Another Year

I take no credit for this - my wife's creation.

Just a quick note to wish everyone a peaceful and happy end to 2014.  My own Christmas break started off with an invoice from my local health centre. They had received a request for my medical records from the Mayo Clinic as I had signed up for the Mayo research study. It hadn't occurred to me there would be a charge for this - after all it is making a contribution to medical research. Anyway, although £24 won't bankrupt me, it wasn't quite the Christmas card I was expecting when I opened the letter!

I will be back in 2015 to pass on anything I can find out about CLIPPERS. If anyone has any news to share please contact me or post in the forum.

Best Wishes

-Bill

Probable CLIPPERS since 2011.

P.S. After writing this post, I received very nice emails from Jessica Sagen and Dr Tobin at the Mayo, telling me that costs incurred providing records for their research will be covered from their research budget. So thanks very much to them for that.

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Nothing to see here (probably)

A birthday card I saw
  recently - seriously!

It's all been a bit quiet on the CLIPPERS front lately, so apologies for the slightly sporadic updates at the moment. Another one of these complicated single-case studies has appeared though, so I'll give you a quick run-down. The essential feature of this 62-year old woman's story is that she was diagnosed with CLIPPERS after an episode of shingles which was concentrated on her left ear, eye and face. There is quite a lot of detail about different treatments and symptoms but essentially, when CLIPPERS symptoms first appeared, a left-sided brain lesion was seen on MRI which later developed into a more classical CLIPPERS pattern of lesions towards the back of the brain. This is an interesting case, but as is quit common at the moment, one that is so unusual it is hard to draw too many firm conclusions. I picked up on a couple of things in the paper though.

Firstly the authors speculate that (my paraphrasing) shingles and CLIPPERS in this case are related due to the "time-course" and "laterality". So the time-course means that one follows the other; but just because  the bus arrives after I stand at the bus-stop doesn't mean that I caused the bus to arrive by standing there - correlation versus causation. Secondly, "laterality" means "same-side"; so here, the shingles manifested on the same side as the subsequent brain-lesions. However, for the sake of argument consider that the shingles were completely unrelated to CLIPPERS and were a random occurence (the so-called "null-hypothesis"). Then there is a 50% chance they would manifest on the same side as the initial CLIPPERS lesion even if they had nothing to do with CLIPPERS. Of course, if we see more cases like this then the arguments for time-course and laterality strengthen.

To be fair the authors do go on to say that they "do not believe that the CLIPPERS syndrome is directly caused by the ... viral infection" and flag well the parts of their discussion which are speculation. I hope these cases keep being reported as my impression is that the diversity of CLIPPERS cases appearing over the last couple of years suggests that it could be part of a much larger puzzle concerning a variety of more common brain conditions.

It will be interesting to see if any more cases involving shingles appear. I had facial shingles in 2014 (also on the left-side) after developing CLIPPERS in 2011. In my case, shingles was almost certainly a consequence of immune-suppression from CLIPPERS treatment and being generally run-down. I am pleased to report, that in my case at least, shingles has not caused any resurgence in CLIPPERS symptoms.

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Steps in the right direction ... hopefully

Rainy London

To counteract the grey skies, shortening days and dipping temperatures in the UK, there has been a hint of progress in our understanding of CLIPPERS. In their paper Effective antituberculous therapy in a patient with CLIPPERS: New insights into CLIPPERS pathogenesis, Dr Mele and colleagues describe a CLIPPERS case which was initially diagnosed and treated as suffering from CNS tuberculosis. After 18 months of treatment the patient no longer had significant symptoms and only slight MRI abnormalities. 

The interesting thing is that 6 months after tuberculosis treatment was stopped, the patient relapsed and then improved again when tuberculosis treatment was restarted. My reading of the paper is that the first treatment round should have guaranteed that no tuberculosis was present yet they still improved when treated for it again. At this point the patient was re-appraised and treated for CLIPPERS with Prednisolone at which point more marked improvement was seen.

So the interesting result is that improvement in a CLIPPERS patient was seen whilst being treated with drugs not usually used for CLIPPERS. The authors note that one of these drugs (rifampicin) is anti-inflammatory and is also thought to be helpful for rheumatoid arthritis. They speculate in some detail about the possible mechanisms by which this drug may operate.

