Consult the medical resource doctors trust

UpToDate is one of the most respected medical information resources in the world, used by over 360,000 doctors and thousands of patients to find answers to medical questions.

  • Content written by a faculty of over 4,000 physicians from leading medical institutions
  • Unbiased: free of advertising or pharmaceutical funding
  • Evidence-based treatment recommendations
  • Continuously updated to incorporate new medical findings

Stiff-person syndrome

INTRODUCTION

Stiff-person syndrome (SPS, formerly called stiff-man syndrome) is an uncommon disorder characterized by progressive muscle stiffness, rigidity, and spasm involving the axial muscles, resulting in severely impaired ambulation [1,2]. SPS is often associated with type 1 diabetes mellitus, which is a reflection of shared pathogenetic features.

PATHOGENESIS

An autoimmune process was originally postulated to underlie SPS since the disorder often occurred in conjunction with a variety of autoimmune diseases. These include thyroiditis, vitiligo, pernicious anemia, and (particularly) type 1 diabetes mellitus [1,3-6].

Additional insight into an autoimmune mechanism was provided by the observation of polyclonal and oligoclonal IgG antibody elevations in the cerebrospinal fluid of the majority of patients with SPS [6,7]. These antibodies were found to target GABAergic (gamma amino butyric acid) neurons and their nerve terminals. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD).

Outside the central nervous system, a high concentration of anti-GAD antibodies also recognize pancreatic beta cells; this may explain the link between SPS and type 1 diabetes [8]. (See 'Type 1 diabetes mellitus' below and "Pathogenesis of type 1 diabetes mellitus".)

Anti-GAD antibodies — Circulating anti-GAD antibodies are present in approximately 60 percent of patients with SPS [6,9]. These antibodies can be reliably detected using a commercially available radioimmunoassay [10,11]. The relevance of these antibodies to the pathogenesis of SPS is supported by the following observations:
To continue reading this article you need to subscribe.

