Crowd-funding: Listeriosis Prevention Pack

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. 

We have therefore designed a Barts MS Listeriosis Prevention Pack and now need £7,000 for a manufacturing run. These packs will be distributed to all patients prior to alemtuzumab treatment; please note these packs are not only for Barts Health patients; we plan to distribute them to other centres if they want them. 

If you would like to support this programme you can make a donation via our Barts Health crowdfunding site. 

Thank you.

ABN Guidance on preventing Listerial Infection

Some background reading: 

Evans & Redmond. Older Adult Consumer Knowledge, Attitudes, and Self-Reported Storage Practices of Ready-to-Eat Food Products and Risks Associated with Listeriosis. J Food Prot. 2016 Feb;79(2):263-72. doi: 10.4315/0362-028X.JFP-15-312.

Consumer implementation of recommended food safety practices, specifically relating to time and temperature control of ready-to-eat (RTE) food products associated with listeriosis are crucial. This is particularly the case for at-risk consumers such as older adults, given the increased listeriosis incidence reported internationally among adults aged ≥60 years. However, data detailing older adults' cognitive risk factors associated with listeriosis are lacking. Combining data about knowledge, self-reported practices, and attitudes can achieve a cumulative multilayered in-depth understanding of consumer food safety behavior and cognition. This study aims to ascertain older adults' cognition and behavior in relation to domestic food handling and storage practices that may increase the risks associated with L. monocytogenes. Older adults (≥60 years) (n = 100) participated in an interview and questionnaire to determine knowledge, self-reported practices, and attitudes toward recommended practices. Although the majority (79%) had positive attitudes toward refrigeration, 84% were unaware of recommended temperatures (5°C) and 65% self-reported "never" checking their refrigerator temperature. Although most (72%) knew that "use-by" dates indicate food safety and 62% reported "always" taking note, neutral attitudes were held, with 67% believing it was safe to eat food beyond use-by dates and 57% reporting doing so. Attitudes toward consuming foods within the recommended 2 days of opening were neutral, with 55% aware of recommendations and , 84% reporting that they consume RTE foods beyond recommendations. Although knowledgeable of some key practices, older adults self-reported potentially unsafe practices when storing RTE foods at home, which may increase risks associated with L. monocytogenes. This study has determined that older adults' food safety cognition may affect their behaviors; understanding consumer food safety cognition is essential for developing targeted food safety education.

Drugs doing more than one thing, it's not always good

Morrow SA, Rosehart H, Sener A, Welk B. Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis. J Neurol Sci. 2018 385:39-44.

Bladder dysfunction is common in persons with MS (PwMS), often due to muscle overactivity. Anti-cholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched-cohort study was to determine if anti-cholinergic medications affect objective measures of cognition in PwMS. 

We recruited PwMS starting either oxybutynin or tolterodine (cases). Cases and controls were tested with the Brief International Cognitive Assessment for MS (BiCAMS) battery prior to starting anti-cholinergic medications and 12weeks later.

  The primary outcome was change on the Symbol Digit Modalities Test (SDMT) between groups; secondary outcomes were changes on the other BiCAMS measures. Analysis to assess the significance of between group differences was performed at 12weeks. Forty eight PwMS starting anti-cholinergic medications and 21 matched PwMS controls were recruited. There was a significant difference (p<0.001) in the change on the cognitive measures over 12 weeks between groups. The controls demonstrated improvement, consistent with practice effect, while the cases remained unchanged. This study demonstrates that anticholinergic medications may have a negative effect on cognition in PwMS.

Anti-cholinergic drugs block acetyl (ace-eee-tile) choline activity. Aceyl choline is a neuro-transmitter. Acetylcholine functions in both the central nervous system (CNS) and the peripheral nervous system (PNS). In the CNS, cholinergic projections from the basal forebrain to the cerebral cortex and hippocampus support the cognitive functions of those target areas. In the PNS, acetylcholine activates muscles and is a major neurotransmitter in the autonomic nervous system.The autonomic nervous system is a control system that acts largely unconsciously and regulates bodily functions such as the heart rate, digestion, respiratory rate, pupillary response, urination, and sexual arousal. There are two main classes of acetylcholine receptor, nicotinic and muscarinic. Block acetylcholine and you can get dry mouth constipation  flush skin.

You can get leakage from a bladder because the muscle is contracting too much, anti-cholingrerics can block this. If you can't go, cholinergic agonists can contract the bladder to empty it.  However in addition to blocking over active bladder, it can block nerve action involved in thought processes. 

Why is this important? Because it shows you that the body can use the same system to control more than one function. They could be have universal good things but they can be opposing one good and one bad. Many of the the agents that promote remyelination have alternative functions and don't be surprised is some of those found to be useful in myelination may have unwanted effects. But do we need to take remyelinating drugs forever or just for a short time so that myelination starts?

Education: What is a nerve impulse?

What is a nerve impulse? How does a nerve axon generate it and allow signalling using impulses from one place to another?

