Causes of Stiff Person Syndrome
Stiff person syndrome is primarily an autoimmune disorder caused by antibodies against glutamic acid decarboxylase (GAD) in most cases, or against amphiphysin in the paraneoplastic variant, resulting in impaired GABAergic inhibition in the central nervous system. 1, 2
Autoimmune Pathogenesis
The underlying mechanism involves intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in inhibitory neurons of the brain and spinal cord. 2 This autoimmune process disrupts normal GABAergic neurotransmission, which is the fundamental pathophysiologic defect in SPS.
Anti-GAD Antibody-Associated SPS (Classic Form)
Anti-glutamic acid decarboxylase (GAD) antibodies are present in most patients with classic SPS, targeting the rate-limiting enzyme for production of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). 1
These antibodies are found in both cerebrospinal fluid and serum, with evidence suggesting they directly impair GABA synthesis. 2, 3
The strong association with several MHC-II alleles supports the genetic predisposition to this autoimmune process. 2
Classic SPS frequently coexists with other autoimmune diseases, particularly type 1 diabetes mellitus, providing additional evidence for its autoimmune etiology. 3
Paraneoplastic SPS
Anti-amphiphysin antibodies are the hallmark of paraneoplastic SPS, which is commonly associated with breast cancer. 1, 4
This variant occurs almost exclusively in females with a mean age of 60 years. 4
The cancer itself triggers the autoimmune response, with tumor excision and chemotherapy producing marked clinical improvement in some patients. 4
Other Autoantibodies
Antibodies directed against GABA(A) receptor-associated protein can be observed in some patients. 1
Antibodies against the glycine-α1 receptor have also been identified in certain cases. 1
Clinical Variants and Their Causes
The classification of SPS reflects different autoimmune targets and clinical presentations:
Classic SPS: Associated with anti-GAD antibodies, presenting with progressive rigidity of axial and limb muscles. 5, 1
Paraneoplastic SPS: Linked to anti-amphiphysin antibodies and underlying malignancy, most commonly breast cancer. 5, 1, 4
Focal or segmental SPS: A variant where autoimmune attack is more localized, such as stiff limb syndrome where symptoms are confined to the limbs. 5, 1
Progressive encephalomyelitis with rigidity and myoclonus (PERM): A severe variant representing more extensive autoimmune involvement. 1
Supporting Evidence for Autoimmune Etiology
Several lines of evidence confirm the autoimmune nature of SPS:
Association with other autoimmune diseases and autoantibodies is frequently observed. 3
Improvement with immunomodulatory therapies, including corticosteroids, provides functional evidence of immune-mediated pathogenesis. 3
The presence of intrathecal antibody synthesis demonstrates active immune processes within the central nervous system. 2
Response to B-cell modulating therapies supports the role of humoral immunity in disease pathogenesis. 2
Common Pitfalls
Do not dismiss SPS based on negative anti-GAD antibodies alone, as other autoantibodies (amphiphysin, GABA(A) receptor-associated protein, glycine-α1 receptor) may be responsible. 1
In female patients with cervical region stiffness and advanced age, always screen for breast cancer and anti-amphiphysin antibodies, as this represents a distinct paraneoplastic variant requiring cancer-directed therapy. 4
The association with other autoimmune diseases, particularly diabetes, supports early consideration of immunotherapy even before antibody results return. 6