A neurologist calls ...

The greenest caterpillar I ever saw!

... or rather, I call on a neurologist. 

Last week was my first (and likely only) appointment this year with my neurologist who has been managing my care since I was diagnosed in 2011. Since I last saw him my drug regime changed slightly due to some worries about blood tests. My understanding was that my total white cell count was dropping too low which would make me susceptible to infection. 

My neurologist clarified this by explaining that there are several different types of cells in the total. The one which was causing concern in my case was the neutrophil count. The web tells me that neutrophils fight infection and if there are too few of them even bacteria normally found in the mouth, on the skin and in the stomach can cause serious problems. Now the drug (Azathioprine) I take for CLIPPERS aims to reduce the lymphocyte count - lymphocytes are the cells associated with CLIPPERS. But clearly for whatever reason, both cell counts were being driven down over the summer. He was reassured by my more recent test results and my Azathioprine dose is high enough (based on body weight) to still be having an effect on lymphocytes. We did the usual eye-tracking and finger-pointing tests and some checks on muscle-tone and reflexes and nothing cropped up there.

We also had a discussion about long term Azathioprine use. Unfortunately we don't know for sure if that is what is keeping me well. I said that if the risks of serious illness associated with taking Azathioprine long-term were low then I felt I had more to lose if I stopped taking it and suffered a CLIPPERS relapse. He said he agreed but it was hard to be definitive because of the lack of knowledge about how CLIPPERS works. So I said I would keep taking the tablets. 

It is also sobering when reminded that my status is "in remission from cerebellar disease" which sounds like I am stuck in some kind of waiting room.

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Living With CLIPPERS by Bill Crum is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

The Alien in the Room

No aliens here.

Wow. It is 5 years since I was diagnosed with (probable) CLIPPERS and pumped full of intravenous Prednisolone for a week. I was still in hospital and waiting for an MRI to show "radiological improvement" before they would let me out. At the time there were considerable question marks, not only about the long-term prognosis for CLIPPERS, but also about whether the diagnosis was correct or whether I might have something potentially worse. Since then, I have made steady progress and been remarkably stable health-wise. But I am careful not to become complacent.

I am a child of the video-game generation and have been playing games of various kinds virtually my whole life. I tend to like games which have a strategic, exploratory and/or puzzle component but am not averse to a bit of (video-game) ultra-violence, especially if combined with one of the above. Currently I am playing a game which I stayed away from for a while as I thought it would be too far outside my comfort-zone - Alien : Isolation. This is a game set in the Alien universe where, to cut a long story short, your character is stranded on a space-station being stalked by a predatory alien and with virtually no effective weapons. You can't kill this creature, you can only hide from it, distract it and occasionally make it retreat for a very short while. The creature wanders the corridors, travels through air-vents and is systematically searching for you. When it finds you, you come to a grisly end. Spooky.

It made me think about my experience with CLIPPERS. Like my character in the game, I know I am trapped in an environment with something nasty which I can't see and can't do much about. In the game, sometimes the alien disappears for a while, sometimes you can hear it rattling around nearby vents and sometimes it comes out of the vents and searches the rooms. In the game I am always listening and looking for signs the alien is near and in real life, although CLIPPERS doesn't seem very close at the moment, I am still looking for signs that it may be lurking nearby. Unlike in the game, if CLIPPERS reappears I can't hide from it, but at least I have a bit more idea what to expect. Also, in the game, I know I will ultimately have a chance to escape completely and I'm hoping the same will one day be true of CLIPPERS.

Update: With Azathioprine reduced to 150mg/day, my white blood cell count has stabilised at 3.4 which is acceptably abnormal. No signs to date that this dose reduction has had any unwanted CLIPPERS effects.

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An interesting treatment case

My local sun-bathing blackbird.