The impulse may be thought of as a message or wave.  A ‘message’, for example on a telegraph, or a ‘wave’ in the sea initiates at one point and ends up elsewhere. The message needs the medium: the wave may have travelled great distances, but it cannot exist without the sea, whereas the sea itself has not moved. Likewise, the anatomical connectivity of an axon does not change as impulses are transmitted. A telegraph message requires an unbroken line. If the telegraph line somewhere between Laramie and Denver in the old West is broken, then the message does not get through and the bandits might escape justice. There is a similarity here with the nerve impulse and the axon. The axon has to make the impulse and provide a conduit for its conduction.

Old fashioned telephonic communication required unbroken hardwiring. So does our nervous system.

You also have the idea that a wave has an energy that must be somehow provided. So for light waves in a torch, there must be a working battery that's switched on. Or a storm out in the Atlantic can make a wave on the sea. A message or a wave requires energy, and so does a nerve impulse. The message or wave requires a medium to allow travel. The nerve impulse is dependent upon the axon for its initiation, maintenance and propagation, and the energy to make nerve impulses comes from our food.

The energy to make a wave may be provided far out to sea, and then the wave propagates long distances.

The nerve impulse itself is a brief change in electrical potential across the membrane of the nerve (taking something like one half of one-thousandth of a second to occur). This depends on the distribution of salts in solution (inside and outside the membrane) and on remarkable proteins controlling which of these salts can cross the membrane. 

Some of these proteins are called sodium channels, but they certainly require their own blog post, as they are so fundamental and so important. When those proteins change their state, they can generate a change in electrical potential across the membrane. 

Such a change in electrical potential produces an event, but to turn it into a message, it has to travel without being diminished. The nerve fibre helps to do just that because it has the salt controlling proteins all the way along its length, and they are assigned to the impulse, as the impulse travels along the nerve. This event changes less and less as it moves along, and would peter out without help, but it can't because of the way the sodium channels in the membrane of the nerve actively amplify it. On the other hand, if you block the sodium channels with a drug, like a local anaesthetic, then you can block impulse conduction.

One thought might make this easier to explain, and this is that the nerve axon has to set up a battery beforehand, in order to make the impulse. The way it does this is by using the energy in food to sort charged particles of salt and distribute them in an unequal way on either side of the nerve membrane. These charged particles of salt are called ions. Using energy, the nerve arranges for there to be many fewer sodium ions on the inside of the membrane than the outside. It tries to exclude sodium ions from inside the axon. 

"Sodium" sounds quite exotic, but sodium ions are formed when we put table salt into our mouths and allow the salt to dissolve, and we have lots of sodium ions inside us, in our body fluids. The sea also has lots of sodium in it, more indeed than our body fluids. Once this gradient of sodium ions have been set-up, it is like a battery that can be utilized to generate an impulse, in a way similar to switching on a torch from time to time to make a flash of light.

The nerve impulse is the biological equivalent of a TTL pulse in electronic communication. It is propagated change in electrical potential, lasting about 0.5 milliseconds at one point, but there is a tail on it, or a so-called after potential, so the axon is affected by the passage of the impulse for a little while afterwards

How is an impulse initiated? It is initiated by another electrical signal arising in a neuron, for example, or at a sensory nerve ending, that causes the sodium channels at one end of the axon to switch on. The impulse is then propagated away from that locality by the presence of other sodium channels distributed along the length of the axon.

How fast does a nerve impulse propagate along an axon?

Up to about 50 or 60 metres per second in humans, that is over 200 km per hour, or over 125 miles per hour, if you want. So you need a sports car and an autobahn to replicate such fast transmission. 

You need a fast car to beat a nerve impulse.

I'll explain more about axons in my next post. Please ask me any questions below!

Liver toxicity with Teriflunomide (Aubagio) explained

Are you on Teriflunomide (Aubagio)? Then this post is for you. 





Toxicology. 2018 Feb 7. pii: S0300-483X(18)30017-9. doi: 10.1016/j.tox.2018.02.003. [Epub ahead of print]

Mitochondrial dysfunction induced by leflunomide and its active metabolite.

Xuan J, Ren Z, Qing T, Couch L, Shi L, Tolleson WH, Guo L.

Abstract

Leflunomide, an anti-inflammatory drug used for the treatment of rheumatoid arthritis, has been marked with a black box warning regarding an increased risk of liver injury. The active metabolite of leflunomide, A771726, which also carries a boxed warning about potential hepatotoxicity, has been marketed as teriflunomide for the treatment of relapsing multiple sclerosis. Thus far, however, the mechanism of liver injury associated with the two drugs has remained elusive. In this study, cytotoxicity assays showed that ATP depletion and subsequent LDH release were induced in a time- and concentration-dependent manner by leflunomide in HepG2 cells, and to a lesser extent, by A77 1726. The decline of cellular ATP levels caused by leflunomide was dramatically exacerbated when galactose was substituted for glucose as the sugar source, indicating a potential mitochondrial liability of leflunomide. By measuring the activities of immuno-captured mitochondrial oxidative phosphorylation (OXPHOS) complexes, we found that leflunomide and A77 1726 preferentially targeted complex V (F1FO ATP synthase), with IC50 values of 35.0 and 63.7 μM, respectively. Bongkrekic acid, a mitochondrial permeability transition pore blocker that targets adenine nucleotide translocase, profoundly attenuated mitochondrial membrane depolarization, ATP depletion, and LDH leakage induced by leflunomide and A77 1726. Substantial alterations of mitochondrial function at the transcript level were observed in leflunomide-treated HepG2 cells, whereas the effects of A77 1726 on the cellular transcriptome were much less profound. Our results suggest that mitochondrial dysfunction may be implicated in the hepatotoxicity associated with leflunomide and A77 1726, with the former exhibiting higher toxicity potency.

