Stiff Person Syndrome
- Author: Nancy Theresa Rodgers-Neame, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
Stiff person syndrome is rather unique among neurologic diagnoses because of its lack of significant similarity to any other neurologic diseases. Although rare, once observed it is quite unforgettable. Possibly the closest related disease is tetanus because both conditions affect peripheral inhibition via central mechanisms and both conditions inhibit central gamma-aminobutyric acid (GABA) systems.
In 1956, Moersch and Woltmann, who also coined the term stiff man syndrome, first clearly described stiff person syndrome as a neurologic clinical entity at the Mayo Clinic. The eponym for this syndrome, Moersch-Woltmann syndrome, is one of the few instances in which the eponym may be the most inclusive and at the same time the most appropriately limiting name for the disease. The term stiff person may be seen to exclude infants, and stiff man is inappropriate for children and women; perhaps stiff individual most perfectly describes the affected patient.
Clinically, stiff person syndrome is characterized by muscle rigidity that waxes and wanes with concurrent spasms.[3, 4] Usually, it begins in the axial muscles and extends to the proximal limb muscles, but the severity of the limb muscle involvement may overwhelm the axial muscle involvement (stiff limb syndrome).[5, 6, 7, 8, 9, 4] Some confusion has occurred as a result of cases that include other neurologic findings, such as encephalomyelitis, epilepsy, cerebral palsy, or cerebellar deficits, sometimes in addition to the classic clinical syndrome.[10, 11, 12, 13, 14, 15, 16]
The pathophysiology of the disease is autoimmune.[17, 18, 19, 20, 21, 9, 3] The most common pathologic correlate, anti–glutamic acid decarboxylase (GAD) antibodies, has been associated with a wide range of neurologic diseases. It is also associated with a number of non-neurologic diseases, including diabetes mellitus and thyroiditis.
Endocrinologists were excited by a discovery in the 1980s of an antibody to a 65-kd protein that was strongly associated with adult-onset diabetes mellitus and stiff person syndrome. It is found in a particularly large subset of patients with diabetes, and endocrinologists hoped that it would be the major breakthrough needed to cure this disease in millions of patients worldwide. They were disappointed to find that the 65-kd protein was GAD, an enzyme largely found in the central nervous system (CNS), and, unfortunately, the pathophysiologic link between diabetes and glutamic acid decarboxylase remains unclear.
Since that time, the antibody has been found in patients with a number of neurologic diseases, a scenario that is easier to understand because the pathophysiologic link to neurologic disease is easier to explain. The range of diseases encountered includes seizures, cerebellar dysfunction, cortical dysfunction, and myelopathy, but the association between function of the enzyme and the consequence of the disease is most clear in patients with stiff person syndrome.
In stiff person syndrome, spinal interneurons function to inhibit spontaneous discharges from spinal motor neurons, primarily through the action of glycine. However, this is only one inhibitory input for the motor pathway that includes GABA-mediated inhibition from the cortex, brain stem, and cerebellum. If GAD function is inhibited significantly, then GABA available for these functions is decreased and muscles become continuously stimulated by the motor neurons. Additional possible pathophysiologic etiologies in patients negative for GAD antibody include postsynaptic elements such as synaptophysin, amphiphysin, gephyrin, and GABA-transaminase.
Glutamate is an excitatory amino acid synthesized from glucose via the Krebs cycle. It has several fates within the cell. Glutamate can be packaged for release from synaptic clefts, and it can be acted on by several transaminases to transform it to either glutamine or GABA. Following release from the synapse, glutamate is absorbed either by reuptake mechanisms by the neurons or, more commonly, by astrocytes. GAD is nearly ubiquitous in the CNS and is located in or near the synaptic button. It is rate limited primarily by the availability of free glutamate. However, GAD is not the only source of GABA. The Krebs cycle also serves to synthesize GABA via GABA-transaminase.
