to address the social determinants of health is not new. However, it seems to be gaining traction as a mainstream topic.

On my flight back from MENACTRIMS in Dubai, I was catching up on some of my reading and read the following two articles that are of the moment. You know that when both the NEJM and the BMJ simultaneously review and discuss social medicine something is afoot.

Scott D. Stonington et al. Case Studies in Social Medicine — Attending to Structural Forces in Clinical Practice. N Engl J Med 2018; 379:1958-1961.

Excerpt: …. In this issue, the Journal launches Case Studies in Social Medicine, a series of Perspective articles, to highlight the importance of social concepts and social context in clinical medicine. The series will use discussions of real clinical cases to translate these tools into terms that can readily be used in medical education, clinical practice, and health system planning….

Ann Robison. Social prescribing: coffee mornings, singing groups, and dance lessons on the NHS. BMJ 2018;363:k4857

Excerpt: ….. “Dance lessons for the lonely on NHS,” led the Daily Mail in October. “GPs should prescribe hobbies like ballroom dancing, gardening and art classes to millions of people because it is often better than drugs,” said the Telegraph. This “social prescribing” is being touted widely as a panacea, including for loneliness, obesity, depression, and osteoarthritis. The health and social care secretary, Matt Hancock, is a fan: he wants social prescribing to relieve pressure on the NHS and improve patients’ outcomes…..

I have little doubt that social prescribing will make a massive difference to the way we manage MS. MS not only shreds the brain it shreds social networks. PwMS are frequently depressed, combine this with unemployment, divorce, poverty and reduced benefits and social isolation is not far away for a lot of pwMS. This is why we need to think differently about the holistic management of MS. The difficulty we have as healthcare professionals is to tackle this problem sensitively and with compassion. It is vital that we are not patronising when taking a social history and addressing social problems. A lot of pwMS think this not part of the neurology teams remit.

If you have any ideas on how about social prescribing in the MS space we would be interested to hear about them. Maybe you have examples of things that are working already.

Some of you may recall our readers’ response to the post on the BBC Radio 4 dramatisation of ‘An Instinct for Kindness’. Allyson the main character of the play is an example of someone who may have benefited from social prescribing. Do you agree?

Guest post: digital services for MSers

As we all are aware, there is an increasing number of organisations developing and providing digital services to help make life easier for people with MS.

Salford Royal has partnered with Shift.ms and Clever Together, a Healthcare Advisory Group, to understand the value of digital services from the viewpoint of people with MS.

Clever Together are specialists in involving people in the process. Using Clever Together’s online workshop software, the plan is to host a discussion for two weeks from Monday 12th November to understand the value of digital services from the viewpoint of MSers.

The insight is expected to broadly focus on exploring the following ‘exam questions’:

What is the state of the art when it comes to digital support for MS patients, as determined by them?
How do people with MS currently use digital to manage their MS?
How would people with MS like to use digital support in the future?
What are the barriers / potential enablers?
What value do people with MS place on information received from different sources? (e.g. from healthcare providers, charities and the experience of other people with MS)
In what format and through what channels do people with MS prefer to receive information? (e.g. written, printed, video, audio)

We note that these are not necessarily the questions that we will ask directly, but rather the questions to drive the development of the engagement within the online workshop and its subsequent analyses.

Please join the discussion via the following URL: https://shiftms.clevertogether.com/?src=bartsms

Thank you

George Pepper

Cofounder Shift.ms

Why is Prof G dissatisfied?

I have been espousing the message that time is Brain in the treatment of MS, but the NHS makes it difficult to practice what you preach. MS services in the NHS are not configured at present to react quickly in terms of new referrals and as a result, MSers pay the price. In the last few months, two MSers have lost brain and spinal cord because of how long it has taken them to get into the Barts-MS system. This upsets me and leaves me feeling very dissatisfied with my NHS practice.