When you balance the risk, is the benefit worth it? All medicines have side effects. Laughter is the only medicine that I know of without side effects (or no visible signs of one)! Understanding the nature of side effects is an art form, a study named toxicology. The goal as far as I'm aware is to at least mitigate the more serious side effects by determining susceptibility.

Before teriflunomide (Aaubagio) came on the scene, there was leflunomide, which is anti-inflammatory treatment used in rheumatoid arthritis. It's active component is teriflunomide (also known as A77 1726), so not surprisingly they have similar side effects, particularly considering that they have similar blood levels at the recommended treatment dosages. The most important side effect is the liver dysfunction. It is therefore prohibited in those with existing severe hepatic impairment and two weekly blood monitoring is a must for the first six months (see EMA summary of product characteristics for aubagio). The exact mechanism by which the liver injury occurs has always remained somewhat of a mystery.

The clue to side effects may be in the mode of action of the medicine. The mode of action of teriflunomide is thought to be via inhibition of dihydroorotate dehydrogenase, a key mitochondrial enzyme in pyrimidine synthesis. Drug-induced mitochondrial dysfunction is thought to be a major cause for liver injury in many medicines. This is not surprising since mitochondria are major source of cellular energy production.

Therefore, using liver cells in the laboratory the authors investigate whether, leflunomide and teriflunomide both cause mitochondrial toxicity.

They discovered that when liver cells were exposed to the two drugs, the production of energy (ATP) by the mitochondria started to decrease in a dose dependent manner, suggesting that this may be the mode of toxicity. There was also evidence of damage to cellular integrity (through the leakage of LDH) throughout. Leflunomide, unlike teriflunomide was demonstrated to cause a more severe liver injury, however.

Overall, in either case it would be important to avoid exacerbating a per-exisiting liver disorders by adding these drugs on top. Although mandatory, regular monitoring can lull one into a false sense of security, most side effects by nature are unpredictable.

Guest post: Why hasn't the reality of hidden disabilities caught on yet?

Twice in the past couple of months I’ve been reduced to tears because I’ve seen media stories about people with hidden disabilities being treated appallingly by people in customer-facing positions who should be the ones leading the way when it comes to helping those who might need that extra bit of help. In both the stories, the two women were told they didn’t “look disabled.” 

As someone with MS who most of the time looks perfectly healthy, it’s something that really resonates. I hope that you will share this post far and wide, if nothing else so that every individual who reads this will remember that old saying “don’t judge a book by its cover.”



STORY 1 – the lady who needed the toilet
Perdi Parris has multiple sclerosis and one symptom is bladder issues. She was at a Slug & Lettuce pub and was barred by the security guard (who works for a third party) from using the disabled toilet. She had a radar key to access the toilet (which is locked from the outside and only accessible by people with radar keys) and had two forms of ID that confirmed her condition. Read more. 

STORY 2 – the lady who booked special assistance at the airport only to be told “you don’t need it”
Nathalie Allport-Grantham has Ehlers-Danlos syndrome and Marfan syndrome. She had pre-booked special assistance when flying from Stansted Airport on Ryanair. She uses a wheelchair some of the time but not all. She was given a wheelchair on arrival but it was taken away when she reached the lounge and wasn’t returned. She was forced to walk to the gate, where she was expecting help to board the plane. She explained to the special assistance staff (special assistance is contracted out to Omniserv) that she’d booked assistance and she needed help to board. They essentially told her she didn’t look disabled enough. They said she’d have to pay £50 to check her bag into the hold if she couldn’t carry it herself, that she should be queuing up with everyone else to board the plane, and that she was wasting their time. Read the full story. 

What can we learn from this?

1. Not all disabilities are visible: There’s no excuse these days for people to say “you don’t look disabled.” We can’t see mental health issues or learning difficulties; we can’t see pain, bladder issues, bowel issues, cognitive issues. Often it may not be immediately apparent if someone is visually impaired or hearing impaired. In fact the list goes on. The only time someone may ever actually “look” disabled is if they’re missing a limb* or some other visible part of the body, using a wheelchair or carrying a stick. I don’t know the statistics, in fact I don’t even know if there’s been any sort of survey as to how many people in the UK live with invisible disabilities, but I’d bet you anything that there are far more people out there with hidden disabilities than visible ones. So, if you want to be seen as disability-friendly you need to remember that many of the people you come across aren’t going to “look” disabled. 
* Sometimes that might not even be apparent straight away. I know several amputees and when I first met them I didn’t realise they were missing limbs!

