Another cautionary tale

Chewing the cud, or at least the hay, in Kent.

A recent article reminded me about the dangers of classing myself simply as "someone with CLIPPERS". Probabilities are funny things; when considering someone who is otherwise well, the lifetime chance of them getting diagnosed with CLIPPERS is very small indeed. The lifetime chance of them getting diagnosed with CLIPPERS AND some other condition is even smaller. However, for someone who already has a diagnosis of CLIPPERS, their chance of getting some other condition is just the same as anyone else (unless CLIPPERS has some mysterious protective effect which seems unlikely).

In their article "Stroke mimicking relapse in a patient with CLIPPERS syndrome" (unfortunately, not freely available), Dr Lefaucher and colleagues from Rouen describe exactly this latter set of circumstances.  A 52-year old man who had been diagnosed with CLIPPERS four years previously presented with double vision and ataxia, both common symptoms of CLIPPERS. After running some tests, a particular kind of stroke affecting a similar region of the brain as CLIPPERS was diagnosed and the patient was treated accordingly. In the paper, the authors briefly discuss whether disease processes associated with CLIPPERS could have made this kind of stroke more likely in this patient. They suggest that damage to small vessels after inflammatory disease (i.e. like CLIPPERS) could be a risk factor for subsequent stroke. However they also say, with a slightly odd choice of words, that the association between CLIPPERS and stroke in this case is simply "fortuitous" - I think I prefer the term "coincidental" but I'm pleased they concede that it could be just "one of those things" (my phrasing).

As someone in reasonable health, apart from CLIPPERS, and approaching middle-age this article reminded me that just because I drew the short straw in terms of rare cerebellar disease, doesn't mean that I am immune from any of the more common conditions that can appear as we age. So it's definitely worth doing the usual things to stay healthy to avoid as far as possible any other surprises.

Read other articles in this series at Living With CLIPPERS.


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

Glimpses of CLIPPERS Neuropathology

Seeing blobs on contrast-enhanced MRI and not being able to tie my shoe-laces up is one thing, but figuring out the root cause(s) and mechanism(s) of CLIPPERS is complicated. In fact it is probably far more complicated than I imagine, and I already think it is complicated. One of the most valuable resources for scientists investigating CLIPPERS is access to brain-tissue for direct investigation. Until some suitable animal model displaying CLIPPERS-like features is found, we have to rely on sporadic and sometimes opportunistic access to brain-tissue samples from patients. 

I have a couple of reports from such studies in my CLIPPERS folder. These are hard for me, as a layman (and someone who left biology behind a long time ago) to discuss as I am aware of my lack of understanding and cautious about passing it on. Anyway, here goes ....

The first report is from a conference last year (The International Congress of Neuroimmunology). The title nicely summarises the study:  "Neuropathological evaluation of four Danish cases of CLIPPERS: Evidence of generalized neuroinflammation but no pre-lymphoma". (Unfortunately the full text does not seem to be publically available, however as a conference paper it was less than half a page of text anyway - a bit mean of the publisher though.) One of the four cases had been autopsied so presumably the whole brain was available for analysis. Perhaps the most interesting finding was that some broader evidence of inflammation was found in brain tissue - "A similar, but less prominent, T-cell infiltration was found in the normal appearing cerebral cortex" - which would not light up in contrast-enhanced MRI i.e. not in visible lesions. Perhaps the most reassuring finding was that "Our study does not suggest that CLIPPERS is a pre-lymphoma condition".

The second report was of a single, quite severe case, of CLIPPERS in an elderly woman who subsequently died of other causes. In their paper "Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): postmortem findings", the authors found less extensive inflammation - "The dura, cortical gray and white matter, ..., were unremarkable." They also remarked that "... our case does show that evolution to lymphoma, even after several years, is not inevitable in CLIPPERS."

So, in these small studies, there are already some interesting agreements and disagreements. It is possible the the variation in CLIPPERS presentation and patients may explain things, or differences in the experimental methods which I have not picked up on. Small steps.

Read other articles in this series at Living With CLIPPERS.

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

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.

Read other articles in this series at Living With CLIPPERS.

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

CLIPPERS: State of the Nation

Greeek Cat on Patrol

The third, and most important, paper that appeared over the summer is to be published in the journal Clinical and Experimental Immunology. This paper, entitled CLIPPERS: Review of an increasingly recognized entity within the spectrum of inflammatory CNS disorders, is an up-to-date and substantial review of CLIPPERS in terms of definition, patients and treatments. I'll just pick a few things from the paper to talk about here. 

One is that the "pathogenetic concepts in CLIPPERS are principally still based on assumptions and speculations" which means that the cause and mechanism of CLIPPERS is still unknown.The authors emphasise that finding a unique cause is necessary for CLIPPERS to be confirmed to be a unique condition (as opposed to a strange variant of some other condition).

On the evidence so far, the authors say that the average age when CLIPPERS appears in is between 43 and 53 (this is only the average and obviously there are people much older and much younger who have CLIPPERS). They say there is some evidence that men are slightly more likely to be affected - or at least reported. These figures are based on more cases than were available when I speculated on who gets CLIPPERS in January 2012. Interestingly they also claim that the "clinical course ... seems to be relapsing-remitting". Although I progressed fairly slowly (over a few months) before treatment, I was definitely getting worse and didn't get as far as any remission before treatment. I'd be interested to hear whether anyone out there had remissions independent of treatment.