This is a very interesting article and I don't pretend to understand the detail. As I am not a doctor, there may be short-comings that I don't appreciate (not least the usual problems of diagnosis) so some caution is required. However, the authors should be applauded for not claiming too much. They report a single interesting case and discuss possible consequences including the potential use of response to rifampicin in diagnosis, but do not go over the top. In my opinion, this work is perhaps more valuable for providing possible clues and new directions for research rather than suggesting alternative CLIPPERS treatments. It is also the sort of paper that may well attract some interesting letters from other academics in the next few months. I will keep watch.

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Extending CLIPPERS (again)?

As time goes on, there seem to be more case studies which veer away from the characteristics of the original cohort described by Dr Pittock. In this recent report "An extended chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids phenotype", Dr Lane and colleagues describe an interesting new case with some unusual features. (Unfortunately full text for this article is not available on-line, but those interested could try emailing the senior author Dr Robin Howard and asking for a pre-print.)

The earliest symptoms of the woman in this case study were initially right-sided facial weakness with abnormal cold sensations on her left leg. It was over a year before scans revealed CLIPPERS-type brain lesions. However in this case there were more wide-spread lesions ("cortical involvement") than in some other reported cases and she suffered seizures. The CLIPPERS symptoms improved immensely after 5 days of high-dose steroids (although at 500mg/day rather than the 1000mg/day I received). Of interest to me  is that this patient was then moved onto a tapered dose of Prednisolone starting at 60mg/day (like me) and subsequently onto Azathioprine (like me, but dosage not reported). She has apparently remained well 6 months on. 

My experience is not directly comparable to this patient as my symptoms were much more in the "classic" vein (i.e. limited to double-vision, balance, speech, symmetric facial and limb numbness). However interesting to see the use of Azathioprine when it seems more common to prescribe Methotrexate or Cell Cept. I'm not convinced Azathioprine is a magic bullet but suspect that different people react to the disease and the treatment in different ways; but I am not a doctor.

Interestingly, my doctor said recently he still has no idea why some people seem to relapse on these "steroid-sparing" agents but remain well on steroids, as both treatments should have essentially the same action.

In other news I finally got round to sending my consent forms back the Mayo for their study.

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Historical CLIPPERS cases

Holiday snap from Southern Italy

I recently read an interesting short communication entitled "CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases" by Dr Kerrn-Jespersen and colleagues from hospitals in Denmark. As regular readers of this blog will know, the term "CLIPPERS" was first used in 2010 in the now well-known paper by Dr Pittock and colleagues. They observed a consistent pattern of symptoms and treatment responses in a group of patients over several years which led them to the conclusion that a single previously unreported condition was responsible. 

CLIPPERS is very rare, which is presumably why it was not identified earlier. However, it is reasonable to suspect that there were other cases out there "in the wild" before 2010; these cases were presumably either diagnosed as something else or diagnosed as some generic inflammatory condition. In the Danish paper, the authors searched their hospital records between 1999 and 2013 for cases with descriptions reminiscent of CLIPPERS. After some investigation they found 3 patients (= 12.5% of their initial list of suspects) who justified being reclassified with a CLIPPERS diagnosis. This number may seem small, but it is from a limited number of European centres over a limited time-period and suggests there could be significant further cases out there.

 

Perhaps the most important practical outcome of the study for us patients is that the follow-up of their 3 cases confirmed that early and sustained treatment was important to minimise longer-term problems.

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Brief Repository Update

Colin the Caiman

I received an email from Dr Tobin at the Mayo Clinic recently to update me on their CLIPPERS Respository project. This is a systematic approach to CLIPPERS research which involves gathering as much information about patients as possible in one place to enable detailed research. If you have a diagnosis of CLIPPERS and want to take part, you can read more on the CLIPPERS Repository page.

Anyway, they are currently focussing on patients who had tissue samples available and they have 12 enrolled to date which they are very pleased with. This data is enabling them to take a more comprehensive look at the common features of the condition across different people with less doubt about the possibilities of other diseases being present. There should be some more news about this in the near future.

They are also still very much interested in recruiting people with a CLIPPERS diagnosis but who didn't have tissue samples taken. These people (like me) are still a valuable resource and will form a larger cohort which can be used in the next phase of the research. I have signed up and will update you about the process when I get my enrolment kit.

Apparently, some other laboratories are talking to the Mayo about the possibility of performing different analyses on some of the samples. I think this is particularly exciting as it means there may be a competitive element which will help drive the research. I am hopeful that with this kind of approach some progress can be made in finding out more about what CLIPPERS really is, and how to best treat it.

