A World of CLIPPERS

This map, taken from Google Analytics, shows where everyone who has visited this blog comes from. Perhaps as expected, the most visitors so far have come from the USA (3877) and the UK (2680). But there have also been visitors from many other countries, including Canada (559), Australia (392) and Germany (214). From the map you can see there have been visitors from South America, Europe, Africa, Russia, China and Japan amongst others.

So if we assume that most people visiting are associated with someone who has (suspected) CLIPPERS, then it seems to be a truely global condition. So thanks to all who continue to visit the blog. I'll keep writing while there are still things to say, so let me know if you hear anything interesting about CLIPPERS.

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.

The Tip of the Iceberg?

General Wolfe, originally from my neck of the woods.

 A paper reviewing the state of CLIPPERS was presented at the 2013 meeting of the American Academy of Neurology. It was called "CLIPPERS: Rare Disease or Tip of the Iceberg? A Case Report and Literature Review".

The abstract linked to above is actually much less revealing than is implied by the title. The main part of the paper seems to be another CLIPPERS case study (at least as much as I can deduce from the abstract). The patient in this case was a 70 year old woman who as usual did not find an alternative diagnosis and did respond to high-dose Prednisolone. Frustratingly, there is a lack of follow-up detail here as, apparently the patient had no further steroids and was OK at 8 weeks, but from the abstract we don't know if she remained well longer term.

The promised critical review of the literature concluded that "CLIPPERS syndrome may be more common than realized" which has been the conclusion of many of the more extensive published papers. So I conclude we will have to wait a while for a more definitive assessment of the prevalence of CLIPPERS.

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.

Another Strange Case of CLIPPERS

Now that CLIPPERS has been recognised for a little while the number of new papers simply documenting cases has declined. There is at least some agreement about what constitutes CLIPPERS, even if there isn't a definitive test for it, so reporting new cases isn't, in itself, scientifically interesting. Of course, if the number of reported cases goes up, new research about the epidemiology of CLIPPERS may be required.

 

The new cases that are being reported seem to be unusual or novel in some way. A recent one from Dr Buttmann and colleagues in Germany concerns a 49 year old woman who has symptoms suggestive both of CLIPPERS and primary angiitis of the CNS (PACNS) (otherwise known as cerebral vasculitis, which was a candidate diagnosis for me for a short while). As well as the usual CLIPPERS symptoms this patient also had severe headaches and a seizure as well as other symptoms more associated with cerebral vasculitis than CLIPPERS. Dr Buttmann speculates whether this patient had unusual CLIPPERS, another condition which appeared like CLIPPERS or some combination of both conditions.

I have to say that, from my perspective, although these isolated cases are interesting, what I really want to see is something more detailed about number of reported cases and treatment options and responses in a large population. It is quite possible this information doesn't exist at present. It's a tricky situation as I obviously wouldn't wish CLIPPERS on anyone, or want the number of cases to rise. However, larger scale research may not happen when the number of cases stays small and there are already some treatments available.

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.

People With CLIPPERS to October 2012

I've heard from some more people who have been diagnosed with CLIPPERS and thought you might be interested in a breakdown. (I won't be passing on further details unless told to - have a read of PeopleWithClippers if you want to go public.)

Australia: 1, Belgium 1, Canada: 1, Netherlands: 1,
Spain: 1, USA:3 (+1?), UK: 1 (me!)
= 9 (or 10?) total

So there's a few of us and possibly more who are reading quietly in the background. From what people have told me about their background and symptoms I can see no pattern at all in terms of possible causes or demographics. I would be surprised if anything was that obvious since the doctors involved in the various research papers have presumably gone through patient backgrounds with a fine-toothed comb. Still I hoped something might leap out - never mind, have to wait for the professionals to figure out what is going on.

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.

Being a smart aleck?

smart aleck = someone who is pretentious about their own cleverness

Just For the Record

A couple of months ago I posted an entry here moaning about a CLIPPERS case study which I felt confused cause and effect and made far too much of a supposed link between CLIPPERS and flu vaccination. Anyway I felt strongly enough to write a letter to the journal in question to point out the weaknesses in the paper. Now letters to journals are sent for external review before publication which took a while, but I thought it a good sign that they didn't immediately reject it. In the end they waited for a review to come back ... and then rejected it, which is of course their privilege. As I put several hours work into this letter and because I think I made some legitimate points I've put a copy below for posterity. In the interests of balance, I've also included the reviewer's comments so you can see why they rejected it and my subsequent email to the editor of the journal saying why I thought the reviewer was wrong too. If you work in academia you frequently think reviewers are wrong and sometimes they are, but often it's just  you being a smart aleck ... ;-)

Regarding ”Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids Following Influenza Vaccination” by Hillesheim et al

To the Editor. – The article titled ”Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids Following Influenza Vaccination” by Paul Hillesheim et al (1) reports a new case of CLIPPERS, a recently characterised inflammatory condition of the central nervous system (2). This is an interesting case which adds to the description of CLIPPERS-like disorders but raises questions about the definition and diagnosis of CLIPPERS. The authors also make an unjustified association between CLIPPERS and recent flu vaccination which is not supported by the available data and is potentially misleading.