However, GAD antibodies alone appear to be insufficient to cause stiff person syndrome, and GAD antibodies are associated with a broad spectrum of disease; consequently, GAD clearly forms only part of the pathophysiology of stiff person syndrome. Possibly, postsynaptic GABA-ergic mechanisms, such as the synaptobrevins involved in tetanus, are involved. Research continues to progress on this interesting subject.[5, 17, 21, 26, 7, 27] Some patients clearly have GAD antibody-negative disease and may also be negative for anti-amphiphysin but otherwise fit the clinical picture.
Stiff person syndrome is rare. Between 2000 and 2005, only 119 cases were identified in the United Kingdom. Age of onset varies (30 to 60 years) and most frequently affects people in their 40s. Stiff person syndrome does not predominantly occur in any racial or ethnic group.
Complications of this disease are multifaceted and may occur at any stage of the disease. In general, complications are responsible for the mortality and morbidity and are discussed in more detail in Complications.
Infants with stiff baby syndrome are at particularly high risk of sudden infant death and require monitoring.
Complications of baclofen pump failure can occur. Cataclysmic exacerbations of the disease have been reported due to baclofen pump failure. At least one death has been reported. In addition, rare malfunctions of the baclofen pump have been associated with excessive release of baclofen intrathecally also resulting in death or permanent disability.
Psychiatric morbidity from this disease is common. The unpredictability of symptoms and the linkage to stressful events only serve to exacerbate the situation. In addition, GABA mechanisms subserve many of the brain's emotional centers, which may contribute significantly to the psychiatric symptomatology.
Musculoskeletal complications are common, particularly in later stages of the disease. Joint deformity, joint dislocation, joint contracture, skeletal fracture, and muscle rupture have been reported.
Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. Stiff person syndrome. Pract Neurol. 2011 Oct. 11(5):272-82. [Medline].
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. 31:421-7.
Duddy ME, Baker MR. Stiff person syndrome. Front Neurol Neurosci. 2009. 26:147-65. [Medline].
Misra UK, Maurya PK, Kalita J, Gupta RK. Stiff limb syndrome: end of spectrum or a separate entity?. Pain Med. 2009 Apr. 10(3):594-7. [Medline].
Blum P, Jankovic J. Stiff-person syndrome: an autoimmune disease. Mov Disord. 1991. 6(1):12-20. [Medline].
Stayer C, Meinck HM. Stiff-man syndrome: an overview. Neurologia. 1998 Feb. 13(2):83-8. [Medline].
Murinson BB. Stiff-person syndrome. Neurologist. 2004 May. 10(3):131-7. [Medline].
Jimenez Caballero PE. Stiff person syndrome: presentation of a case with repetitive complex discharges in electromiograms. Neurologist. 2009 Jul. 15(4):227-9. [Medline].
Barker RA, Revesz T, Thom M, Marsden CD, Brown P. 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 Nov. 65(5):633-40. [Medline].
Ishida K, Mitoma H, Song SY, et al. Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol. 1999 Aug. 46(2):263-7. [Medline].
Lenti C, Bognetti E, Bonfanti R, Bonifacio E, Meschi F. Myoclonic encephalopathy and diabetes mellitus in a boy. Dev Med Child Neurol. 1999 Jul. 41(7):489-90. [Medline].
Mitoma H, Song SY, Ishida K, Yamakuni T, Kobayashi T, Mizusawa H. Presynaptic impairment of cerebellar inhibitory synapses by an autoantibody to glutamate decarboxylase. J Neurol Sci. 2000 Apr 1. 175(1):40-4. [Medline].
Lynex CN, Carr IM, Leek JP, et al. Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders. BMC Neurol. 2004 Nov 30. 4(1):20. [Medline].
Peltola J, Kulmala P, Isojarvi J, et al. Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology. 2000 Jul 12. 55(1):46-50. [Medline].
Aso Y, Sato A, Narimatsu M, et al. Stiff-man syndrome associated with antecedent myasthenia gravis and organ-specific autoimmunopathy. Intern Med. 1997 Apr. 36(4):308-11. [Medline].
Ellis TM, Atkinson MA. The clinical significance of an autoimmune response against glutamic acid decarboxylase. Nat Med. 1996 Feb. 2(2):148-53. [Medline].