Also discussed are the various treatment strategies, focussing on the use of corticosteroids with or without additional immunosuppressants. Interestingly the authors note that the success of the steroid sparing agents (like Methotrexate, Azathioprine, Cyclophosphamide and Rituximab) when used in the absence of steroids has not been proven. It will take more longer-term patient monitoring and reporting to figure this out. I've now been on Azathioprine-only for over a year and OK so far ....

Finally, they note 56 cases reported in the literature. Presumably more cases than that are out there in the wild (including me!). It's hard to estimate the true number of cases - is it twice this number or ten times it or more?

This paper as a whole is a useful and detailed summary of where CLIPPERS is at in 2013. It also confirms there is still a way to go in terms of understanding, diagnosing and reliably treating the disease.

Read other articles in this series at Living With CLIPPERS.

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

CLIPPERS?

Regular readers will know that the individual CLIPPERS case studies coming out now seem to be about CLIPPERS in conjunction with other conditions. I think pure individual cases of CLIPPERS are not adding much to previous research, but studies with large numbers of subjects are much harder to organise, especially with the still relatively small number of cases.

So this new paper is about a case of Lymphoma following CLIPPERS. This  seems to be better argued (at least in my definitely inexpert opinion) than this previous one relating CLIPPERS to previous influenza. This new connection is slightly worrying, as the authors discuss possible mechanisms (that I don't pretend to understand) whereby this case of CLIPPERS was an early indicator of something worse. 

As ever, it is impossible to draw strong conclusions from a study of one patient and, given that this link has not been previously reported, it is certainly not common in the studies which have been seen to date. When I was being diagnosed, I was told some form of Lymphoma was a possible alternative diagnosis and crucially, that it would also respond to steroid treatment but only in the short term. In this paper, the steroid treatment seemed to become less effective quite quickly and MRI subsequently showed a very un-CLIPPERS like lesion, even though the early appearance was CLIPPERS-like. I held my breath for about the first 3 months I was on steroids but when my improvement was sustained, it became less likely to be Lymphoma. So is this case CLIPPERS becoming Lymphoma or early Lymphoma mimicking CLIPPERS? I tend to think it's the latter as diffuse Lymphoma is reportedly very rare and very hard to diagnose. But I am not a doctor so what do I know!?

Read other articles in this series at Living With CLIPPERS.


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

One That Slipped Under the Radar

Or something like that.

I held off talking about this abstract in the hope I might find some more material.

0918: Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS): No Evidence For Antibodies To Neuronal Surface Antigens

P Maddison, P Gozzard, T Jaspan. Nottingham University Hospitals NHS Trust, UK

This was a paper presented at the Association of British Neurologists Annual Meeting 2011. I was hoping in the mean-time a full-length follow-up paper might appear but no joy. I don't pretend to understand the detail of this abstract but what makes it interesting is it is one of the only bits of work I have seen which focuses specifically on possible mechanisms from analysis of tissue samples rather than patient studies. The key phrase is (I think) "we looked for evidence of antibodies to neuronal surface antigens that could be pathogenic, or act as biomarkers of CLIPPERS". Deconstructing this as best I can, the authors believe that CLIPPERS has an auto-immune component which presumably means that antibodies are involved somewhere or other. According to Wikipedia, antigens are things which "evoke the production of ... antibodies" and pathogens are things which cause disease. So in this work, experiments were performed to see if specific kinds of antibodies could be found which either were the cause of CLIPPERS and/or were characteristic of it so that their presence in tissue could be used as a test for CLIPPERS i.e. be a biomarker for CLIPPERS.

Unfortunately they didn't find anything but finish by saying: "It is possible that CLIPPERS could be mediated by other organ-specific antibodies to perivascular antigenic targets in the central nervous system, or alternatively a predominantly cell-mediated immune process.". So the jury is still out on this one.

In other news, my first clinic visit for a while is next week. Will report back as and when.

Read other articles in this series at Living With CLIPPERS.



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

September Sun

A CLIPPER on Holiday

Wales

I've been enjoying the last of the Summer sun in South Wales. The day after we arrived we climbed Corn Du and Pen Y Fan in the Brecon Beacons National Park. I looked at my watch and noticed it was exactly one year to the day since I was discharged from the NHNN with a bag full of pills and a diagnosis of presumptive CLIPPERS. My balance had improved after 5 days of IV steroids but was still not great. I also still had double vision and some strange intermittent jerkiness when walking or talking. A fuller account of those times is here. Now I have a smaller bag of pills and the various symptoms are pretty much resolved. From what I can gather I've had a good result from treatment but this is largely down to the luck of being in the right place at the right time and getting a diagnosis relatively quickly. CLIPPERS is tricky to identify and other things need to be excluded, but equally, it doesn't seem to get better by itself and needs treating. I was definitely in slow decline before and during my time in hospital but the pills are working for now.