2. Don’t pass the buck: The companies that will be remembered out of these stories will be Slug & Lettuce, Stansted and Ryanair. Not Omniserv and not the security company at the pub. There’s no point in saying to a customer that you have fantastic accessibility, diversity and inclusion policies if you then contract out a service and don’t take responsibility for what that company’s staff do on your premises and on your behalf. You’re just as much at fault and it’s your reputation that will also be damaged. I know plenty of people with MS who have been talking about boycotting Slug & Lettuce pubs – I’ve heard no mention of them writing to the security company or boycotting them!?

3. Don’t make it harder for us when it can be difficult enough to admit to ourselves that we need help in the first place: I’ve always been independent and I hate having to ask for help. However, sometimes it’s necessary in order to get the best out of me or a situation. I’m not alone. I know many people with invisible disabilities who find it hard to ask for help. Don’t make it harder for us by humiliating us and suggesting that we’re fakes when we do actually ask.

4. It’s not your place to judge if someone needs help: Do you know the person that you’re talking to and what they go through on a daily basis? No. Then you have no right to judge whether someone who has asked for help actually needs it. You have no idea what effect walking for just five minutes might have on someone. You have no idea whether making someone wait in a queue for the toilet will result in them wetting themselves. I once had to give a detailed account to a theatre usher of what would happen if my friend who has ulcerative colitis wasn’t told immediately where the disabled toilet was when we were out to watch a play. The usher had told him he couldn’t use the disabled toilet because he wasn’t in a wheelchair and refused to tell him where in the building it was. I’ll never forget the look of panic on my friend’s face. It’s something you should never have to see – a full grown adult scared “shitless” (excuse the pun and the language) that he was going to embarrass himself there in front of everyone. So, if someone has asks for help, just give it to them willingly and with a smile on your face. At the end of the day, you don’t know what’s going on within that book cover.

5. Finally, be human and have some faith in humankind: Do you really think that someone is so lazy that they’ll go to the trouble of booking special assistance because they don’t want to walk on the plane themselves or wait in a queue like everyone else? Do you really think someone is so desperate to use a disabled toilet that they’ll go to the trouble of getting a radar key and deny the use of the facility for someone who is disabled? Seriously, have some faith in humankind. Yes, there will always be people out there who take advantage of the system, I’m not saying there aren’t. However, they’re in a tiny minority. The vast majority of people wouldn’t dream of taking advantage of the system and, therefore, the people who you are dealing with are more than likely genuine. We should be a society that helps those who need it, not one that is suspicious of them. 

After posting the two stories on social media, I had people comment saying that they’d been put off applying for a blue badge because they were worried they’d be judged and abused by people for using a disabled parking space when they’re not in a wheelchair (it happens a lot!). I’ve also had people comment saying they won’t fly or use public transport because they’ve heard about others’ bad experiences. If this blog post can help to increase understanding so people with hidden disabilities no longer feel like this, then it’s done its job.

By Trishna Bharadia

Trishna is a multi-award winning advocate for people with multiple sclerosis and chronic illness. Diagnosed with RRMS in 2008, aged 28, she's used her experiences to raise awareness and improve support for people affected by MS and other chronic illnesses. A full-time Spanish-English translator, in her spare time she collaborates with organisations in the UK and abroad, including charities, pharmaceutical firms and nonprofits, to help improve patient experience and engagement. She’s a writer, blogger, vlogger and inspirational/expert patient speaker, as well as advising on projects, research proposals, and diversity strategies, and is a regular contributor in the media for issues relating to MS, chronic illness and disability. She’s a patron/ambassador for several MS/disability charities and is currently a member of “The Ozone” virtual roundtable for key opinion leaders across healthcare specialities. You can follow her on Twitter @TrishnaBharadia and Facebook www.facebook.com/trishnabharadia2015 

My trip to Lucerne and the Charcot Project

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:

The Charcot Project is an initiative that Professor Gold and I launched about 5 years ago to tackle MS from a different perspective; a perspective that MS is caused by a virus and to tackle MS we need to start doing treatment trials using anti-virals. The two leading viral contenders are EBV and HERVs.  If you have any queries about the slides please feel free to ask. 

In this presentation, I stress the point that I have made several times before that MRI activity (new Gd-enhancing lesions) and relapses are not MS, the disease. If they were the disease they would predict MS outcomes whether or not you are on a DMT. The data indicates they only predict outcomes when you are on a DMT. Based on Prentice criteria of what constitutes a surrogate end-point for a disease both relapses and MRI activity fail. 

I then review the observation that changes occur weeks to months in the white matter before a new focal lesion occurs. This would indicate something is happening in the brain of pwMS prior to inflammation ('Field Hypothesis'). This may explain the Prineas lesion, i.e. oligodendrocyte apoptosis without overt inflammation. The million dollar question is what is killing the oligodendrocyte? 