Read other articles in this series at Living With CLIPPERS.

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More Medical Ponderings on CLIPPERS

Another paper from Dr Taieb appeared recently, again pondering on the relationship of CLIPPERS to other central nervous system disorders. In this short letter, "A central nervous system B-cell lymphoma arising two years after initial diagnosis of CLIPPERS", he considers a new case where an initial diagnosis of CLIPPERS was made which was based on tests including brain biopsy. Eighteen months later the patient relapsed whilst still taking Prednisolone and a diagnosis of presumed central nervous system B-cell lymphoma was made.

 

These cases are always worrying for those of us being treated for CLIPPERS. I guess the diagnosis had to change as the patient was no longer "responsive to steroids" which is required for CLIPPERS. But as ever, the question is, was this a simple case of mis-diagnosis under difficult conditions (not least as Lymphoma can also respond to steroids initially) or was it suggestive of CLIPPERS progressing to something else? Dr Taieb considers both these scenarios as possible and doesn't offer an opinion about which scenario he thinks most likely. It is also worth mentioning that Dr Taieb says that this case is one patient out of twelve studied in the 2012 French CLIPPERS cohort, the rest of whom (presumably) retained their original CLIPPERS diagnosis.

In other news, my shingles rash didn't get any worse and has largely cleared up. I have no idea if seven days of Acyclovir five times a day helped or not, but the rash stayed fairly localised. From what I have read, this was pretty mild for shingles as any discomfort stayed at the level of an annoying ache.

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CLIPPERS and Grade 1 Lymphomatoid Granulomatosis

In May, I reported on a curious case of CLIPPERS which involved skin lesions. There have now been two follow-up letters discussing this case. In the first, Dr Taieb (who has also published CLIPPERS-related papers) suggests that CLIPPERS could be a manifestation of a grade 1 Lymphomatoid Granulomatosis which is thought to be a pre-lymphoma condition. The key comment (from my reading) is that grade 1 Lymphomatoid Granulomatosis and CLIPPERS may be indistinguishable in terms of diagnosis and treatment response. In addition,  grade 1 Lymphomatoid Granulomatosis "does not necessarily progress to grades II or III" which would presumably explain why there are so many "stable" cases of CLIPPERS out there.

 

In response to this, the original author, Dr Kossard suggests this association is premature. My interpretation of the letters is that it is hard to be sure, even from studying tissue samples, about any possible relationship between CLIPPERS and Lymphomatoid Granulomatosis. It does seem, though, that the net is very gradually tightening around CLIPPERS in terms of figuring out exactly what it is and where it sits in relation to other rare conditions.

 

 

In other not-so-exciting news, I came out in a painful rash on my face which I initially thought was caused by  insect bites but got gradually larger. I was quite surprised to be told by my doctor I had shingles. Of course, being immune-suppressed, means that despite this rash being fairly small on the scale of shingles, no chances are being taken. So now I am taking anti-viral medication five-times a day as well as anti-viral ointment for my eye (as the rash is closer than it looks on the picture).

 

Read other articles in this series at Living With CLIPPERS.

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News Update

About 3 weeks ago, I had my first brain-scan of 2014, this time at the Institute of Neurology in London. I did ask my neurologist whether they were going to try anything different, as the IoN scanners are more research-oriented, but he told me they were just spreading the load of clinical imaging cases. It's funny, that having scans less often is in some ways more stressful because you wonder what might have been going on in the interim. Anyway, I have now had the unofficial feedback on the scans which was that:

"Everything is good. There was a tiny bit of signal change in the pons, as before and no enhancement. No change from last year."

So this is good news, especially as I have now been off Prednisolone for two years. Sounds like a bit of residual CLIPPERS-related damage which I will have to put up with, but I can't associate that with anything specific in day-to-day life.

Read other articles in this series at Living With CLIPPERS.

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An interesting case study

Swarming Bees in Kent

I recently came across an interesting CLIPPERS case report (Paroxysmal dysarthria and ataxia in chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in which the patient had some experiences in common with mine. I have to be a bit careful as it is very tempting to pick out the bits I relate to while ignoring the bits I don't.

