Position Paper: Rethinking Thymectomy

abstracts & commentary

Sources: Gronseth GS, Barohn RJ. Practice parameter: Thymectomy or autoimmune myasthenia gravis. Report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2000;55: 7-15; Kissel JT, et al. Treatment of myasthenia gravis: A call to arms. Neurology 2000;55:3-4.

Thymectomy is "…advisable in practically all patients with uncomplicated myasthenia gravis (MG)" (Adams RD, Victor M, Ropper AH. Principles of Neurology. 6th ed. New York, NY: McGraw Hill; 1997:1469). Practice parameter guidelines from the Quality Standards Subcommittee of the American Academy of Neurology now give pause to this suggestion. Searching the National Library of Medicine’s Medline database from 1966 to 1998, 310 articles discussing MG and thymectomy were identified. Review of these, including references, garnered 28 controlled, non-blinded, studies discussing 21 MG cohorts (due to overlap of patient groups) treated with and without thymectomy. Thymectomy was not randomly assigned, and surgical technique (trans-sternal vs trans-cervical) was in many cases not specified. Follow-up varied from three to 28 years, and the number of patients lost to follow-up was usually omitted.

Thymectomy and improvement were significantly associated in only seven of 15 studies reporting medication-free remission, eight of 12 studies reporting patients on or off medication, eight of 13 reporting improvement, and four of 13 reporting survival. Most studies showed no significant benefit. Thymectomized patients were twice as likely to achieve medication-free remission, 1.7 times as likely to improve, and 1.6 times as likely to become asymptomatic. They also tended to be younger and female (usually associated with better outcomes), yet generalized and severe (usually associated with poorer outcomes). Controlling for these variables resulted in conflicting findings. Thymectomy for non-thymomatous MG is a therapeutic option but its benefit has not been conclusively established.

Commentary

Controlled trials will be needed to determine the true efficacy of thymectomy in MG. Alternative forms of immunosuppressive therapy are also necessary, aimed at both the B-cell (antibody forming) and T-cell (final common pathway) arms of the autoimmune response to nicotonic Ach receptors in MG. Developing tolerance to the precise MG antigen, presently unknown, or inducing production of inactive, rather than active, autoantibodies are alternative approaches that must be examined. Vaccination, by oral, nasal, or systemic route using an inciting antigen is an approach presently being investigated in multiple sclerosis (Weiner HL. Ann Rev Med 1997;48:341-351), with suppression of lymphokine-releasing T cells the purported mechanism. Torpedo AchR has been the antigen used experimentally in allergic MG (Okumura S, et al. Ann Neurol 1994;36:704-713), although human AchR receptor subunits may be effective as well (Lindstrom JM. Muscle Nerve 2000;23:453-477). Toxins conjugated to AchR, with the intent to kill B cells, have not been successful. Using monovalent Fab fragments of the immunoglobulin to bind autoantibody would prevent complement fixation as these fragments lack the Fc region of the immunoglobulin. Crosslinking of ACh receptors would also be constrained in the absence of the bivalent F(ab)2 fragment. However, Fab is too rapidly cleared from the bloodstream for this approach to be effective. Further study is necessary to pursue the best treatment for MG. —michael rubin

Regarding myasthenia gravis (MG):

a. thymectomy is indicated in most cases of nonthymomatous MG.

b. controlled studies should be undertaken to determine the true place of thymectomy in the treatment of MG.

c. human AchR receptor subunits may be used as a vaccination to treat MG.

d. the use of monovalent Fab fragments, administered IV to bind pathologic autoantibody as a treatment for MG will soon be FDA approved.

e. T cells play no significant role in the pathogenesis of MG.