Bone Marrow Transplantation, (1999) 23, 397–399 1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt
Case report Myasthenia gravis and polymyositis as manifestations of chronic graftversus-host-disease S Tse1, EF Saunders2, E Silverman3, J Vajsar4, L Becker5 and B Meaney4 Department of 1Pediatrics, 2Hematology and Oncology, 3Rheumatology, 4Neurology and 5Pathology, The Hospital for Sick Children, Toronto, Canada
Summary: Myasthenia gravis and polymyositis are each a rare manifestation of immune dysregulation in chronic graftversus-host disease (cGVHD). We report a 4-year-old boy with idiopathic acquired aplastic anemia who developed myasthenia gravis 22 months and polymyositis 69 months after an allogeneic BMT (5/6 matched, MLC-nonreactive). The occurrence of both syndromes in one patient is unique. Autoimmune dysfunction may be associated with the development of cGVHD as demonstrated by the high incidence of prior aplastic anemia in BMT patients presenting with myasthenia gravis and polymyositis. Recognition of these neurologic manifestations is important in the diagnosis and treatment of cGVHD. Keywords: chronic graft-versus-host disease; myasthenia gravis; polymyositis
Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic BMT which is associated with a high degree of morbidity and mortality. cGVHD commonly involves the skin, eyes, mouth, bowel, liver, lung and immune system.1 Myasthenia gravis (MG) and polymyositis (PM) have been reported as rare manifestations of cGVHD.1–15 This report illustrates a case of MG and PM developing sequentially after an allogeneic BMT in a single patient. Case report In December 1990, a 4-year-old boy received an allogeneic BMT from his 5/6 serologically HLA-matched, MLC-nonreactive sister (mismatch A3/29) for treatment of severe idiopathic acquired aplastic anemia. He was conditioned with CY (200 mg/kg) and total body irradiation (300 cGy, single dose). MTX and CsA were given as GVHD prophylaxis. Engraftment of all three lines occurred by day 28 and Correspondence: Dr EF Saunders, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada, M5G 1X8 Received 27 February 1998; accepted 14 September 1998
was followed by grade III acute GVHD (aGVHD) of the skin. When oral prednisone was instituted, the rash resolved promptly. On day 48, the patient developed diarrhea, respiratory distress, and elevated liver enzymes. Biopsies of his bowel and lungs demonstrated evolving GVHD (acute to chronic) over the next 8 months. He required bowel rest, ventilatory support (3 weeks), high-dose pulse methylprednisolone and antithymocyte globulin. In April 1991, following a generalized seizure thought to be secondary to the CsA, his medication was changed to azathioprine (AZA). He continued treatment with prednisone and AZA with resolution of his symptoms by October 1991. The patient remained well and his immunosuppressives were stopped in January 1992. In April 1992, he represented with dyspnea; an openlung biopsy confirmed reoccurrence of cGVHD in his lungs. He was restarted on prednisone and AZA, with good symptomatic response. As prednisone was tapered in October 1992, he developed ptosis, dysarthria, generalized weakness, dysphagia and dyspnea. Nerve conduction studies, a positive Tensilon test and elevated acetylcholine receptor antibodies confirmed a diagnosis of severe MG. A CT scan of the chest excluded thymic enlargement. Treatment with pyridostigmine, atropine, AZA, thymectomy and plasmapheresis, resulted in only short-term remission. Thalidomide was added in February 1993, with subsequent improvement. He was discharged in April 1993 on thalidomide, pyridostigmine, atropine, prednisone and AZA. By November 1993, he had recovered and was on no medication. The donor reported no symptoms of MG and tested negative for acetylcholine receptor antibodies. The patient was well until September 1996, when he presented with a 3-month history of progressive muscle weakness, myalgia, contractures, an elevated creatine kinase (CK) level of 1993 IU/l (n ⬍ 200 IU/l). He had muscle tenderness and proximal muscle weakness of all extremities (graded 4/5 on the MRC scale). No fasciculations or clonus were noted. There were flexion contractures of both elbows and ankles. He toe-walked with a broad-based gait. Trendelenburg test was negative. The remainder of the physical examination was unremarkable. Laboratory tests showed elevated CK (1357 IU/l), AST (155 U/l), ALT (168U/l), and ALP (151 U/l). The antismooth muscle antibody titer was positive at 1:40. Rheuma-
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tologic markers (RF, ANA, mitochondrial antibody), thyroid function, immunoglobulins, complement levels, metabolic tests (carnitine, ammonium, free fatty acids, betahydroxy-butyrate), and viral antibody titers were normal. Whole body MRI showed diffusely abnormal high signal changes within the proximal muscles of the upper and lower limbs. The electromyogram had fibrillations and lowamplitude short-duration motor-unit potentials consistent with a myopathic process. Nerve conduction studies were normal. Biopsy of the right deltoid (Figure 1) showed large geographic areas of myonecrosis and a vigorous histiocytic reaction associated with a mixed inflammatory infiltrate consisting mainly of T-lymphocytes. A few lymphocytes were found around the occasional blood vessel. There was no perifascicular atrophy. No tubuloreticular inclusions were identified by EM. Stains for bacteria and fungi were negative. The pathologic and clinical findings were consistent with a severe myositis. He was treated with prednisone 2 mg/kg/day. Clinical improvement occurred in 2 days, and he was discharged on the same dose of prednisone. At his 1-month follow-up visit, it was discovered that the patient had not taken his prednisone. However, he was much improved and his CK level had fallen to 482 IU/l. Liver enzymes had normalized. The patient and family refused to restart prednisone. Follow-up at 2 and 4 months revealed no muscle tenderness or contractures, and continued improvement of muscle strength with minimal residual proximal-muscle weakness. His serum CK resolved by 4 months to 173 IU/l, and he was functioning normally in his daily activities. Discussion Chronic GVHD has been defined1 as GVHD occurring more than 100 days after BMT and may present as an extension of aGVHD, after a disease-free interval or without precedent. The disease commonly involves the skin, eyes, mouth, bowel, liver, lung and immune system.1 The literature reports eight cases of MG2,4–8 and 29 cases of PM1,3,8–15 as unusual manifestations of cGVHD. Our case
Figure 1 Biopsy of right deltoid muscle, showing myonecrosis and a vigorous histiocytic reaction.