Read the rest of this article and others like it

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2010 UpToDate, Inc.
References Top
  1. Helfgott, SM. Stiff-man syndrome. From the bedside to the bench. Arthritis Rheum 1999; 42:1312.
  2. Shaw, PJ. Stiff-man syndrome and its variants. Lancet 1999; 353:86.
  3. Werk, EE Jr, Sholiton, LJ, Marnell, RT. The "stiff-man" syndrome and hyperthyroidism. Am J Med 1961; 31:647.
  4. George, TM, Burke, JM, Sobotka, PA, et al. Resolution of stiff-man syndrome with cortisol replacement in a patient with deficiencies of ACTH, growth hormone, and prolactin. N Engl J Med 1984; 310:1511.
  5. Lorish, TR, Thorsteinsson, G, Howard, FM Jr. Stiff-man syndrome updated. Mayo Clin Proc 1989; 64:629.
  6. Solimena, M, Folli, F, Aparisi, R, et al. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff- man syndrome. N Engl J Med 1990; 322:1555.
  7. Solimena, M, Folli, F, Denis-Donini, S, et al. 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.
  8. Vincent, SR, Hokfelt, T, Wu, JY, et al. Immunohistochemical studies of the GABA system in the pancreas. Neuroendocrinology 1983; 36:197.
  9. Dinkel, K, Meinck, HM, Jury, KM, et al. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998; 44:194.
  10. Murinson, BB, Butler, M, Marfurt, K, et al. Markedly elevated GAD antibodies in SPS: effects of age and illness duration. Neurology 2004; 63:2146.
  11. Chang, T, Lang, B. GAD antibodies in stiff-person syndrome. Neurology 2004; 63:1999.
  12. Dalakas, MC, Li, M, Fujii, M, Jacobowitz, DM. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001; 57:780.
  13. Harrison, LC, Honeyman, MC, Schmidli, RS, et al. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet 1993; 341:1365.
  14. Baekkeskov, S, Nielsen, JH, Marner, B, et al. Autoantibodies in newly diagnosed diabetic children immunoprecipitate human pancreatic islet cell proteins. Nature 1982; 298:167.
  15. Atkinson, MA, Maclaren, NK, Scharp, DW,et al. 64,000 MW autoantibodies are predictive of insulin dependent diabetes. Lancet 1990; 335:1357.
  16. Kim, J, Namchuk, M, Bugawan, T, et al. Higher autoantibody levels and recognition of a linear NH2-terminal epitope in the autoantigen GAD65, distinguish stiff-man syndrome from insulin-dependent diabetes mellitus. J Exp Med 1994; 180:595.
  17. Daw, K, Ujihara, N, Atkinson, M, Powers, AC. Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J Immunol 1996; 156:818.
  18. Lohmann, T, Hawa, M, Leslie, RD, et al. Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus. Lancet 2000; 356:31.
  19. Pugliese, A, Solimena, M, Awdeh, ZL, et al. Association of HLA-DQB1*0201 with stiff-man syndrome. J Clin Endocrinol Metab 1993; 77:1550.
  20. Meinck, HM, Ricker, K, Hulser, PJ, Solimena, M. Stiff man syndrome: neurophysiological findings in eight patients. J Neurol 1995; 242:134.
  21. Grimaldi, LM, Martino, G, Braghi, S, et al. Heterogeneity of autoantibodies in stiff-man syndrome. Ann Neurol 1993; 34:57.
  22. Folli, F, Solimena, M, Cofiell, R, et al. 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.
  23. De Camilli, P, Thomas, A, Cofiell, R, et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of stiff-man syndrome with breast cancer. J Exp Med 1993; 178:2219.
  24. Wessig, C, Klein, R, Schneider, MF, et al. Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome. Neurology 2003; 61:195.
  25. Murinson, BB, Guarnaccia, JB. Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology 2008; 71:1955.
  26. Sommer, C, Weishaupt, A, Brinkhoff, J, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet 2005; 365:1406.
  27. Dropcho, EJ. Antiamphiphysin antibodies with small-cell lung carcinoma and paraneoplastic encephalomyelitis. Ann Neurol 1996; 39:659.
  28. Ellis, TM, Atkinson, MA. The clinical significance of an autoimmune response against glutamic acid decarboxylase. Nat Med 1996; 2:148.
  29. Daras, M, Spiro, AJ. 'Stiff-man syndrome' in an adolescent. Pediatrics 1981; 67:725.
  30. McEvoy, K. Stiff-man syndrome. In: Office Practice of Neurology, Feske, S, Samuels, M (Eds), Churchill-Livingstone, New York, 1996, Ch. 130.
  31. Stayer, C, Tronnier, V, Dressnandt, J, et al. Intrathecal baclofen therapy for stiff-man syndrome and progressive encephalomyelopathy with rigidity and myoclonus. Neurology 1997; 49:1591.
  32. Kimura, J. Electrodiagnosis in Diseases of Nerve and Muscle: Principles and Practice, 2nd edition, FA Davis, Philadelphia, 1989, p. 558.
  33. Moersch, FP, Woltman, HW. Progressive fluctuating muscular rigidity and spasm ("stiff-man" syndrome); report of a case and some observations in 13 other cases. Mayo Clin Proc 1956; 31:421.
  34. Berger, C, Meinck, HM. Head retraction reflex in stiff-man syndrome and related disorders. Mov Disord 2003; 18:906.
  35. Tinsley, JA, Barth, EM, Black, JL, Williams, DE. Psychiatric consultations in stiff-man syndrome. J Clin Psychiatry 1997; 58:444.
  36. Henningsen, P, Clement, U, Kuchenhoff, J, et al. Psychological factors in the diagnosis and pathogenesis of stiff-man syndrome. Neurology 1996; 47:38.
