Anti-GAD antibodies and breast cancer in a patient with stiff-person syndrome: a puzzling association

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(1)Article. Anti-GAD antibodies and breast cancer in a patient with stiff-person syndrome: a puzzling association SINNREICH, M., et al.. Reference SINNREICH, M., et al. Anti-GAD antibodies and breast cancer in a patient with stiff-person syndrome: a puzzling association. European Neurology, 2001, vol. 46, no. 1, p. 51-2. DOI : 10.1159/000050758 PMID : 11455186. Available at: http://archive-ouverte.unige.ch/unige:44725 Disclaimer: layout of this document may differ from the published version..

(2) Eur Neurol 2001;46:51–52. Anti-GAD Antibodies and Breast Cancer in a Patient with Stiff-Person Syndrome: A Puzzling Association M. Sinnreich a, F. Assal a, S. Hefft a, M.R. Magistris a, C. Chizzolini b, T. Landis a, P.R. Burkhard a Departments of a Neurology and b Immunology, University Hospital, Geneva, Switzerland. Stiff-person syndrome (SPS) is characterized by painful involuntary muscle contractions leading to stiffness and spasms [1] affecting the trunk and proximal limb muscles. The condition may occasional-. 51 Downloaded by: Université de Genève 129.195.0.205 - 12/9/2014 1:25:01 PM. Short Reports.