The first is a patient with quite advanced MS who was reasonably well controlled on fingolimod. She moved to London to join her husband from a European country. She, unfortunately, ran out of fingolimod tablets before seeing me and by the time she arrived in our service she had rebound disease activity with severe brainstem and spinal cord disease activity. She was off her feet with the loss of bowel and bladder function.

The second case was also a European who has been living in the UK for 10 years. His first attack was a brainstem attack that occurred almost 2 years ago. He was initially seen in accident and emergency department of a district hospital. It took him almost a year to see a neurologist and then 6 months for a diagnostic workup to be completed before being referred to me. It took me just shy of 3 months to see him in my new patient MS clinic. By the time I saw him it was 21 months since he had his initial attack. His EDSS was 4.5. He now has bladder and bowel problems, unsteadiness of gait, double vision, weakness in his legs, incoordination in his limbs and depression. He has also lost his job and is unlikely to be able to resume work. His MRI is a full house of poor prognostic factors; high lesion load, Gd-enhancing lesions, posterior fossa and spinal cord lesions, black holes on T1 imaging and some early brain atrophy.

What did we do? We have put both these patients on natalizumab as part of our #BrainAttack paradigm, i.e. to get on top of the MS disease activity before we even have their JCV serostatus back. If they turn out to be JCV positive we can derisk their PML risk, by switching their treatment or offering them extended interval dosing (EID).

All MSologists have patients who have had catastrophic relapses whilst waiting for a diagnostic workup and/or DMTs. We also know that MS activity tends to be clustered, i.e. one of the best predictors of a relapse is a recent relapse. Instead of putting patients with possible early symptomatic MS at risk from having to wait why don’t we to treat them all with natalizumab to protect their brains and spinal cords? This is analogous to treating stroke.

Why natalizumab? It is one of our most effective DMTs, it works very quickly, it is given as an IV infusion, hence there is no problem with adherence and is very safe for up to 12 months. It is also relatively safe in pregnancy. During this 12 month period, the neurologist and the patient can then decide what strategy they want to pursue in the long-term. This could be to continue natalizumab long-term or to switch to another DMT, or in the case of an alternative diagnosis the drug can be stopped.

At Barts-MS we want to promote the #BrainAttack strategy and to potentially do a trial. Please note that if you adopt the #BrainAttack paradigm you need to commit to at least 6 months, and potentially 12 months, of natalizumab treatment, to prevent patients from developing anti-natalizumab or anti-drug antibodies. We rely on the continued administration of natalizumab to trigger high-zone tolerance and to switch off NAB development. We learnt about this when natalizumab was initially pulled from the market in the US after the initial PML scare. Those patients have 1, 2, 3 or 4 infusions were much more likely to become persistently NAB-positive and if this occurs they can never be treated with natalizumab again.

Please note that another issue with these two MSers is that they were both foreigners who grew up outside the UK and simply did not know how to navigate the NHS systems. I think everyone who lives in the UK knows how to navigate the NHS and to be more demanding. I am sure if these MSers had been native to the UK they would have found a way to expedite their appointments. This is no excuse. The tragedy for me is that both these MSers have acquired significant disabilities as a result of NHS systems. I now going to explore the possibility of setting-up an urgent DMT assessment clinic to try an avoid this from happening again.

ProfG

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Guest Post: DrMaria from Spain explains about relapses

Hello everybody

First of all, I would like to introduce myself. I am Maria Mateo, I am a Neurology registrar from Spain and I have the pleasure of spending three months at Barts-MS to learn about MS.

As a part of my stay here, I have been attending MS clinics. As we know, MS patients can experience a broad variety of symptoms during their disease that can be difficult to explain. Thus, I have noticed that some MS patients have difficulties interpreting whether their symptoms are due to a new relapse or not, or if their symptoms are related to something else. Therefore, I have thought that it would be useful to clarify some main concepts around MS relapses.

What is a relapse?

