Clinical features in patients with long-lasting macrophagic myofasciitis
Authors: Mehdi Aoun-Sebaiti
Romain Kroum Gherardi
Nilusha Ragunathan-Thangarajah
Jessie Aouizerate
Maryline Couette
Josette Cadusseau
François Jérôme Authier
Muriel Rigolet
Journal: Frontiers in Neurology (2014)
Discipline: CLINICAL MEDICINE
Keywords: CCL2; aluminum; chronic fatigue syndrome; mild cognitive impairment; myalgias
Affiliations: Faculty of Medicine, INSERM U955-Team 10 , Créteil , France., Faculty of Medicine, INSERM U955-Team 10 , Créteil , France ; Reference Center for Neuromuscular Diseases Garches-Necker-Mondor-Hendaye , Créteil , France., Neurology Department, Henri Mondor University Hospital , Créteil , France., Faculty of Medicine, INSERM U955-Team 10 , Créteil , France ; Reference Center for Neuromuscular Diseases Garches-Necker-Mondor-Hendaye , Créteil , France ; Paris Est-Créteil University , Créteil , France., Reference Center for Neuromuscular Diseases Garches-Necker-Mondor-Hendaye , Créteil , France ; Paris Est-Créteil University , Créteil , France.

Abstract:  Macrophagic myofasciitis (MMF) is an emerging condition characterized by specific muscle lesions assessing abnormal long-term persistence of aluminum hydroxide within macrophages at the site of previous immunization. Affected patients usually are middle-aged adults, mainly presenting with diffuse arthromyalgias, chronic fatigue, and marked cognitive deficits, not related to pain, fatigue, or depression. Clinical features usually correspond to that observed in chronic fatigue syndrome/myalgic encephalomyelitis. Representative features of MMF-associated cognitive dysfunction include dysexecutive syndrome, visual memory impairment, and left ear extinction at dichotic listening test. Most patients fulfill criteria for non-amnestic/dysexecutive mild cognitive impairment, even if some cognitive deficits appear unusually severe. Cognitive dysfunction seems stable over time despite marked fluctuations. Evoked potentials may show abnormalities in keeping with central nervous system involvement, with a neurophysiological pattern suggestive of demyelination. Brain perfusion SPECT shows a pattern of diffuse cortical and subcortical abnormalities, with hypoperfusions correlating with cognitive deficiencies. The combination of musculoskeletal pain, chronic fatigue, and cognitive disturbance generates chronic disability with possible social exclusion. Classical therapeutic approaches are usually unsatisfactory making patient care difficult. 