This case is somewhat atypical; in 19 reported cases to date only 3 others did not suffer diplopia. In addition, the present case does not exhibit the distributed pattern of enhancing punctuate lesions seen previously but has a larger focal lesion within the central pons. The current case is also at the upper end of the reported age range – only one older case has been described, with 13 out of 19 cases aged between 45 and 75 (Figure 1). Clearly though, this case is CLIPPERS-like and could simply represent population variation in a condition which is currently poorly understood.

Figure 1

The connection with influenza vaccination warrants further investigation. Dr Hillesheim associates vaccination with CLIPPERS in the article title but I am of the strong belief that this is misleading and unwarranted. The authors make several statements which are technically true but not defendable in this context. For instance, “… this is the first reported case of CLIPPERS after vaccination” and “vaccination … raises the tantalizing possibility that this may be the triggering event”.  While it is strictly true that the patient was vaccinated shortly before symptom onset, no evidence for a linkage with CLIPPERS is presented and no mechanism is suggested. It is quite right that the vaccination is recorded, but its significance cannot be established from this single case. Finally, the authors list existing neurologic complications of vaccination and state “CLIPPERS is another complication that should be added to this list”. There is no evidence to support this assertion and indeed no other reported CLIPPERS cases have mentioned vaccination. Therefore it is premature to make this connection on the basis of a single case and to link CLIPPERS with vaccination in the article title.

I should declare an interest; I was diagnosed with CLIPPERS in September 2011 and am currently well on tapering Prednisolone and Azathioprine. I am not one of the literature cases. The first and only flu vaccination I received was in November 2011.

1. Hillesheim PB, Parker JR, Parker JC, Jr., Escott E, Berger JR. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids following influenza vaccination. Arch Pathol Lab Med. 2012;136(6):681-5. doi: 10.5858/arpa.2011-0428-CR.

2. Pittock SJ, Debruyne J, Krecke KN, Giannini C, van den Ameele J, De Herdt V, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain. 2010;133:2626-34. doi: 10.1093/brain/awq164.

Comments for the Author

The author does make a valid point in that it cannot be assumed that influenza vaccination directly leads to CLIPPERS; however, I do not believe that Hillesheim et al are implying an absolute cause and effect. They are merely reporting a case of a patient who developed CLIPPERS after receiving the vaccination. With this being such a rare disease with no definitive undeniable cause/trigger or mechanism only associations can be made between the disease and its possible causes, which is what the article is doing, similar to the other reports of CLIPPERS in the literature, until enough cases are reported to find investigable commonalities.

My Response

I still believe Dr Hillesheim over-emphasises the vaccination aspect in his original paper but accept this is a matter of opinion. However as noted in my letter, his statement that CLIPPERS "is another complication ..." (of influenza vaccination) "... which should be added to this list" surely goes too far; however the reviewer disagrees and so  I must defer.

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.

People With CLIPPERS

The elusive Cyril.

You may have noticed a new page has appeared below the title-bar - People With CLIPPERS.  I've now heard privately from several people who have been diagnosed with CLIPPERS and thought it would be great if we can use the power of the InterWeb to record and map some of these cases in a suitably anonymised fashion. So if you have been diagnosed with CLIPPERS please take a look and see if you want to contribute a brief summary of your CLIPPERS experience. There's absolutely no obligation and no nefarious, underhand motivation on my part except for thinking it would be fantastic to get more cases listed here than have appeared in any of the scientific papers published to date.

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.

Who Gets CLIPPERS?

There have been a few reported cases of CLIPPERS now and I wondered if there was any pattern. There's not enough cases or consistency of reported information to go into much detail but I thought it worth a look.

So simple things first, there's been an even split in the cases reported to date of 8 men and 9 women. Including me and the one female and one other male CLIPPERS patient I've heard about so far makes for 10 men and 10 women. On the limited information available it doesn't seem that men are any more or less likely to be diagnosed with CLIPPERS than women.

The next most obvious thing to look at is age at onset of symptoms.