I saw a new case study recently which suggested a variant on treatment. In their paper,

IFN beta 1a as Glucocorticoids-Sparing Therapy in a Patient with CLIPPERS, Dr Rico and colleagues, discuss a CLIPPERS patient who suffered approximately one relapse a year when tapering steroid treatment was used. The initial high-dose treatment gave (incomplete) improvement but once the lower dose treatment ended, the symptoms returned. This patient was first seen in 1996, well before CLIPPERS had been defined as an entity in the medical literature. The doctors suspected an auto-immune disease but had ruled out Multiple Sclerosis (MS) so they decided to try an alternative imuuno-suppressant therapy, namely interferon beta 1a. I don't know anything about this treatment beyond the fact that it has been used to treat MS. The patient subsequently only suffered one relapse every 4 or 5 years and relapses did not permanently worsen his condition.

 

However, the patient was also maintained on a corticosteroid dose equivalent to 25mg Prednisolone every 2 days which makes the interpretation of his improvement less clear. In addition, the authors report that when this corticosteroid was withdrawn a new relapse followed. So it is not clear to me how these two parts of the treatment are working and whether both are required or whether it is the continual low-dose steroid which is important. The authors also repeat an assertion I have read elsewhere, namely that "... except for methotrexate and possibly rituximab, no drug has been able to have sustained control of the disease without combined oral glucocorticoids ...". Maybe I need to put my hand up, as I have been stable on Azathioprine for 4 years after steroids were tapered to zero. Of course, technically I am an IPPER not necessarily a CLIPPER (see previous post) so may be atypical, and there is no guarantee I will stay this way (especially with my currently meandering white blood cell count and treatment changes). Unfortunately, treatment response is just one more part of the CLIPPERS story where there is still a lot of variability and uncertainty.

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Update

Reflection on a London tube-train - curved glass.

Regular readers may recall I was having problems maintaining a reasonable white blood cell count while on 200mg/day Azathioprine. Since then, my readings went up slightly (3.a-little-bit) and then dipped down again to 2.7 at which point the doctors decided action was required. Of course I feel fine day to day but if the white blood cell count gets too low I could be at risk from infections - and this is someone who travels on public transport to work so I'm concious of being exposed to bugs from other people most days. So I was told to reduce my dosage from 100mg AM + 100mg PM to 100mg AM + 50mg PM , a 25% reduction overall. 

I am in uncharted territory now - and a bit paranoid to be honest - as I have been on this dose for 4 years and have no idea what the critical level is or how tightly connected the white blood cell count is to the chance of CLIPPERS relapse. My thinking is that this dose change is simply returning the white blood-cell count to the intended effect of the therapy in the first place so everything should be OK. I have my first blood test since changing the dose this week and I will keep you posted.

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Living With CLIPPERS by Bill Crum is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

CLIPPERS or IPPERS?

Not a family-friendly beach!

In a recent letter, Dr Taieb remarks that "most reported cases of CLIPPERS are in fact only ... PPERS due to the short follow-up and the absence of biopsy". So he is pointing out that in the absence of biopsy the "Chronic Lymphocytic" part of CLIPPERS is unproven. (He also takes out the "I" for Inflammation but I would argue that MRI findings in presumptive CLIPPERS patients suggest some form of inflammation.) I am happy to call myself an IPPER instead of a CLIPPER (as I am one of those unbiopsied cases). I'm not sure what the alternative is - pePPERS? 

This hides a serious debate about diagnosis of CLIPPERS - the CLIPPERS population is a mix of folk with different kinds of diagnostic tests and different levels of diagnostic confidence. We have all at least had most other conditions excluded. Dr Taieb also suggests that a relapsing-remitting pattern should form part of the diagnosis for CLIPPERS (like in Multiple Sclerosis). However, that would mean that I don't have CLIPPERS as I have, so far, been relapse-free on medication since my first onset.

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Up and down, like the FTSE 100.

Wormwood Scrubs Common (London)

Well not quite as bad as the FTSE 100 but that's another story (not helped by lots of people on strike and those that aren't on strike going into meltdown over potential Brexit). Of course I'm talking about my meandering white blood cell count which has been wandering a bit further than it should recently.