Retracted: No

PubPeer comments:
 The work of Rigolet et al. deals with macrophagic myofasciitis. It is not surprising that it comes from the group led by Gherardi and Authier at Creteil (Val-de-Marne, France). Indeed, this pathology is almost exclusively observed in this center despite few exceptions. To define this  pathology the authors report a tripod consisting of (i) musculoskeletal pain (arthromyalgias), (ii) chronic fatigue and (iii) cognitive disorders. The authors state that this association defines precisely this syndrome. What about the difference with the clinical signs associated with Lyme disease in its chronic form? What are the differences with depressive states that psychiatrists are familiar with? To support the thesis of a recognition of this disease, the authors cite the so-called ORPHANET classification which is a French classification of rare diseases. This classification recognizes macrophagic myofasciitis but this is not surprising since among their supporters we note the AFMtelethon who has always funded this group for this disease. The second recognition alleged by the authors is that of the International Statistical Classification of Diseases and Related Health Problems (ICD) in which the macrophagic myofasciitis would be recognized by the term M608.This international classification is regularly updated. In the versions of 2008, 2010 and 2014, macrophagic myofasciitis does not appear contrary to what the authors write in their paper. The code M 60.8 (and not M608) corresponds to the generic term  other myositis . In conclusion, it seems there is no international recognition of the  disease contrarily to what has been written by the authors. A correction should be done for this inexact assertion. , 
 The definition of macrophagic myofasciitis (MMF) does not seem very simple to me. The locally observed lesion is now well characterized. Nevertheless, it seems essential to include in this definition the delay between the last vaccination and muscular biopsy. In the work of Rigolet et al. the authors suggest a delay of at least two years. ![file] One may wonder why the authors included patients whose delays are less than 24 months. ![file] This inclusion has no sense since the authors themselves set criteria that they do not hold. In addition, including non-pathological cases distorts their statistical data which then have no medical interest. , 
 A simple question! When you receive vaccines containing aluminum at different times in your life and when on your muscle biopsy you find aluminum in macrophages, how do you know which vaccine this aluminum corresponds to? In this case, could anyone tell me how Rigolet et al. have established their item: ![file] , 
 #3 That is a good point, Chromis Vanderbilti. From the Frontiers page I see that the manuscript was edited by Christopher Shaw, and reviewed by Lucija Tomljenovic (among others), so they would be the people to approach with the suggestion that the paper s statement of fact needs a correction. If I recall correctly, the paper was originally part of a Frontiers  Research Topic on  Aluminium Toxicity and Human Disease , although Frontiers subsequently disbanded the research topic in early 2017 and left the various papers without their collective umbrella. https: web.archive.org web 20161002055704 http: journal.frontiersin.org:80 researchtopic 2270 aluminum-toxicity-and-human-disease , 
 Another analysis that surprises me in the article by Rigolet et al. The authors analyze the  large series of patients published in the literature. ![file] All the references highlighted in red are from the same group (namely Gherardi and Authier). Since it is difficult to know, reading these papers, if some patients are common in these different works, it seems inappropriate to refer these cases as in this table. Furthermore, one may imagine that some of these patients are included in the analysis of Rigolet et al. Such important data should be explicated by the authors (if they accept to answer my question). , 
 Rigolet et al. stated ![file] ![file] To be sure that the authors are right, they should demonstrate that their reference population does not display a recruitment bias. Indeed, if the majority of their population has muscle biopsy 4 -5 years after their last vaccination, this distribution does not exclude the tail of the normal distribution. I am certain that the authors have the correct answer for deciphering these two possibilities , 
 In the summary: ![file] In the text of the review: ![file] This is not very precise , 
 #2 You are right, the inclusion criteria are really problematic. The problem of the time elapsed from the last vaccination and biopsy is very important. If you inject vaccine with aluminum adjuvant, it seems likely to find this adjuvant if biopsy is performed a few time after this injection. For Gherardi and Authier (Lupus 2012), this time should be superior to 18 months. This is not the case in this series: ![file] On can read also: ![file] So, the authors have information for only 183 cases. What about the other 110 cases? If the authors have no information about the timing of vaccination, they can t conclude that presence of aluminum is pathological. Consequently, these cases should be excluded from the analysis. , 
 #1 It is a pity that Figure 1 has a vertical scale in % rather than absolute numbers, making it less-than-obvious how many cases are included in the histogram. If you add up the percentage values they sum to 107%, which doesn t seem right. Anyway, my guess - based on the granularity - is that there are 64 cases. ![file]  To define this  pathology the authors report a tripod consisting of (i) musculoskeletal pain (arthromyalgias), (ii) chronic fatigue and (iii) cognitive disorders. The authors also concede that there is also a baseline incidence of this triad of symptoms, occurring for unknown reasons, unrelated to vaccination (and to the delay since last vaccination)... thus the four cases in the histogram with symptoms appearing with less than 24 months since vaccination are held to be sporadic, or idiopathic, or  non-pathological . ![] I infer from this that the same baseline is present throughout the histogram, with another ~four cases expected to arise through sheer misfortune within a 24-48 month delay and so on, so that for the entire delay range of 0-96 months, about 16 cases are idiopathic. **A quarter of the entire sample**. Is there a flaw in this extrapolation? , 
 About the association multiple sclerosis and macrophagic myofasciitis: ![file] I am surprised to read 9.3%. In reference 22 (Gherardi et al. Brain 2001;124:1821-1831) multiple sclerosis was found in 6 50 patients (12%). In reference (Authier et al. Brain 2001;124:974-983) multiple sclerosis was found in 8 92 patients (8.7%). Curiously, this reference from the same centre is not quoted. Reference 12 (Gherardi and Authier. Immunol Allergy Clin N Am 2003;23:699-712) is a review. The percentage of multiple sclerosis was estimated at 9.3% but the authors don t mention the population that yielded such a result. What is the total number of patients presenting both MS and MMF in the database? This database contains the files of 293 patients. 9.3% of the total of the database = 27.249 a result that is obviously impossible. , 
 There are many problems with the statistics of this paper. It seems that the database of this team contains 293 cases: ![file] 19% of them suffered from autoimmune disease ![file] If one calculates 293 x 0.19, the result is 55.67 cases. I have two comments: - this percentage is obviously not established on the total number of patients of the database. Could the authors precise the number of patients for which they have this information. - I have never found series of MMF and autoimmune patients published in the literature. 55 cases is an important number of cases. I can t imagine that no original publication describes this association. ,