report is the first reported with both MG and PM developing after allogeneic BMT in a single patient. All reported cases of MG following BMT had a prior history of cGVHD. MG is an autoimmune neuromuscular disease in which antibodies are directed against the acetylcholine receptor. cGVHD, similar to autoimmune diseases, may be associated with the development of autoantibodies. Passive transfer of antibodies resulting in MG can be excluded, as donor antibodies would be removed by 6–12 months and all reported cases of MG developed 22–60 months from BMT. In addition, no acetylcholine receptor antibodies have been detected in the serum of the donors. Differences between donor and recipient acetylcholine receptors could cause the graft to produce antibodies against recipient receptors, resulting in MG. Viral infections may further provoke antigenic differences in the acetylcholine receptors and generate an immune reaction.16,17 The presence of antinuclear and antimuscular antibodies in some patients suggests a more generalized autoimmune dysregulation. Since most BMT recipients are taking immunosuppressants for GVHD, MG may not be seen until such drugs are discontinued, as in our patient. PM in cGVHD is clinically similar to idiopathic PM.3 Most cases had a prior history of cGVHD; but in 10, PM presented as the sole manifestation of cGVHD.3,8,10–12,14,15 The onset of PM has been reported 2 to 36 months postBMT. Interestingly, our patient presented 69 months after his BMT, when his cGVHD had been quiescent for 34 months. We considered other possible causes of muscle weakness, but found no evidence of electrolyte abnormalities, steroid myopathy, muscle atrophy, neuropathies, delayed secondary malignancies, infectious myositis (influenza, toxoplasma, coxsackievirus B, parvovirus, hepatitis B), myotoxic drugs, endocrinopathies (thyroid, pituitary), or deficiencies of muscle enzymes. Juvenile dermatomyositis was eliminated based on the lack of rash. The remaining diagnoses were idiopathic PM, which is extremely rare in children, and more likely, GVHDrelated PM. Most patients responded to prednisone with an improvement in muscle strength and CK levels, but refractory cases required immunosuppressive agents.1,3,8,9,13 The activity of the cGVHD rather than severity of the myositis determined prognosis. Our patient partially responded to only 2 days of therapy, followed by a prolonged spontaneous recovery phase. Although the initial rapid response to corticosteroids was in keeping with GVHD-related PM, most cases reported in the literature described longer treatment to induce remission. The pathophysiology of GVHD-related PM is not well understood. Evidence of immunodeficiency, autoimmunity and immunologic dysregulation have been described.18 T cell dysregulation may lead to T cell-mediated injury and unregulated B cell autoantibody formation. Sensitization of muscle antigens by viral infections, connective tissue disorders, tumours or trauma can further direct injury against the muscle fibers. Our patient originally had aplastic anemia, which can be associated with immune dysfunction, autoimmune disorders and thymomas.19 The literature demonstrates that of the nine cases of cGVHD-related MG, six (67%) had aplastic
Myasthenia gravis and polymyositis from chronic GVHD S Tse et al
anemia as the underlying disease.2,4–6 Similarly, in 18 cases of cGVHD-related PM (cases without a diagnosis were excluded), eight (44%) had aplastic anemia.1,8,9,13,14 The relationship between underlying aplastic anemia and these rare complications of cGVHD is unclear, although one could speculate that immune dysregulation both before and after transplant plays a role. MG and PM are extremely unusual manifestations of immune dysregulation in cGVHD and the occurrence in a single patient is unique. With the increasing number of long-term survivors of BMT, it is important to recognize these two manifestations as signs of cGVHD. Standard treatment is with corticosteroids and other agents such as AZA or CSA may be used for treatment failures.
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Acknowledgements This paper was prepared with the assistance of Editorial Services, The Hospital for Sick Children, Toronto, Ontario, Canada.
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