As my CLIPPERS medication of choice, Azathioprine, willfully interferes with the immune system (which is presumably why it helps keep CLIPPERS at bay), it is expected for my white blood cells to be more thinly populated compared with the norm. The expected range is somewhere between 4 and 7 (I am not a doctor) and mine tends to hover between 3 and 4. About 7 weeks ago it dipped to a historic low of 2.6 and there was much muttering amongst the medics behind closed doors which resulted in me being allowed to stay on Azathioprine for now, but in exchange for having further tests every 3 weeks or so.

On the next test the count had gone back up to 3.something - hurrah! However, on the one I had last week it had dipped back down to 2.9; this is still better than my previous historic low of 2.8. So the tests will continue and I'll let you know if anything strange happens. 

There are no specific symptoms associated with low white blood cells but I was already being as careful as possible to avoid sources of infection - lots of hand-washing and keeping hands away from my mouth, nose, eyes etc. Public transport in the mornings makes me uneasy - too many germs! My doctor emphasised that if I get fevers or unexplained illness I need to see him immediately - presumably under these circumstances I will be able to bypass the 3 week wait for an appointment that is the current situation here.

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Unwanted Dips

Spring in my parent's back garden

I recently got called back by my local docs as my total white blood cell count has dipped below my usual acceptably low level of 3-and-a-bit. Apparently in an ideal world it would be above 4 and in my world it usually hovers around 3.2 or a little higher or lower. In March it was 2.6 beating my previous record of 2.8 a couple of years ago. At this point there was apparently some head-scratching behind the scenes as usually, at least at my practice, a level this low would often trigger a change or cessation of the medication causing it to dip - in my case Azathioprine. I have now been taking 100mg Azathioprine twice a day for about 4 years and not had too many problems on it to date. 

My neurologist has advised I remain on my current level of medication and have full blood counts every 3 weeks. I think one issue is that no-one knows the correct levels of medications for CLIPPERS except in general terms and the only thing they know about me is that I have been essentially symptom-free while taking Azathioprine. (Of course this doesn't prove that Azathioprine is the *reason* I have been symptom-free). So I think all concerned are a bit loathe to mess with the meds in case it triggers something worse. Having said that I have been told to be very watchful of illnesses which feature high temperatures / fevers and get myself down to the surgery ASAP if one appears. I'm having some more blood taken tomorrow, so in a few days should know if this is a blip or a trend. It's worth mentioning that I had no reason to think there were any problems so although these blood tests are a bit tedious after five years  they are well worth keeping up with as things can and do change.

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Living With CLIPPERS by Bill Crum is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

Diagnosing CLIPPERS Using MRI is Tricky

Spring is in the air, as evidenced by this recent visitor who has successfully found a way through the garden fence and is getting bigger.

Contrast-enhanced MRI of my brain in 2011.
The bright spots in the middle indicate CLIPPERS-related damage.

One of the hallmarks of CLIPPERS is the characteristic pattern of enhancing lesions many of you will have seen in MRI. It is tempting to regard the presence of a pattern like this as sufficient evidence to diagnose CLIPPERS, particularly when there is no clear alternative. Unfortunately, life is rarely that simple and there may be other reasons why patterns of lesions like this can develop.

Dr Taieb and colleagues have helpfully written a guide to diagnosis in these cases. Their paper, Punctate and curvilinear gadolinium enhancing lesions in the brain: a practical approach, examines 39 cases of their own where similar patterns of brain lesions occur, together with other reported cases, and details the many different problems which could be the cause. (Unfortunately, this paper isn't freely available to read from Springer - you can try asking Dr Taieb for a pre-print.)

This (above) is perhaps the most interesting part, a diagnostic flow-chart for when lesions are present. Interestingly Dr Taieb suggests brain-biopsy only as a last resort. Fitting CLIPPERS into a standard diagnostic process is clearly important. This paper may not be the last word on the subject but is a step in the right direction.