Dinkel K, Meinck HM, Jury KM, Karges W, Richter W. Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol. 1998 Aug. 44(2):194-201. [Medline].
Butler MH, Solimena M, Dirkx R Jr, Hayday A, De Camilli P. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome. J Exp Med. 1993 Dec 1. 178(6):2097-106. [Medline].
Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology. 2001 Sep 11. 57(5):780-4. [Medline].
Lernmark A. Glutamic acid decarboxylase--gene to antigen to disease. J Intern Med. 1996 Nov. 240(5):259-77. [Medline].
O'Sullivan EP, Behan LA, King TF, Hardiman O, Smith D. A case of stiff-person syndrome, type 1 diabetes, celiac disease and dermatitis herpetiformis. Clin Neurol Neurosurg. 2009 May. 111(4):384-6. [Medline].
Geis C, Beck M, Jablonka S, et al. Stiff person syndrome associated anti-amphiphysin antibodies reduce GABA associated [Ca(2+)](i) rise in embryonic motoneurons. Neurobiol Dis. 2009 Jul 23. [Medline].
Butler MH, Hayashi A, Ohkoshi N, et al. Autoimmunity to gephyrin in Stiff-Man syndrome. Neuron. 2000 May. 26(2):307-12. [Medline].
Dalakas MC. Stiff person syndrome: advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009 Mar. 11(2):102-10. [Medline].
Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med. 1999 Oct 5. 131(7):522-30. [Medline]. [Full Text].
Ziegler B, Strebelow M, Rjasanowski I, Schlosser M, Ziegler M. A monoclonal antibody-based characterization of autoantibodies against glutamic acid decarboxylase in adults with latent autoimmune diabetes. Autoimmunity. 1998. 28(2):61-8. [Medline].
Hadavi S, Noyce AJ, Leslie RD, Giovannoni G. Stiff person syndrome. Pract Neurol. 2011 Oct. 11(5):272-82. [Medline].
Ciccoto G, Blaya M, Kelley RE. Stiff person syndrome. Neurol Clin. 2013 Feb. 31(1):319-28. [Medline].
Sarva H, Deik A, Ullah A, Severt WL. Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports. Tremor Other Hyperkinet Mov (N Y). 2016. 6:340. [Medline].
Bhatti AB, Gazali ZA. Recent Advances and Review on Treatment of Stiff Person Syndrome in Adults and Pediatric Patients. Cureus. 2015 Dec 22. 7 (12):e427. [Medline].
Rakocevic G, Floeter MK. Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes. Muscle Nerve. 2012 May. 45(5):623-34. [Medline]. [Full Text].
Hayashi A, Nakamagoe K, Ohkoshi N, Hoshino S, Shoji S. Double filtration plasma exchange and immunoadsorption therapy in a case of stiff-man syndrome with negative anti-GAD antibody. J Med. 1999. 30(5-6):321-7. [Medline].
Goldkamp J, Blaskiewicz R, Myles T. Stiff person syndrome and pregnancy. Obstet Gynecol. 2011 Aug. 118(2 Pt 2):454-7. [Medline].
Brashear HR, Phillips LH 2nd. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology. 1991 Oct. 41(10):1588-92. [Medline].
Brown P, Rothwell JC, Marsden CD. The stiff leg syndrome. J Neurol Neurosurg Psychiatry. 1997 Jan. 62(1):31-7. [Medline].
Culav- Sumic J, Bosnjak I, Pastar Z, Jukic V. Anxious depression and the stiff-person plus syndrome. Cogn Behav Neurol. 2008 Dec. 21(4):242-5.
Dalakas MC. Intravenous immunoglobulin in patients with anti-GAD antibody-associated neurological diseases and patients with inflammatory myopathies: effects on clinicopathological features and immunoregulatory genes. Clin Rev Allergy Immunol. 2005 Dec. 29(3):255-69. [Medline].
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 Jan 15. 156(2):818-25. [Medline].
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 Dec 1. 178(6):2219-23. [Medline].