(3) 52. plasm, without signs of cancer progression. Second, the patient improved markedly on immunomodulatory treatment and is doing well ever since. Third, prior to the development of breast cancer the patient presented multiple autoantibodies, some of which leading to overt endocrinopathy. These arguments, in the absence of antiamphiphysin antibodies, considered specific for paraneoplastic neurological disorders [10], favor a nonparaneoplastic origin for the neurological symptoms, despite incidental cooccurrence of breast cancer, a common malignancy in elderly women. However, there remains the theoretical possibility of a paraneoplastic origin to our patient’s SPS, which should be considered, if GAD expression by the tumor was to be demonstrated. The peculiar association found here, as well as in 1 other case [8], and the fact that GAD has never been shown to be expressed in breast cancer cells, should encourage further studies to clarify this issue. Acknowledgments We thank Dr. M. Buttler, Yale University School of Medicine, New Haven, Conn., USA and Dr. J. Honnorat, INSERM-U 433, Lyon, France for autoantibody testing. References 1 Moersch FP, Woltman HW: Progressive fluctuating muscular rigidity and spasms (‘stiff-man’-syndrome): Report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin 1956;31:421–427. 2 Saiz A, Graus F, Valldeoriola F, Valls-Solé J, Tolosa E: Stiff-leg syndrome: A focal form of stiff-man syndrome. Ann Neurol 1998;43:400–403. 3 Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, Vicari AM: Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988;318:1012–1020. 4 Folli F, Solimena M, Cofiell R, Austoni M, Tallini G, Fassetta G, Bates D, Cartlidge N, Bottazzo GF, Piccolo G, De Camilli P: Autoantibodies to a 128-kD synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med 1993;328:546–551. 5 Howard FM: A new and effective drug in the treatment of the stiff-man syndrome: Preliminary report. Proc Staff Meet Mayo Clin 1963;38:203– 212. 6 Solimena M, Folli F, Aparisi R, Pozza G, DeCamilli P: Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 1990;322:1555–1560. 7 Brashear HR, Phillips LH: Autoantibodies to GABA-ergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991;41: 1588–1592. 8 Silverman IE: Paraneoplastic stiff limb syndrome. J Neurol Neurosurg Psychiatry 1999;67:126–127. 9 Rosin L, De Camilli P, Butler M, Solimena M, Schmitt HP, Morgenthaler N, Meinck HM: Stiff-man syndrome in a woman with breast cancer: An uncommon central nervous system paraneoplastic syndrome. Neurology 1998;50:94–98. 10 Antoine JC, Absi L, Honnorat J, Boulesteix JM, de Brouker T, Vial C, Butler M, De Camilli P, Michel D: Antiamphiphysin antibodies are associated with various paraneoplastic neurological syndromes and tumors. Arch Neurol 1999;56:172–177. Michael Sinnreich, MD, PhD Department of Neurology, University Hospital Rue Micheli-du-Crest 24, CH–1211 Geneva 14 (Switzerland) Tel. +41 22 3723311, Fax +41 22 3728299 E-Mail [email protected]. Short Reports Downloaded by: Université de Genève 129.195.0.205 - 12/9/2014 1:25:01 PM. ly extend to face, hands and feet, or remain focally restricted [2]. An autoimmune, nonparaneoplastic or paraneoplastic origin has been postulated [3, 4]. We present a woman with SPS and breast cancer in whom the two conditions seem unrelated. In January 1998 a 85-yearold woman complained of sustained involuntary muscle contractions leading to permanent stiffness of both thighs and the right arm. Symptoms were amplified by emotional upset or when startled, and disappeared during sleep. Gait was greatly impaired. Since 1977 she was suffering from recurrent bilateral uveitis. In spring 1998 Hashimoto’s thyroiditis was diagnosed. In July 1998 a ductal carcinoma of the breast was treated surgically followed by antihormonal therapy (tamoxifen). Examination revealed pupillary irregularities due to the uveitis. There were neither oculomotor abnormalities nor nystagmus. There was increased muscle tone in the right arm and in the lower extremities. Palpation of the hamstrings and quadriceps muscles revealed permanent cocontraction with inability to relax. Electromyographic examination revealed continuous motor activity in the hamstring and quadriceps muscles with normal motor unit potentials. Electrical stimulation of the median nerve provoked marked and sustained contractions of both quadriceps. Serum was positive for antithyroglobulin and antimicrosomal antibodies compatible with Hashimoto’s thyroiditis. M2-type antimitochondrial and anti-21-ß-hydroxylase antibodies were present with no signs of biliary cirrhosis or adrenal insufficiency, even after ACTH stimulation. Anti-islet antibodies were markedly elevated (1/640) as determined by immunohistochemistry, as were anti-glutamic acid decarboxylase (GAD) antibodies (250,060 mGAD U/ml, normal ! 70) determined by radioimmunoassay. CSF contained elevated IgG levels with oligoclonal bands and was positive for anti-GAD antibodies, as determined qualitatively by immunocytochemistry. It is noteworthy that despite elevated anti-GAD antibody titers no diabetes mellitus was present. Fasting glucose and HbA1c values were normal and oral glucose tolerance test was negative. Antiamphiphysin autoantibodies were negative, as were anti-Hu, anti-Yo and anti-Ri antibodies. MRI imaging of the whole neuraxis was unremarkable. Baclofen treatment (25 mg t.i.d.) slighty improved the patient’s stiffness. Diazepam was not tolerated. Plasmapheresis and IVIG treatment were only of short-lived benefit. High-dose steroid therapy (methylprednisone 500 mg i.v. per day for 5 days) brought substantial improvement allowing the patient to walk freely without support. Treatment was continued successfully with low-dose prednisone orally (0.4 mg/kg every other day) and the patient remained symptom free since. Improvement of SPS patients treated with diazepam [5], baclofen or vigabatrin suggested altered GABA-mediated inhibition as a pathophysiological mechanism for this condition. The association of SPS with pernicious anemia, thyroiditis, adrenal insufficiency, ovarian failure, myasthenia gravis, hypoparathyroidism, adrenalitis, vitiligo and diabetes mellitus hinted at an autoimmune basis for the disease in some patients. These two hypotheses were merged with the report of antibodies to GAD in both serum and CSF of a patient with SPS and diabetes mellitus [3]. Subsequently these antibodies were demonstrated in 70% of patients with SPS [6], and improvement of symptoms was observed with regimens including corticosteroids, plasmapheresis and IVIG [7]. Paraneoplastic SPS was first described in 1993, identifying antiamphiphysin antibodies in 3 patients with SPS and breast cancer [4]. Recently 2 patients were reported with SPS, breast cancer and anti-GAD antibodies [8, 9], where the SPS was attributed to a paraneoplastic origin. In our patient the SPS appears to be unrelated to the cancer. First, the patient’s symptoms continued to worsen after removal of the neo-.

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