CLIPPERS News

The debate about possible mechanisms for CLIPPERS continues. A short response to the paper by Dr Ortega (describing CLIPPERS as a complication of Multiple Sclerosis) has recently appeared. I don't pretend to understand the detail of the argument but more discussion about possible causes can only be a good thing and may eventually lead to firmer diagnostic criterion.

Read other articles in this series at Living With CLIPPERS.

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

Cause and Effect?

Hmmm ...

 Another single CLIPPERS case study has hit the press with free access to the full text too. This one was accepted for publication last October so has been hanging around a bit already. This study raises some interesting questions about the nature of CLIPPERS and in my view - but what do I know? - tries to make itself more interesting than it otherwise might be with unwarranted speculation about a possible cause of CLIPPERS. Also, to my mind this case seems similar but somewhat atypical compared with previous cases (the usual disclaimer about my lack of medical knowledge should  be born in mind).

CLIPPERS or CLIPPERS-like?

The presenting symptoms (right-hand numbness and paresthesia) are not shared with any of Pittock's original cohort of 8 subjects although they are features of some patients later illness (including my own). In addition patients in the Pittock cohort exhibited diplopia either at onset or later on; diplopia is not reported in this case at all. The second issue is the radiological (i.e. MRI) appearance. I work with MRI images a lot but I am not trained to read them for diagnosis. Nevertheless the scans in Figure 1D, 1E and 1F of this new case do not look like the comparable ones for patients 5 thru 8 in Pittock's figure 1. The new case looks to have a single large enhancing lesion but the Pittock cases have multiple smaller lesions centred in the same region but getting smaller and more diffuse further away. Symptoms should roughly correlate with lesion location so the atypical symptoms and lesion appearance may be related.

Now because there is no definitive test or definition of CLIPPERS syndrome it is hard to draw a line in the sand and say one case is CLIPPERS and another isn't if both have had the same possible other disorders excluded. So an important outstanding question is "Is CLIPPERS a well-characterised condition as described by Pittock et al or is it a broader spectrum of disorders than those originally considered?". Hillesheim et al in this new paper describe CLIPPERS as a "diagnosis of exclusion" (which it is currently) but do not provide any discussion about similarities with or differences from previous cases which would have been a more valuable contribution IMHO.

Anyway, I'm not a doctor so this is one for the medics to argue about.

Rant!

The thing that annoyed me more about this case is the association with vaccination. (As those who live in the UK will know we have had our share of vaccination scares in the last few years). To begin with Dr Hillesheim remarks that the patient had the influenza vaccine 2 weeks before first CLIPPERS symptoms; it is quite right that this information should be recorded.

However, he then says that this is the first cases of CLIPPERS "associated with the administration of the influenza vaccine". Now "associated with" is a carefully chosen phrase which doesn't quite mean "caused by" but implies that one is observed together with the other. But let's think about this in another way. How many men over the age of 70 do you think received a flu vaccination last year and didn't get CLIPPERS? I have no idea but I bet it's hundreds of thousands if not millions. So should I write a paper entitled "Influenza vaccination associated with not getting CLIPPERS"? Absolutely not - it's just misleading and unscientific. Or how about this - I was on holiday in Rhodes two weeks before I got symptoms so should possible triggers for CLIPPERS include cheap cocktails, Greek toilets or cramped European flights? Of course not. Or we could ask how many other CLIPPERS cases developed symptoms shortly after vaccination? None that I can recall (but of course let me know if you know different).

Now to be fair, later on the authors list a whole series of rare neurological complications of vaccination so maybe there could theoretically be a basis for CLIPPERS to be considered as a new one. However they state plainly "CLIPPERS is another complication that should be added to this list". What, on the basis of one case, without even any speculation about a mechanism for cause and effect? Again, absolutely not and I can't help thinking the influenza aspect has been promoted from being a small part of the clinical case just to increase publication impact and maybe get some positive press. Finally the authors say that "Vaccination for influenza ... raises the tantalizing possiblity that this may be the triggering event". Well in my own personal case study being conducted in the UK (on myself), "Over-consumption of Greek gin and tonics ... raises the tantalizing possiblity that this may be the triggering event". Unfortunately I won't get a publication out of it.

Rant over - normal service will be resumed shortly.

Read other articles in this series at Living With CLIPPERS.

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

WE Ask The Questions

Now that I've got over my acute CLIPPERS symptoms and having hit a stable patch supported by various pills there's been some more time for reflection. That is reflection on the state of CLIPPERS rather than the reflection of a few months ago which without, wanting to be melodramatic, was more focussed on questions like "Will I make it as far as Christmas?".

Why I've Got CLIPPERS ...

... as suggested by a variety of people.

When something unexpected happens it's a natural reaction to think about the cause. For medical conditions establishing cause is often part of the diagnostic process. However there are many illnesses for which there is no obvious cause. Put another way it's hard to find a common link between people which might either explain the cause or at least predict who is more likely to be affected. So far with CLIPPERS there hasn't been an identified cause or common link, just a description of symptoms, findings and treatment response. However that hasn't stopped many suggestions being put forward (by others) for why I probably have CLIPPERS. So just for the record here they are.