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.

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.