  37. Mitsumoto, H, Schwartzman, MJ, Estes, ML, et al. Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol 1991; 238:91.
  38. Maccario, M, Baugh, JR, Mena, H. Sudden death in Moersch-Woltman. Neurology 1984; 34:407.
  39. Nakamura, N, Fujiya, S, Yahara, O, et al. Stiff-man syndrome with spinal cord lesion. Clin Neuropathol 1986; 5:40.
  40. Soykan, I, McCallum, RW. Gastrointestinal involvement in neurologic disorders: Stiff-man and Charcot-Marie-Tooth syndromes. Am J Med Sci 1997; 313:70.
  41. Henningsen, P, Meinck, HM. Specific phobia is a frequent non-motor feature in stiff man syndrome. J Neurol Neurosurg Psychiatry 2003; 74:462.
  42. Ameli, R, Snow, J, Rakocevic, G, Dalakas, MC. A neuropsychological assessment of phobias in patients with stiff person syndrome. Neurology 2005; 64:1961.
  43. Armon, C, McEvoy, KM, Westmoreland, BF, McManis, PG. Clinical neurophysiologic studies in stiff-man syndrome: Use of simultaneous video-electroencephalographic-surface electromyographic recording. Mayo Clin Proc 1990; 65:960.
  44. Matsumoto, JY, Caviness, JN, McEvoy, KM. The acoustic startle reflex in stiff-man syndrome. Neurology 1994; 44:1952.
  45. Schmierer, K, Valdueza, JM, Bender, A, et al. Atypical stiff-person syndrome with spinal MRI findings, amphiphysin autoantibodies, and immunosuppression. Neurology 1998; 51:250.
  46. Roobol, TH, Kazzaz, BA, Vecht, CJ. Segmental rigidity and spinal myoclonus as a paraneoplastic syndrome. J Neurol Neurosurg Psychiatry 1987; 50:628.
  47. Nicholas, AP, Chatterjee, A, Arnold, MM, et al. Stiff-persons' syndrome associated with thymoma and subsequent myasthenia gravis. Muscle Nerve 1997; 20:493.
  48. Piccolo, G, Martino, G, Moglia, A, et al. Autoimmune myastenia gravis with thymoma following the spontaneous remission of stiff-man syndrome. Ital J Neurol Sci 1990; 11:177.
  49. Martin, R, Meinck, HM, Schulte-Mattler, W, et al. Borrelia burgdorferi myelitis presenting as a partial stiff man syndrome. J Neurol 1990; 237:51.
  50. Requena, I, Arias, M, Pardo, J, et al. [Syndromes of continuous muscular activity: Report of a central case (stiff-man) and a peripheral case (neuromyotonia) associated with neuroborreliosis]. Rev Neurol 1995; 23:129.
  51. Andreadou, E, Kattoulas, E, Sfagos, C, Vassilopoulos, D. Stiff person syndrome: avoiding misdiagnosis. Neurol Sci 2007; 28:35.
  52. Ryan, SG, Sherman, SL, Terry, JC, et al. Startle disease, or hyperekplexia: Response to clonazepam and assignment of the gene (STHE) to chromosome 5q by linkage analysis. Ann Neurol 1992; 31:663.
  53. Meinck, HM, Ricker, K, Hulser, PJ, et al. Stiff man syndrome: Clinical and laboratory findings in eight patients. J Neurol 1994; 241:157.
  54. Barker, RA, Revesz, T, Thom, M, et al. Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 1998; 65:633.
  55. McCabe, DJ, Turner, NC, Chao, D, et al. Paraneoplastic "stiff person syndrome"; with metastatic adenocarcinoma and anti-Ri antibodies. Neurology 2004; 62:1402.
  56. Hutchinson, M, Waters, P, McHugh, J, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology 2008; 71:1291.
  57. Howard, FM, Jr. A new and effective drug in the treatment of stiff-man syndrome. Mayo Clin Proc 1963; 38:203.
  58. Cohen, L. Stiff-man syndrome. Two patients treated with diazepam. JAMA 1966; 195:222.
  59. Silbert, PL, Matsumoto, JY, McManis, PG, et al. Intrathecal baclofen therapy in stiff-man syndrome: A double-blind, placebo-controlled trial. Neurology 1995; 45:1893.
  60. Voci, JM, al-Hakim, M, Dokko, Y, Katirji, MB. Intravenous methocarbamol in the treatment of stiff-man syndrome. Muscle Nerve 1993; 16:434.
  61. Liguori, R, Cordivari, C, Lugaresi, E, Montagna, P. Botulinum toxin A improves muscle spasms and rigidity in stiff-person syndrome. Mov Disord 1997; 12:1060.
  62. Spehlmann, R, Norcross, K, Rasmus, SC, Schlageter, NL. Improvement of stiff-man syndrome with sodium valproate. Neurology 1981; 31:1162.
  63. Prevett, MC, Brown, P, Duncan, JS. Improvement of stiff-man syndrome with vigabatrin. Neurology 1997; 48:1133.
  64. Hattan, E, Angle, MR, Chalk, C. Unexpected benefit of propofol in stiff-person syndrome. Neurology 2008; 70:1641.
  65. Piccolo, G, Cosi, V, Zandrini, C, Moglia, A. Steroid-responsive and dependent stiff-man syndrome: a clinical and electrophysiological study of two cases. Ital J Neurol Sci 1988; 9:559.
  66. Karlson, EW, Sudarsky, L, Ruderman, E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994; 37:915.
  67. Barker, RA, Marsden, CD. Successful treatment of stiff man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 1997; 62:426.
  68. Khanlou, H, Eiger, G. Long-term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobin. Mayo Clin Proc 1999; 74:1231.
  69. Dalakas, MC, Fujii, M, Li, M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001; 345:1870.
  70. Brashear, HR, Phillips LH, 2nd. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991; 41:1588.
  71. Baker, MR, Das, M, Isaacs, J, et al. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry 2005; 76:999.
white circle LOG IN
white circle DEMO