Tonsillectomy, Appendectomy Linked to Increased MS Risk

Megan Brooks

June 26, 2013

People who had their tonsils or appendix out before their 20th birthday have a small but "statistically significant and clinically important" increased risk of developing multiple sclerosis (MS), a new meta-analysis suggests. But it's unclear why.

"MS has a multitude of potential interacting influences and it is not currently clear how the surgeries identified in this review will lead to increased MS risk and under what conditions," Shawn N. Fraser, PhD, from Athabasca University, Alberta, Canada, who worked on the review, told Medscape Medical News. "There may be some underlying factor common to MS and inflammatory conditions requiring surgery like appendicitis and/or a tonsillitis."

The analysis was published online in BMC Neurology.

Interpret Cautiously

"The obvious concern that people might have is that they shouldn't have tonsillectomy because that might put them at increased risk for MS, but there is no way of telling from this study whether that is the case," Nicholas LaRocca, PhD, vice president, healthcare delivery and policy research for the National Multiple Sclerosis Society, told Medscape Medical News.

"In any event, trying to determine what are the risk factors for MS is an important area of study and even if we identify something that is associated with the risk of MS, even if it doesn't have a causal relationship, that's important because it can give us hints about other things that may be going on," Dr. LaRocca added. He wasn't involved in the study.

The exact cause of MS is largely unknown, but there is some speculation that a history of surgery may be involved. To investigate further, Dr. Fraser and colleagues performed a formal "Cochrane style" systematic review and meta-analysis of 33 relevant observational case-control studies that evaluated the risk for MS after tonsillectomy, appendectomy, or other surgery. The studies included 27,373 individuals with MS and 211,756 individuals without MS.

They found that having tonsillectomy or appendectomy before age 20 increased the risk for a subsequent diagnosis of MS.

Table. Multiple Sclerosis Risk by Surgery Exposure

Exposure Pooled Odds Ratio (95% Confidence Interval) P Value
Tonsillectomy before age 20 (12 studies) 1.32 (1.08 - 1.61) .006
Appendectomy before age 20 (7 studies) 1.16 (1.01 - 1.34) .04


"In terms of absolute risk, this review suggests a 30% increase in risk in the eventual development of MS for those who have had tonsillectomy before 20 years of age," Dr. Fraser told Medscape Medical News.

He explained that in those without a close family history of MS, this is an increase in the absolute risk of developing MS from roughly 13 per 1000 to 17 per 1000. In those with a close family history of MS, the risk increases from roughly 25 to 33 per 1000. These risk estimates are from the National Multiple Sclerosis Society.

Their analysis did not find any statistically significant association between tonsillectomy or appendectomy occurring after age 20, adenoidectomy or "other surgery" occurring at any age, and the subsequent risk for MS.

Link Plausible

Several theories linking tonsillectomy to MS risk have been put forth over the years, the researchers say. Of particular interest is the reported association between recurrent tonsillitis and Epstein-Barr virus (EBV) infection and reactivation. For example, a recent meta-analysis of case-control and cohort studies found a greater than 2-fold increased relative risk (RR) for MS in people with a history of infectious mononucleosis (RR, 2.17; 95% confidence interval, 1.97 - 2.39), they note.

There are also similarities between MS and appendicitis, the researchers point out. Appendicitis may indicate inadequate immunologic function, thereby providing an association of both EBV and appendicitis (resulting in appendectomy) with MS.

In addition, several epidemiologic and experimental studies support the hygiene hypothesis in both appendicitis and MS, which holds that immunopathology may be an unanticipated consequence of advances in sanitation and public health.

Dr. LaRocca said this was a "careful analysis of existing studies" but added, "a lot of the studies were fairly old and the relationships were fairly modest."

"Assuming this meta-analysis is indicative of a real relationship, then one wonders what could possibly explain this. Is it the surgery itself or is it something associated with the surgery that is also associated with MS," Dr. LaRocca noted.

The study team acknowledges that their analysis has several limitations, including a "lack of high-quality studies included" and concludes that "more rigorous prospective studies, with high statistical power, are needed to prove an effect."

The study was supported by the Academic Research Fund of Athabasca University. The authors and Dr. LaRocca have disclosed no relevant financial relationships.

BMC Neurol. Published online May 6, 2013. Abstract


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