I then review the epidemiology evidence supporting EBV and possibly HERVs as the viral aetiology of MS. I complete the lecture with some experiments that need to be done to prove that EBV is the cause of MS. Simple? I wish! Trying to get funding for studying the viral cause of MS is very difficult and slow, but we will get there, eventually. 

ProfG    

What is your risk of developing PML on fingolimod?

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

Will this new data lead to a change in practice? 

PML under fingolimod therapy not attributed to previous natalizumab treatment is very rare and the risk is estimated to be less than 1:10,000 patients.

19 confirmed PML cases in >225,000 fingolimod-treated patients (>508,000 patient-years) as of the 30th of November 2017.

The estimated risk (95% CI) is 0.084 (0.051; 0.131)/1,000 patients and the incidence rate (95% CI) is 3.74 (2.25; 5.84)/100,000 patient-years exposure.)

• Two cases had confounding medical conditions (1 previous cancer and 1 ulcerative colitis/immunosuppressive therapy).
• One patient had previous NTZ exposure for 10 months (3 years and 9 months before PML diagnosis).
• In one patient, PML occurred during 3 months of NTZ exposure, after 4.5 years of fingolimod treatment; this patient also had a history of recent exposure to steroids.
• Demographics: age range from 34 to 71 years, with a female preponderance (14 of 19 cases) and a diverse geographic distribution.
• Fingolimod exposure ranged from 18 to 84 months. 18 of the 19 patients had fingolimod ranging between 29 and 84 months while one had received fingolimod for 18 months.
• There was no pattern of sustained grade 4 lymphopenia (defined as absolute lymphocyte count ≤200 cells/µL and based on the reported absolute lymphocyte count values in 15 of 19 cases).
• JCV DNA PCR test was positive in all cases.

In the past, there has been no clear correlation between opportunistic infection risk and lymphocyte counts on fingolimod. As a result of this, the FDA did not mandate the monitoring of lymphocyte counts in pwMS on fingolimod in routine clinical practice. In comparison, the EMA implemented the same requirements that were part of the fingolimod trial programme; i.e. dose interruption was done if the total, or absolute, lymphocyte count dropped below 200. The latter is quite common in people with MS on fingolimod. To reconcile the differences between the FDA and EMA we suggested a half-way house mark and to only interrupt fingolimod dosing if the counts dropped below 100. 

Only the minority of PML cases (~20%) on fingolimod had counts below 200. Does this mean we now have to change this recommendation? I think it would seem reasonable to go back to the 200 cut-off as recommended by the EMA. 

Does this mean that the FDA will now have to change their recommendations? I am sure they will. The FDA is a data-driven organization and are likely to respond to this new information. 

Unfortunately, fingolimod does not move from the list of DMTs that can't be derisked regarding immunosuppression and opportunistic infections, to the list of DMTs that can potentially be de-risked. The majority of opportunistic infections still occur in pwMS with lymphocyte counts above 200. 

NOTE: If you are on fingolimod and your lymphocyte count is below 200 please speak to your neurologist or clinical nurse specialist. If you don't know your lymphocyte count you should find out. As we can't derisk fingolimod you must be please remain vigilant of any new symptoms, this includes neurological and systemic symptoms, that could suggest an opportunistic infection. 

ProfG    

Guest post: The argument for legalising cannabis for medicinal use

Note: This is a post which talks about the effects of PPMS in a way that some readers may find upsetting.

We are a regular family who has been virtually decimated by MS.

My wife (Vicky) was a very respected primary teacher, teaching in a challenging school in Walsall when she was diagnosed with Primary Progressive MS in her mid-30s, a little over 10yrs ago.

We have two daughters: Sophie is studying for a nursing degree in children's nursing, and Megan is studying on a BTEC course with a view to a career in the police force.

Within 3-4 yrs of diagnosis, Vicky was forced to give up the career she loved despite every effort made by all parties, measures which included Vicky being lifted from a taxi (access to work scheme) onto her mobility scooter to continue her work.

Since the early days of diagnosis, Vicky has suffered daily with severe stabbing nerve pain in her left shoulder. She has tried every drug there is acupuncture, electro-acupuncture, nerve injections, chili patches and so on and so on; literally, everything the NHS and private clinics have to offer.

Fast forward to where cannabis comes in. Vicky has very little function, is doubly incontinent and has carers come in whilst I work Monday, Tuesday, and Wednesday. I take over at all other times.

It is important to bring the carers into the story because this is where our first brush with the law comes in regarding cannabis.

I had been trying to grow some cannabis in a spare upstairs bedroom, not very successfully I might add.

One of the carers or care agency reported a smell of cannabis coming from upstairs. This was frustrating on two points: one because upstairs is out of bounds, as we live on the ground floor adapted for Vicky. The second is there would have been very little smell due to very little growth and was more than likely found by snooping around. I said two points, in actual fact, it's three: the carers see Vicky cry in pain on a daily basis.