Fiol M, Cammarota A, Rivero A, Pardal A, Nogues M, Correale J. Focal stiff-person syndrome. Neurologia. 2001 Feb. 16(2):89-91. [Medline].
Floyd S, Butler MH, Cremona O, et al. Expression of amphiphysin I, an autoantigen of paraneoplastic neurological syndromes, in breast cancer. Mol Med. 1998 Jan. 4(1):29-39. [Medline].
Gerschlager W, Schrag A, Brown P. Quality of life in stiff-person syndrome. Mov Disord. 2002 Sep. 17(5):1064-7. [Medline].
Goppert D, Gardill K, Beischer W, Wietholter H. [The stiff-man syndrome with diabetes mellitus type 1 and autoimmune thyroiditis]. Dtsch Med Wochenschr. 2000 Jul 7. 125(27):826-9. [Medline].
Johnstone AP, Nussey SS. Direct evidence for limited clonality of antibodies to glutamic acid decarboxylase (GAD) in stiff man syndrome using baculovirus expressed GAD. J Neurol Neurosurg Psychiatry. 1994 May. 57(5):659. [Medline].
Lohmann T, Hawa M, Leslie RD, Lane R, Picard J, Londei M. Immune reactivity to glutamic acid decarboxylase 65 in stiffman syndrome and type 1 diabetes mellitus. Lancet. 2000 Jul 1. 356(9223):31-5. [Medline].
Martino G, Grimaldi LM, Bazzigaluppi E, Passini N, Sinigaglia F, Rogge L. The insulin-dependent diabetes mellitus-associated ICA 105 autoantigen in stiff-man syndrome patients. J Neuroimmunol. 1996 Sep. 69(1-2):129-34. [Medline].
Meinck HM, Ricker K, Hulser PJ, Schmid E, Peiffer J, Solimena M. Stiff man syndrome: clinical and laboratory findings in eight patients. J Neurol. 1994 Jan. 241(3):157-66. [Medline].
Nicholas AP, Chatterjee A, Arnold MM, Claussen GC, Zorn GL Jr, Oh SJ. Stiff-persons' syndrome associated with thymoma and subsequent myasthenia gravis. Muscle Nerve. 1997 Apr. 20(4):493-8. [Medline].
Raju R, Foote J, Banga JP, et al. Analysis of GAD65 autoantibodies in Stiff-Person syndrome patients. J Immunol. 2005 Dec 1. 175(11):7755-62. [Medline].
Saravanan PK, Paul J, Sayeed ZA. Stiff person syndrome and myasthenia gravis. Neurol India. 2002 Mar. 50(1):98-100. [Medline].
Shariatmadar S, Noto TA. Plasma exchange in stiff-man syndrome. Ther Apher. 2001 Feb. 5(1):64-7. [Medline].
Solimena M, Butler MH, De Camilli P. GAD, diabetes, and Stiff-Man syndrome: some progress and more questions. J Endocrinol Invest. 1994 Jul-Aug. 17(7):509-20. [Medline].
Solimena M, De Camilli P. Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 1991 Oct. 14(10):452-7. [Medline].
Sommer C, Weishaupt A, Brinkhoff J, Biko L, Wessig C, Gold R, et al. Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin. Lancet. 2005 Apr 16-22. 365(9468):1406-11. [Medline].
Takenoshita H, Shizuka-Ikeda M, Mitoma H, et al. Presynaptic inhibition of cerebellar GABAergic transmission by glutamate decarboxylase autoantibodies in progressive cerebellar ataxia. J Neurol Neurosurg Psychiatry. 2001 Mar. 70(3):386-9. [Medline]. [Full Text].
Vincent A, Grimaldi LM, Martino G, Davenport C, Todd I. Antibodies to 125I-glutamic acid decarboxylase in patients with stiff man syndrome. J Neurol Neurosurg Psychiatry. 1997 Apr. 62(4):395-7. [Medline].
Warich-Kirches M, Von Bossanyi P, Treuheit T, et al. Stiff-man syndrome: possible autoimmune etiology targeted against GABA-ergic cells. Clin Neuropathol. 1997 Jul-Aug. 16(4):214-9. [Medline].