 

Anyway, this patient, a 56 year old man, was treated with 1g Prednisolone / day for three days followed by lower dose oral Prednisolone (30mg / day). The really interesting part is what happened immediately after the high-dose treatment. Quoting from the paper, "... 3 days after the first steroid pulse therapy, the patient presented with paroxysmal exacerbation of dysarthria and paroxysmal limb ataxia". Here, "paroxysmal" means "sudden outburst", dysarthria is speech disturbance and limb ataxia is problems with muscle control of limbs. They go on to say "These attacks lasted several seconds and recurred 20 or more times each day".

 

I have mentioned before, that I had what superficially seems a very similar experience when first treated with high-dose steroids. My problems came when initiating an action (e.g. getting up from the sofa, answering the telephone, crossing the road) and resulted in very restricted "stiff-limbed" motion and inability to talk for several seconds. I had to carefully plan things in advance so I didn't freeze at the wrong moment - especially when crossing the road! Unlike this patient, I had no additional treatment and my episodes gradually reduced in frequency and severity over a few weeks. I don't know if this strikes a chord with anyone else, but it is the first time I remember seeing this effect reported in a paper.

 

I'm currently waiting on a report of a recent "routine" brain-scan - will update when I get it.

 

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CLIPPERS Research Update

A good day for sun-bathing!

A couple more brief papers appeared recently showing that research and discussion into the possible mechanisms involved in CLIPPERS is on-going.

The first considers the relationship of CLIPPERS to a form of cerebral vasculitis - this was on the list of possible diagnoses I encountered in 2011. Interestingly, this paper (CLIPPERS With Chronic Small Vessel Damage: More Overlap With Small Vessel Vasculitis) is written from the perspective of the neuropathologist and makes the point that to-date there has been perhaps more emphasis on neuroimaging rather than direct examination of tissue. Presumably, this is partly because of the practical challenges of brain biopsy in the regions typically affected in CLIPPERS. The key finding in their described CLIPPERS case is that "small vessel injury" could be seen despite vasculitis not forming part of the original disease description. They do concede that vasculitis might not be the root cause of the observed vessel damage but carefully consider the evidence for this and other causes.

The second paper, Diffusely Infiltrating Central Nervous System Lymphoma Involving the Brainstem in an Immune-Competent Patient,  considers a case initially thought to be CLIPPERS but, after failing to respond to steroids, subsequently found to be lymphoma. I have to say, that the contrast-enhanced imaging in this case, particularly figure 1c, does not look quite the same as similar images of other CLIPPERS patients I have seen but .... I am not a doctor. The whole issue of the relationship of CLIPPERS to CNS lymphoma is vital to resolve. It is not clear to me whether it is simply a diagnostic issue or whether, as some have suggested, there may be a biological relationship between the two conditions.

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Yet Another Curious Case of CLIPPERS

 A very interesting variant on CLIPPERS which may offer more research clues has recently appeared. In the paper, "Neurotropic T-cell lymphocytosis : a cutaneous expression of CLIPPERS",  a patient is described who satisfies the current diagnostic criteria for CLIPPERS. However, in addition this person also suffered from sub-cutaneous ("beneath skin")  lesions for some years before, and after, their CLIPPERS diagnosis. The authors points out the similarities in the composition of the skin lesions compared with what is observed in CLIPPERS brain lesions. They make the point that sampling  tissue outside the brain to test for CLIPPERS would be very helpful for diagnosis. However, in this case a brain biopsy for direct comparison was not available so at least one key part of the puzzle is currently missing. 

This is certainly the only case like this that I have read about; the observations are intriguing. I think that time will tell whether this turns out to be a key insight or an interesting aside.

Read other articles in this series at Living With CLIPPERS.

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CLIPPERS News

 

(Unfortunately the biggest CLIPPERS news this week is not about the neurological condition but about the owner of the American basketball team. I can't compete with that, but can offer a couple of more modest news items. )

I met my neurologist yesterday and, to summarise, "no news is good news". I am being maintained on Azathioprine and will be scanned again in the next few weeks to be on the safe side. Vision (follow-the-finger) was judged good and balance/walking also OK. I'm not brilliant at standing on one leg with my eyes shut but would argue that was also the case before CLIPPERS arrived on the scene!

Last week, I received an update from Dr Tobin at the Mayo Clinic regarding the CLIPPERS repository. As a result of it appearing on this blog, 9 people have signed up so far (including me). Dr Tobin thinks this is an excellent response given the rarity of the condition, and this number of volunteers will allow the team to expand on their originally planned work.

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The CLIPPERS Repository

Spring at Last!