Relapses are episodes of relatively sudden onset (over hours or days) new symptoms or worsening of existing MS symptoms. They usually get gradually worse over a period of time, normally a few days. Then, they remain for a period of time and later on (typically after some weeks) the symptoms start to gradually improve, either partially or completely. Relapses reflect disease activity and they must be detected an assessed properly. Steroids are the most common therapy used to treat relapses in order to shorten the symptoms and accelerate the recovery.

There are some considerations that can help us to distinguish real relapses from other conditions:

They must last at least 24 hours. As you know, MS patients experience many clinical issues over time. You can notice mild variations in these symptoms that are not related to new disease activity, so they should remain relatively stable. For this reason, at some point, this temporary worsening of symptoms can be misunderstood as a relapse. Thus, this time requirement can help us to distinguish relapses (more than 24h) from fluctuations symptoms (shorter, more variable).
Symptoms must occur at least 30 days from the start of the last relapse. Otherwise, the clinical change can be secondary to the same relapse or cluster of lesions causing multiple new symptoms. Neurologists refer to this a multifocal (many sites) relapse.
Other causes need to be ruled out. Frequently, other conditions can worsen existing symptoms or even produce new ones and mimic a relapse. For instance, hot weather or more frequently fever and infections can cause relatively sudden clinical changes over hours or days (pseudo-relapse, see below). Thus, these conditions must be assessed and ruled out when a relapse is suspected. The most frequent infections associated with pseudo-relapses are viral upper respiratory tract or urinary tract infections.

What kind of symptoms can you notice?

Any MS symptom can be a relapse, but the clue is that they should appear relatively suddenly. You must notice a change from your previous clinical state. For instance, you can notice one or several of these symptoms:

Weakness in a leg or an arm
Sensory disturbances: areas of numbness, pins and needles or pain
Visual loss, double vision
Bladder or bowel issues
Dizziness, balance and coordination impairment
Mobility or gait disturbances
Fatigue
Memory and concentration impairment

What other conditions can mimic a relapse?

Pseudo-relapse: A pseudo-relapse is a period of clinical worsening that could mimic a relapse but that is not related to disease activity. Pseudorelapses are caused by some intercurrent process such as a fever or an infection. Once this process is reversed you should get better. The most common causes are:

Heat: hot weather, hot shower, fever.
Infections: especially virus (flu) or urinary infections.

Paroxysmal symptoms: They are neurological signs or symptoms that occur with a sudden onset and a sudden end. They last a short period of time (often seconds), they are usually repetitive and stereotyped (same symptoms repeating themselves with each episode). Some examples of paroxysmal symptoms are Lhermitte’s sign (electric-shocklike sensation down back when bending your neck), trigeminal neuralgia (paroxysms of facial pain), tonic spasms (spasms of the arm and/or legs), dystonia (writing movements of a part of the body), myoclonus (sudden jerking movements), dysarthria (slurred speech).

Progression: It is a slow and progressive worsening of symptoms, over weeks, months or even years. In this case, you could not be able to identify a significative worsening from one week to another. This is indicative of the gradual loss of nerve fibres and function that characterises more advanced or progressive MS.

I hope this post has helped better understand your disease and clarify some doubts that can come up quite often.

CoI: I have received honoraria from Sanofi-Genzyme and UCB Pharma for preparing and grant for an online subscription from Sanofi-Genzyme.

Treating carry-over PML after immunodepletion

Treating PML in the presence of immunodepletion is not necessarily a death sentence. There are some solutions on the horizon.

At present we don’t have an anti-viral agent that works against the JC virus that causes PML (progressive multifocal leukoencephalopathy). Therefore we have to rely on your own immune system to fight and clear the virus if you develop PML. This is why we wash out natalizumab with plasma exchange or stop the immunosuppressive when somebody develops PML. A problem arises when we can’t reconstitute CNS immunosurveillance or your immune system. The latter can happen with IRTs (immune reconstitution treatments) and potentially with anti-CD20 therapies (they do reduce CD8+ T-cells as well) or in people with persistent lymphopenia post fingolimod or dimethyl fumarate or other DMTs for that matter. This is where immunotherapies are needed.