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Rare Disease Day 2016

In just over a week it is Rare Disease Day 2016. "The main objective of Rare Disease Day is to raise awareness amongst the general public and decision-makers about rare diseases and their impact on patients’ lives." This can only be a good thing, although I must admit to being a bit out of my comfort zone with these mass movement things. However, they have an important role to play, especially for conditions as rare as CLIPPERS. 

Rare Diseases UK have information about the scale of the problem where I am located - but the numbers translate more or less to most other places. The most important relationship is that although there may be very few sufferers of any particular rare condition (even down to a handful), the number of identified rare conditions is so large (around 7000) that (in the UK) 7% of the population will be affected by a rare condition at some point in their lives.

CLIPPERS seems to be a rare condition amongst rare conditions at the moment. Four-fifths of rare diseases have a genetic component and there is no evidence of that (so far) in CLIPPERS. Three-quarters of rare diseases affect children and although there are a few reports of CLIPPERS in children, most reported cases seem to be in adults, with some hints that it is more prevalent when heading towards middle age. According to Rare Diseases UK, a rare condition may affect up to 30,000 people in the UK, but I doubt there are more than 20 diagnosed cases of CLIPPERS here at the moment. Please prove me wrong on this if you know different and I'll report back here.

So, like it or not, to be diagnosed with CLIPPERS is to be a member of a small and exclusive club, and unless CLIPPERS turns out to a be a "missing link" which unlocks the mysteries of other, better-known, conditions, then it is cross-community campaigns like Rare Disease Day which can do the most to push the agenda of CLIPPERS as a rare disease in the wider world.

P.S. I received a nice graphic - posted below - from Cameron Von St. James, a mesothelioma cancer caregiver and advocate. Cameron works with the Mesothelioma Cancer Alliance to spread awareness of another rare disease, Mesothelioma, caused by exposure to asbestos, as well as all rare diseases.

Image provided by www.mesothelioma.com.

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Auto-immune or not?

Recent posts have been few and far between - sorry about that. I hope to up the frequency a little now that small details like getting a new job have been resolved.

CLIPPERS has been proposed as an "autoimmune disease", a view supported by the fact that effective treatment is focussed on immune-suppressing agents such as Prednisolone, Methotrexate and Azathioprine. With this in mind, there have been a couple of recent news-items on the nature and treatment of other auto-immune disorders which are interesting.

One concerns a possible future treatment for early Multiple Sclerosis which involves destroying and then regenerating the patient's immune system. In a recent trial, this treatment reduced auto-immune attacks on myelin - the cause of MS - by up to 75%. This therapy is at a very early stage of research but the fact there has been proof of concept in human trials is very exciting. Having said that, the technique as it stands involved aggressive chemotherapy which is not trivial to administer or tolerate. Whether this research results in some general principles which can translate to other auto-immune disorders is unclear at the moment, but worth keeping an eye on for the future.

The other story has been floating around in various forms for several years, but was recently revisited in a British newspaper ("Why a diet of worms could be good for you", The Guardian, February 2016). The essence of this story is that in the past our bodies were used to the presence of parasitic worms and developed a complex relationship with them. Quoting the doctor from the article, "I can give a mouse multiple sclerosis, rheumatoid arthritis or colitis, and when I give it worms, the disease goes away. Can we do that in humans too? I don’t see why not.” Researchers think that parasitic worms adjust the immune system of the host to dampen it down which could have beneficial results when auto-immune disease is present. However the mechanisms are not understood and there have been virtually no studies in humans. Given the choice in a few years time of immune-system destroying chemo or having a few worms to stay, I know which I would choose. However, please note that I am not a doctor and definitely not advocating treating CLIPPERS using worms.

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2016

The Round Table (allegedly) in Winchester

Just a quick note to wish everyone who follows this site - or even just visits occasionally - a happy and prosperous 2016. I will endeavour to keep you all updated with any news about CLIPPERS I hear about. As always, if anyone has anything they want to share then please get in touch. Please note that I am changing my preferred email address for the blog to wrcrum@hotmail.com but entries to the old one should still get through.

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Living With CLIPPERS by Bill Crum is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.