The resulting action was a visit from the local police and a stern warning with the instruction not to do it again. The WPC was quite understanding and could see what it was being used for, but said the police had to act as the call had come in from an agency with the additional fact of a minor living in the house.

So that was our first brush with being labeled criminals and our chances of experimenting with cannabis as a pain reliever gone for a while.

The second time (about 7 months after the first) was also as a result of the care agency reporting cannabis to the police, again to the backdrop of Vicky crying in pain.

I had managed to find a more reliable source of cannabis than trying to grow my own. I made the cannabis into butter and was putting this into a healthy smoothie on a daily basis; having been in a precision engineering role since leaving school this process was also carried out to precision.

Absolute success, I would come home from work to find a smiling Vicky who had been pain-free. Sadly she would still have the same stabbing pain at night and this is something we were unable to get on top of as our experimenting was cut short by the involvement of the police once again.


The second reporting also resulted in another reluctant visit from the police but had the extra worry of a safeguarding visit from Social Services for Vicky, followed by an even more worrying visit regarding the safeguarding of Megan.

As the law stands, if I get caught again I run the risk of further action being taken and risk either Vicky or Megan being taken into care. This would also jeopardise Megan's chances of joining the police and could ruin my daughter’s dream.

So after 10 yrs of daily pain, it was being relieved a by a small amount of cannabis in a smoothie. Not enough to be stoned, nor in my opinion enough to suspect, other than what must have been a slight smell in the smoothie. Vicky is now back to crying in pain on a daily basis.

Vicky is now PEG fed, nil-by-mouth and is confined to bed suffering from a severe pressure sore and awaiting a bed at the local hospice to try again to address pain.

At a little over 5st and suffering severe pain and many other complications due to PPMS, I ask anyone why they would want to deny a responsible adult access to a plant that was clearly helping?

The only hope we have is for the Elizabeth Brice Bill to be passed which has its second reading on 23rd February. Our MP has campaigned for this on our behalf.

I would like to hear from anyone who uses cannabis to ease MS symptoms.

by Andy Clarke

Education: Cannabis

If you are interested in the biology of cannabis you can flick through these slides

Cannabis from BartsMSBlog

Neural Stem cells to the Rescue?. Phase I trial results

VK Harris et al. Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural Progenitors in Progressive Multiple Sclerosis
EBiomedicine DOI: https://doi.org/10.1016/j.ebiom.2018.02.002

Highlights

• •
  Repeated intrathecal dosing of autologous MSC-NPs in patients with progressive MS was safe and well tolerated.
• •
  The treatment was associated with functional neurological improvement, particularly in ambulatory patients.

Multiple sclerosis is one of the leading causes of disability in young adults. Our study is the first evidence suggesting that a cell-based therapeutic approach is capable of reversing disability in multiple sclerosis. Results of our study add to existing evidence demonstrating the safety and tolerability of intrathecal administration of autologous mesenchymal stem cell-derived neural progenitors. The study was associated with repeated administrations of cells freshly harvested from culture, as opposed to cryopreserved cells thawed at the bedside, which may have contributed to the observed efficacy of the treatment. The continued development of this therapeutic approach will likely have implications for treating other neurological diseases.

Background

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and is one of the leading causes of disability in young adults. Cell therapy is emerging as a therapeutic strategy to promote repair and regeneration in patients with disability associated with progressive MS.

Methods

We conducted a phase I open-label clinical trial investigating the safety and tolerability of autologous bone marrow mesenchymal stem cell-derived neural progenitor (MSC-NP) treatment in 20 patients with progressive MS. MSC-NPs were administered intrathecally (IT) in three separate doses of up to 1 × 107 cells per dose, spaced three months apart. The primary endpoint was to assess safety and tolerability of the treatment. Expanded disability status scale (EDSS), timed 25-foot walk (T25FW), muscle strength, and urodynamic testing were used to evaluate treatment response. This trial is registered with ClinicalTrials.gov, number NCT01933802.

Findings

IT MSC-NP treatment was safe and well tolerated. The 20 enrolled subjects completed all 60 planned treatments without serious adverse effects. Minor adverse events included transient fever and mild headaches usually resolving in <24 h. Post-treatment disability score analysis demonstrated improved median EDSS suggesting possible efficacy. Positive trends were more frequently observed in the subset of SPMS patients and in ambulatory subjects (EDSS ≤ 6.5). In addition, 70% and 50% of the subjects demonstrated improved muscle strength and bladder function, respectively, following IT MSC-NP treatment.

Interpretation

The possible reversal of disability that was observed in a subset of patients warrants a larger phase II placebo-controlled study to establish efficacy of IT MSC-NP treatment in patients with MS.

Here are exerts from the paper which is open acess

"The clinical feasibility of IT MSC-NP treatment in MS was initially investigated in six patients with advanced MS treated with two to five injections of escalating doses of autologous MSC-NPs. PwMS were followed an average of 7.4 years after initial injection. There were no serious adverse events or safety concerns noted, and the treatments were well-tolerated. Four of the six patients showed a measurable clinical improvement following MSC-NP treatment". 