One strategy is to give unfortunate people with PML in this situation donor anti-JCV lymphocytes that are matched to their HLA (human leukocyte antigens) to fight the infection. In short, this is an immune transplant, i.e. giving them donor-matched T-lymphocytes to fight JCV. The study below uses T-cells that were designed to attack the BK virus a virus that is very similar to JCV.

The logistics of immunotherapy for PML are not insignificant and ideally need to be established before hand so as not to delay treatment. One option is to rely on Pharma to create a bank of HLA-specific cytotoxic T-lymphocytes that are frozen and cane be mobilised within 24-48 hours as a licensed treatment for PML.

When I was at the NIH earlier this year I heard about such a trial and would urge you to contact them if and when the need arises.

Muftuoglu et al. Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2018 Oct 11;379(15):1443-1451. doi: 10.1056/NEJMoa1801540.

JC virus, the cause of progressive multifocal leukoencephalopathy (PML), and the BK virus are genetically similar and share sequence homology in immunogenic proteins. We treated three immunosuppressed patients with PML with ex vivo-expanded, partially HLA-matched, third-party-produced, cryopreserved BK virus-specific T cells. The immunosuppression in these patients was due to the conditioning regimen for cord-blood transplantation in one patient, a myeloproliferative neoplasm treated with ruxolitinib in another, and acquired immunodeficiency syndrome in the third. After T-cell infusion in two of the patients, alleviation of the clinical signs and imaging features of PML was seen and JC virus in the cerebrospinal fluid (CSF) cleared. The other patient had a reduction in JC viral load and stabilization of symptoms that persisted until her death 8 months after the first infusion. Two of the patients had immune reconstitution syndrome. Donor-derived T cells were detected in the CSF after infusion. (Funded by the M.D. Anderson Cancer Center Moon Shots Program and the National Institutes of Health; ClinicalTrials.gov number, NCT02479698 .).

CoI: multiple

Early reflections on ECTRIMS 2018

I am writing this post on the flight back to London from Berlin. Being trapped in a tin tube at over 10,000m above sea level is always a good time to think.

under&over – ProfG’s #1 non-scientific highlight at #ECTRIMS2018

Guess what my #1_scientific_highlight was at #ECTRIMS2018?

Raju Kapoor with ProfG’s #1 scientific highlight at #ECTRIMS2018

The avalanche of neurofilament data, in particular, the serum neurofilament results from the natalizumab SPMS, or ASCEND, trial. This was presented by Dr Raj Kapoor as a late-breaking poster. In summary, it showed that peripheral blood neurofilament levels were responsive to natalizumab therapy regardless of whether or not SPMSers had baseline Gd-enhancing lesions (aka baseline activity).

Why is this so important?

Please remember that the population of SPMSers in the ASCEND trial were very advanced with more than 60% needing a walking stick or sticks, i.e. they were almost off their feet and had markedly reduced reserve in the neuronal system supplying their legs. This study was negative on lower limb function (EDSS and timed-25 foot walk), but positive on upper limb function (9-hole peg test) at 2-years becoming positive at 3 years in the extension study. These results are consistent with MS being a length-dependent central axonopathy. The good news is that these results are now backed-up with data from the hottest biomarker in town.

An interesting observation that has yet to be published from the ASCEND trial is the data showing that natalizumab-treated SPMSers are more likely to have a confirmed disability improvement compared to placebo-treated subjects in the 2-year period of blinded observation. Could the drop of peripheral blood NFL levels indicate not only a reversal of the neurodegenerative pathology but possibly be a marker of neuroregeneration? Pity we don’t have CSF from this trial it would be fascinating to look at regenerative biomarkers, i.e. is there any evidence of axonal sprouting and synaptogenesis on natalizumab?

