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Stiff-person syndrome

Author
Simon M Helfgott, MD
Section Editors
Ira N Targoff, MD
Jeremy M Shefner, MD, PhD
Deputy Editor
Paul L Romain, MD

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]. It is caused by increased muscle activity due to decreased inhibition of the central nervous system (CNS) that results from the blockade of glutamic acid decarboxylase (GAD), an enzyme critical for maintaining inhibitory pathways. The subsequent decline in the levels of gamma amino butyric acid (GABA) in the CNS causes a loss of neural inhibition [3]. SPS is often associated with type 1 diabetes mellitus (T1DM), which may be a reflection of shared pathogenetic features, as well as other autoimmune disorders. It may rarely occur as a paraneoplastic syndrome.

Classic SPS and its major variants, partial SPS and paraneoplastic SPS, are reviewed here. Progressive encephalomyelitis with rigidity and myoclonus (PERM) and other paraneoplastic disorders of the nervous system are discussed in detail separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting the spinal cord and dorsal root ganglia" and "Paraneoplastic and autoimmune encephalitis", section on 'Others'.)

PATHOGENESIS

Several observations suggest an autoimmune component to the pathogenesis of stiff-person syndrome (SPS, formerly called stiff-man syndrome), including an association with type 1 diabetes mellitus (T1DM) and other autoimmune disorders, and the presence of autoantibodies targeting proteins associated with gamma amino butyric acid (GABA)-related neural pathways. It is thought that impairment of GABAergic pathways by autoantibodies and a reduction of brain GABA can lead to the clinical manifestations of stiffness, spasms, and phobias [4]. (See 'Autoimmunity' below and 'Type 1 diabetes' below.)

An autoimmune process was originally postulated to underlie SPS, as the disorder often occurs in conjunction with any one of a variety of autoimmune diseases, particularly T1DM; other associated conditions include thyroiditis, vitiligo, and pernicious anemia [1,5-8]. An association between anti-glutamic acid decarboxylase (GAD) antibodies and SPS has also been noted [8,9]. These antibodies were found to target GABAergic neurons and their nerve terminals. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme GAD [10].

Autoimmunity — The pathogenic role of the anti-GAD antibodies in SPS remains to be defined. GAD is an intracellular enzyme and is not readily accessible to binding by antibodies, although transfer experiments in mice, using serum obtained from affected patients, resulted in recipients becoming stiff. However, in SPS the titer of anti-GAD antibodies does not always correlate with disease activity, and about 30 percent of patients are antibody-negative.

                       

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Literature review current through: Apr 2016. | This topic last updated: Apr 28, 2016.
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