In this current study "eligible patients had clinically definite SPMS or PPMS with significant disability (EDSS ≥ 3.0) that was not acquired within the 12 months prior to enrollment. The inclusion of patients with a relatively stable disease state was designed to allow better discernment between natural disease progression and treatment-related events. To minimize additional variables, patients who were already receiving disease-modifying therapies (DMT) upon entering the study continued as a concomitant treatment through the course of the study". 

"There were no serious adverse events or hospitalizations associated with IT MSC-NP treatment" 

"The safety data was further supported by a lack of any change in brain MRI scans during the study. Specifically, no new T2 lesions or changes in disease burden were observed". 

"The study design was not blinded, and there were no placebo controls". 

Therefore, be warned the power of the placebo should not be under-estimated. The placebo effect where you get better after taking nothing can be immense and has sent many good ideas to their graves.

The primary post-treatment clinical assessments were conducted at three and six months following the third treatment and compared to baseline (pre-treatment) in order to determine trends in efficacy. Of the 20 study subjects, 15 (or 75%) demonstrated neurological improvement associated with IT MSC-NP treatment. 

Improvements were documented in the following areas: EDSS, MRC muscle strength scale, timed 25-ft walk (T25FW), and/or bladder function.Of the remaining subjects, two showed disease worsening despite the treatment, and three subjects showed no change.

The predefined endpoint was adverse effects but secondary endpoints were evidence of efficacy allowing the centre to pick and choose and so data hack to spin the best story. 

                                               EDSS

So as you can see 4 people showed qute a bit of improvement and there were reports of improvement for other outcomes notably the lower limbs and bladder rather than upper limbs and cognition.

So first things first you can see it is not a miracle cure and therefore we need to view these results positively, but also objectively. 

The myth being spun is that stem cells will turn back the clock and for most people here, this is not the case, so we need to understand the reality of these studies. It is a start

This study injected live growing cells and so they are producing a group of "potential goodies" that may be growth factors.

Worldwide occurance of JC virus

Are you JCV positive? What are your chances of being positive? 




Paz SC, Branco LP, Pereira MAC, Spessotto CV, Fragoso YD. Systematic review of published data on the worldwide prevalence of John Cunningham virus (JCV) in patients with multiple sclerosis. Epidemiol Health. 2018. doi: 10.4178/epih.e2018001. [Epub ahead of print]

PURPOSE:

The John Cunningham virus (JCV) is a polyoma virus that infects humans mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies has been described to be between 50% and 90% in human serum. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish real-life values of JCV seropositivity in these individuals.

METHODS:

The present review followed the PRISMA guidelines using the following search terms: "JCV" OR "JC virus" AND "multiple sclerosis" OR "MS" OR "NMO" OR "neuromyelitis optica" AND "prevalence". These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, Medline, SciELO, LILACS, Google Scholar and EMBASE.

RESULTS:

After initial selection, 18 papers were included in the review. These articles reported on the prevalence of JCV antibodies in serum of patients with MS or NMO living in 26 countries. The systematic review identified data on over 29,000 patients with MS/NMO and found overall that 57% of them (16,730 individuals) were seropositive for anti-JCV (range 40% to 69.5%).

CONCLUSION:

The median worldwide prevalence of JCV among adults with MS or NMO was 57%.

If the incidence of JCV was 100%  it could form a good potential to be a target as CD8 and antibody depletion of infected oligodendrocytes but this study suggests it is too low. But at about 60% it is reasonably common that your chances of being positive are high and this will limit your treatment options.

Education: About EBV Infection

A post for people who need to know more about EBV.




EBV is a member of the herpes family of viruses that are common in humans. 

The silent infection and the life-long persistence are the keys to the widespread infection of EBV in the human population. 

In most individuals, EBV infection occurs early in childhood and goes unnoticed.

In contrast, delayed primary infection during adolescence can lead to infectious mononucleosis (IM) = glandular fever. 

EBV primarily targets and remains latent in memory B cells. 

Depending on the type of latency, EBV expresses different sets of latent products. 

In the latency typically seen in IM, up to 12 viral products, including 6 EBV-encoded nuclear antigens (EBNA-LP, EBNA1, EBNA2, EBNA3A, EBNA3B, and EBNA3C), 3 latent membrane proteins (LMP1, LMP2A, and LMP2B) and large quantities of 2 non-coding RNAs (EBERs) are expressed 

A small percentage of latently infected cells intermittently enter the lytic cycle resulting in the release of viral particles

This transition from latency to lytic cycle is triggered by the expression of two immediate early viral proteins, BZLF1 and BRLF1

Almost all MS patients are infected with EBV compared to ~95% non-MS controls. 

Thus, EBV seronegative individuals have almost zero risk of developing MS. 

However, a dramatic upsurge in MS risk is seen when these individuals seroconvert following EBV infection. 