What this new blood NFL analysis tells us that so-called non-relapsing advanced MS is inflammatory and this inflammation is modifiable by a highly effective MDT such as natalizumab. Please note that this was not seen in the data presented on the effect of siponimod on peripheral blood NFL levels at the AAN earlier this year.

I am now convinced that natalizumab is an effective treatment for SPMS. It also further validates serum NFL as a surrogate marker of neuroaxonal damage in MS. Is there now enough data for the regulators, i.e. the FDA and EMA, to evaluate NFL as a surrogate end-point for MS? I personally think so, which is why we have been using CSF NFL levels in clinical practice at Barts-MS for about 3-4 years to aid clinical decision making. We use CSF NFL as an inflammatory biomarker and include it in our treatment target for more advanced MSers.

Once the FDA and EMA accept NFL as a surrogate end-point in MS I would urge Biogen to go back to the regulators to discuss natalizumab getting a label for progressive forms of MS. If Biogen don’t think they have a chance of getting a label change via this route I would urge them to do ASCEND-2 or ASCEND-HAND, i.e. trial of natalizumab in advanced MS only this time extending recruitment into MSers in wheelchairs. Another option is to do the randomised withdrawal study that I proposed last year. The latter would have to be done in the UK, where we are being forced to stop DMTs in MSers who become wheelchair bound. The idea is to randomise people to placebo or natalizumab with the primary outcome being time to confirmed relapse or evident disease activity using MRI and serum NFL levels. Some of you may ask, what about PML? Yes, what about PML? This can potentially be derisked using the current tools including extended interval dosing (EID) in the trial. I have also made the point that JCV and PML are biological problems and they will be cracked with time. We need to keep up on the pressure on the scientific community to solve these problems.

I was asked by a colleague at ECTRIMS if I envisage NFL replacing MRI as an assessment of MS disease activity? Potentially, yes. The good thing about NFL monitoring is that it is an integrator of MS disease activity and will assess both brain and spinal cord activity. This is important because most of us don’t include spinal cord imaging in our monitoring protocols. NFL is also potentially cheaper and easier to standardise and as it is a lab-based immunoassay could really help in resource-poor environments with limited access to MRI. It will also be more convenient for patients; having a blood test is quicker and easier than coming in for an MRI scan. At the moment one company have the monopoly on peripheral blood NFL measurements and are charging an extortionist price for their assays, reagents and the maintenance of their platform. The other good news at ECTRIMS is that competition will be arriving soon in the NFL space. Hopefully from at least another two platforms, one of which who has a large footprint in routine laboratories. We need some good old competition to drive down prices.

In support of NFL replacing MRI monitoring was a poster from Tjalf Ziemssen’s group in Dresden showing that when you do monthly blood NFL levels, NFL levels were noted to rise prior to detecting MRI activity or clinical relapse. This is not surprising; I have data from my PhD on daily urinary neopterin levels, an inflammatory marker, showing the same thing. So yes, I envisage a world in the not so distant future when MSers will be having frequent blood neurofilament levels measured, hopefully, using home finger-prick technology to monitor their MS disease activity. Once we get to this stage then we will be able to apply true precision medicine to individual patients and we will be able to optimise treatments based on real-time biomarker measurements.

We have been working on NFL in MS for over 15 years and to see it transforming MS research and translating so fast into clinical practice makes the work we have done seem worthwhile.

CoI: multiple

ProfG’s MS-related Twitter activity: week 1st-7th October 2018

It is a draw interferon-beta 1 vs. glatiramer acetate 1. #ClinicSpeak There is no difference in the comparative effectiveness between the beta-interferons and glatiramer acetate. But what about the other attributes, e.g. pregnancy, NABs, monitoring, etc. ? https://t.co/b6VygWzrQq pic.twitter.com/90qwG5wAtI

— Gavin Giovannoni (@GavinGiovannoni) October 6, 2018