Overall, the evidence presented in this review supports a relationship between tonsillectomy and appendectomy in childhood and the subsequent risk of MS. More specifically, those with tonsillectomy or appendectomy at
years of age were approximately 30% more likely to be diagnosed with MS in comparison to similar patients who did not have a tonsillectomy or appendectomy at
years of age. The findings of this review do not support an association between tonsillectomy or appendectomy occurring in those
years, adenoidectomy, and “other surgery” occurring at any age and the subsequent risk for the onset of MS. Although we did not find an association between these variables and risk for MS, it is important to note that due to the multi-factorial and heterogeneous nature of MS, surgery may indeed pose a slight risk for certain individuals.
Several theories linking tonsillectomy to MS risk have been postulated over the years. Meurman and Wising [39
] proposed tonsillectecomy as a possible risk factor for MS in that an upper respiratory tract infection may trigger MS or that a locally deficient immune system may facilitate the invasion of an etiologically relevant, infectious agents. Tonsillectomy may leave sufficient lymphoid tissue adjacent to the central nervous system to instigate the exaggerated immune response seen in MS [39
]. Poskanzer (1965) was particulary interested in examining tonsillectomy and MS risk at it predisposes to the development of neurological complications in poliomyelitis, another infection that is much more widespread than is suggested by its neurological manifestations [87
Of particular interest is the association between recurrent tonsillitis and EBV infection and reactivation [100
]. A recent meta-analysis of case–control and cohort studies found a statistically significant combined relative risk (RR) for MS in those with a past history of infectious mononucleosis (RR = 2.17; 95% CI, 1.97-2.39) [101
]. Furthermore, others have found statistically significant elevated levels of antibody to some common infectious agents, other than EBV, in children and adults with MS compared to controls [92
]. Krone and collegues [104
] postulate that these findings reflect a dysregulation of immune function as a consequence of the development of the disease. They assert that immune dysregulation in MS is likely to be an early event preceding the onset of MS disease by many years or even decades [14
]. It is likely that the elevated antibody concentrations do not directly cause MS but rather reflect a shift in patterns of immune reactivity away from protection towards enhancement of the risk of disease. These authors suggest that studies on MS-associated infectious agents could lead to the identification of specific antigenic determinants involved in the generation and maintenance of immune dysregulation.
There seems to be similarities between MS and appendicitis, which often results in appendectomy. More recently, scientists have recognized the role of the appendix as part of the body’s immune system, as it contains white blood cells and acts as a reservoir for “good” bacteria for the gut [107
]. The role of the appendix is to contain “good bacteria”; when bacteria in the intestines die or are purged from dysentery or cholera, the “good bacteria” are replaced from the stores in the appendix. As a result, appendicitis (inflammation of the appendix) may indicate inadequate immunological function [84
]; thereby providing an association of both EBV and appendicitis (resulting in appendectomy) with MS [109
]. Immunological reaction relevant to appendicitis may indicate MS risk as activation of peripheral blood mononuclear cells, including those causing inflammatory destruction of myelin, which occurs in lymphoid tissue [89
]. Appendicitis is a marker of immune characteristics influencing immune-mediated disease risk, as it has a direct role in the development of ulcerative colitis [89
]. Further, CD8+ T-cell deficiency is a feature of both ulcerative colitis and MS [114
There seems to be other possible similarities between MS and appendicitis. First, appendicitis and MS are autoimmune diseases. Both appendicitis and MS are diseases associated with industrialized countries but not developing countries [115
]. MS is a disease largely prevalent in Europe, North America, Australia, and New Zealand, but is rare among Asians and Africans [116
]. Lastly, several epidemiological and experimental studies support the hygiene hypothesis in both appendicitis [115
] and MS [109
], which postulates that immunopathology may be an unanticipated consequence of advances in sanitation and public health [109
Quality of the evidence
One of the main challenges of the review related to the varying definitions of “surgery” in the included studies. Some studies included only tonsillectomy or appendectomy, and some included all surgeries. More importantly, the number of surgeries in individual patients (prior to MS onset) would have been a significant variable to assess; however, none of the included studies reported this as a potential risk factor. Another potential limitation pertained to the fact that, with the exception of a single study [89
], the majority of studies reporting on appendectomy did not indicate the reason for surgery; therefore, we had to assume that appendectomy was as a result of appendicitis (infection / inflammation). It must be emphasized that characterizing appendectomy, by underlying diagnosis, may be important when assessing true MS risk.
Ideally, in case–control studies, cases should be representative of the entire population and be identified by independent MS diagnostic criteria. Controls should be randomly selected within the community of the residing representative MS cases. Only nine case–control studies examined in this review selected controls from the community [64
]. To further control for bias, control subjects should have no prior history of disease, representing healthy individuals of the same socio-economic class.
Age at disease onset is very important in MS etiologic studies and ought to have been used as a matching variable to potentially control for bias. The age at disease diagnosis is used to allow researchers a timeframe to assess for potential exposure to associated agents. Ideally, case–control matching ought to be done for universal variables such as age, sex, and age at MS diagnosis. Other matching variables to be considered in MS studies include residence and place of birth. Interviewer blinding, another means of controlling for bias, was done by only one study [94
Potential bias in the review process
The two review authors who assessed the methodological quality were not blinded for authors, journal, or institution. The potential bias caused by the non-blinded quality assessment was expected to be low as neither review author had a conflict of interest. Specifically, the review authors did not have any (financial or other) interest in positive or negative results. Furthermore, we searched the grey literature extensively for eligible studies, presented the search strategy and the inclusion criteria list, and all of the final results of the assessment, so that readers can make their own determinations of the results and our conclusions.
There is a possibility of publication bias or study selection bias in this meta-analysis. For example, by missing unpublished negative studies we may be over-estimating the association between prior surgery and the risk for developing MS. However, a comprehensive search of the published literature for potentially relevant studies was conducted, using a systematic strategy to avoid bias. This was followed by attempts to contact corresponding and first authors, as we recognize that unpublished or negative studies may exist.