Furthermore, individuals who have a history of EBV-associated IM have also been shown to be at increased risk of developing MS.

In the paper below

Overall, 91/101 (90%) of MS cases were EBV positive by l compared to only 5/21 (24%) non-MS cases 

That damned, elusive EBV

Will this study get the field behind the EBV hypothesis once and for all? Or will it be another bun fight?




PLoS One. 2018 Feb 2;13(2):e0192109. doi: 10.1371/journal.pone.0192109. eCollection 2018.

Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells.

Hassani A, Corboy JR, Al-Salam S, Khan G.

Abstract


Multiple sclerosis (MS) is a chronic neuroinflammatory condition of the central nervous system (CNS). It is a major cause of neurological disability in young adults, particularly women. What triggers the destruction of myelin sheaths covering nerve fibres is unknown. Both genetic and infectious agents have been implicated. Of the infectious agents, Epstein-Barr virus (EBV), a common herpesvirus, has the strongest epidemiological and serological evidence. However, the presence of EBV in the CNS and demonstration of the underlying mechanism(s) linking EBV to the pathogenesis of MS remain to be elucidated. We aimed at understanding the contribution of EBV infection in the pathology of MS. We examined 1055 specimens (440 DNA samples and 615 brain tissues) from 101 MS and 21 non-MS cases for the presence of EBV using PCR and EBER-in situ hybridization (EBER-ISH). EBV was detected by PCR and/or EBER-ISH in 91/101 (90%) of MS cases compared to only 5/21 (24%) of non-MS cases with other neuropathologies. None of the samples were PCR positive for other common herpesviruses (HSV-1, CMV, HHV-6). By quantitative PCR, EBV viral load in MS brain was mainly low to moderate in most cases. However, in 18/101 (18%) of MS cases, widespread but scattered presence of EBV infected cells was noted in the affected tissues by EBER-ISH. Immunohistochemical analysis of EBV gene expression in the 18 heavily infected cases, revealed that the EBV latent protein EBNA1, and to a lesser extent the early lytic protein BZLF1 were expressed. Furthermore, using double-staining we show for the first time that astrocytes and microglia, in addition to B-cells can also be infected. To the best of our knowledge, this is the most comprehensive study demonstrating that EBV is present and transcriptionally active in the brain of most cases of MS and supports a role for the virus in MS pathogenesis. Further studies are required to address the mechanism of EBV involvement in MS pathology.

"We seek him here, we seek him there...Is he in heaven - Is he in hell?"

-The Scarlett Pimpernel by E Orczy

No really! The cause of MS is as elusive as the Pimpernel was to the French. Despite mounting evidence, no research group has yet successfully managed to nail EBV to MS. This work by Hassani and colleagues is hope that it may yet happen!

Epstein-Barr virus (EBV) is a member of the Herpes family of viruses and is common in humans. It's target is B cells and can remain dormant or latent in memory B cells for their lifespan. A small percentage, however, do reactivate in what is called the lytic phase.

EBV is associated with more than one disorder, but is thought in MS at least it causes a virus-host immune system response imbalance, with the immune response to the virus to the virus itself being disrupted (Sundström P, Juto P, Wadell G, Hallmans G, Svenningsson A, Nyström L, et al. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology. 2004;62: 2277–2282). Almost all PwMS demonstrate evidence of previous EBV infection, and those who have not been exposed (i.e. seronegative) have almost zero risk of developing MS. The spanner in the works is that ~95% of those without MS have also had previous EBV exposure (Ascherio A, Munch M. Epstein-Barr virus and multiple sclerosis. Epidemiology. 2000;11: 220–224).

The question then becomes can you place EBV successfully in the brain where it can cause MS? And that is what the authors have done. Hassani et al, examined the presence of EBV in 122 post-mortem MS brains and non-MS brains. Others have tried to do this in the past but not successfully for any number of reasons - techniques, sampling etc. They used a PCR technique and a highly sensitive and specific EBER- in situ hydridization (EBER-ISH) technique to localise EBV infected cells in brain tissues.

Surprisingly, they found that EBV was present in 90% of MS cases, but also found no presence of other viruses, such as HSV-1, CMV and HHV-6 that have been previously implicated in MS. Of note, they also found that not only did EBV target B cells, but also infected ~10-15% activated microglia and astrocytes (the innate immune system, see Figure). Therefore, the role of EBV in the inflammatory cascade needs to be looked at in greater detail.

Overall, a very interesting paper and others will now have to re-examine EBV in MS brains using the more sensitive techniques in order to identify scattered and low level EBV infection.

Figure: Double staining for EBV and cellular markers.
Double staining for EBV (EBER-in situ hybridization: dark blue staining) and different cellular markers (immunohistochemistry: brown) in the white matter of 3 different heavily infected MS cases. The pattern of double-staining seen in these 3 cases is representative of that seen in other double-positive cases. (A) EBV and CD20 (B-cell marker), (B) EBV and GFAP (astrocyte marker), (C) EBV and Iba1 (microglia marker). Double positive cells are indicated by the arrows.