I am really pleased and excited to be able to tell you about a new initiative from the Mayo Clinic to start systematically collecting samples (blood/tissue) and records of CLIPPERS patients from around the world. The idea is that by looking in detail at as many cases as possible there is more chance of finding out about what triggers or causes CLIPPERS. Eventually this could lead to simpler diagnosis and more effective treatment. If you are interested in participating you can find out some more about the project on this new blog page, including contact details for Dr Tobin, the lead investigator.

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CLIPPERS: where are we now?

A new article has been published which attempts a comprehensive review of CLIPPERS as it stands in 2013/2014. It is written for medics, but I thought gave a really good general summary of the condition, the research studies, the diagnosis, the treatments and the "still to do". I think it should prove particularly useful for doctors new to the condition. As far as I can tell it is freely available by following the above link, but if that doesn't work for any reason, you could try emailing Dr Dudesek and asking for a "preprint".

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One of the more interesting aspects of research is when scientists have discussions in public via the letters pages of scientific journals. One such letter has appeared in response to a short paper which I discussed briefly last year. Essentially, in the original paper, the authors examined a CLIPPERS patient using some different types of MR image acquired on a modern scanner with a stronger magnetic field than in some previous studies ("3T").

In this letter ("CLIPPERS and its related disorders, relevance of brain 3.0 T MR"), Dr Taieb and his colleagues suggest that although some of the observed differences seen could be due to the stronger magnetic field and different types of images, they may still not be sufficient to distinguish CLIPPERS from two competing conditions (primary angitis of the CNS and B-cell CNS Lymphoma). They very sensibly suggest that more work needs to be done to confirm the original observations in more patients. Also they stress the need to compare the appearance of the MR images directly with that of tissue samples, so that a detailed understanding of how the tissue is affecting the MRI can be obtained.

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Rare Disease Day is Nearly Here

Friday 28th February 2014

A disease or disorder is defined as rare in Europe when it affects fewer than 1 in 2000. A disease or disorder is defined as rare in the USA when it affects fewer than 200,000 Americans at any given time. So CLIPPERS is definitely rare on both counts and probably rare even for an officially rare disease. The hope is that by considering the relationships between rare conditions and more common ones, greater progress can be made in diagnosis, treatment and patient care.

 

http://www.rarediseaseday.org/

 



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A Spanish Case of CLIPPERS

A recent fatal BSOD encountered in my day-job.

I've been holding off discussing this case (CLIPPERS syndrome with atypical distribution of lesions in magnetic resonance imaging of the brain) in the hope I could get hold of the full text - unfortunately I couldn't. Anyhow, these single cases, while interesting, are not always that insightful as these days they have to be atypical (or at least notably different in some way from "classic" CLIPPERS)  to be published. 

What I mean is that, they may be interesting to the specialist, but by throwing in an unusual presentation of symptoms or comorbidities, they can "muddy the waters" (in my view at least) as to what CLIPPERS really is. On the other hand, you could argue that I don't know what I'm talking about (and you'd be right!) and that CLIPPERS could be a broad-spectrum disorder that is still being mapped out by these case studies.

I only got to read the summary of this paper, but the gist seems to be that a 40 year old woman presented with some of the better-known CLIPPERS symptoms (diplopia, ataxia, disarthria) but a non-standard appearance of brain lesions in MRI. The lesions seemed to be in the standard places but more evenly distributed (?) (with the proviso that I'm not 100% certain what "enhancement gradient" means in this context); the authors imply the lesion density remains more constant in different parts of the brain than is typical. The response to treatment with steroids seems to be as expected for CLIPPERS.

So at least there are still papers coming through and things to be learned about CLIPPERS.

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CLIPPERS in 2014

A random crab.

Sorry for the slightly longer than usual gap in posts over the Christmas period. As you might imagine, although CLIPPERS itself doesn't respect holidays, the world of CLIPPERS news seems to, and there has not been much to report since December.

On the approaching horizon is Rare Disease Day 2014 on 28th February. Unfortunately CLIPPERS is too rare to appear on many lists of rare diseases. (However, it does appear on this US site). So if you have a Rare Disease organisation or group in your country, why not bring CLIPPERS to their attention? If no-one knows we're out there it is harder to get help. As for Rare Disease Day, there is a web-page of events world-wide which may help you find your local group.

I look forward to bringing you more CLIPPERS news in 2014 and I hope it is positive.

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