Stiff-Person Syndrome: A Comprehensive Review of a Rare Disease with Emphasis on Pathophysiology, Clinical Features, Diagnostic Challenges and Therapeutic Advances.

Stiff-person syndrome (SPS) is an rare autoimmune neurological disorder that is associated with progressive axial and proximal muscle rigidity, stimulus-sensitive painful spasms, and significant functional disability. The disorder is commonly associated with high-titer antibodies against glutamic acid decarboxylase-65 (GAD65), leading to impaired gamma-aminobutyric acid (GABA)-mediated inhibitory neurotransmission, resulting in persistent motor neuron hyperexcitability. Despite the conventional classification of SPS as a motor disorder, the condition commonly occurs with neuropsychiatric symptoms, such as anxiety, phobic behaviors, and depression that often occur before the motor symptoms and can significantly increase diagnostic error or misdiagnosis. This review summarizes existing knowledge of the epidemiology, immunopathophysiology, clinical spectrum, diagnostic dilemmas, and treatment developments in SPS. This review also discusses the expanded concept of the stiff-person spectrum disorders that include classic SPS, stiff-limb syndrome, SPS-plus forms, and progressive encephalomyelitis with rigidity and myoclonus. Complexity in the diagnosis is associated with clinical heterogeneity, the variability of assays in anti-GAD65 testing, seronegative manifestations, and overlap of functional and psychiatric disorders, which highlights the role of electrophysiological validation and intrathecal immune scale. Management includes symptomatic treatment aimed at increasing GABAergic inhibition combined with disease-modifying immunotherapies, specifically intravenous immunoglobulin and B-cell-directed therapies in cases of refractory treatment. Despite progress in mechanistic comprehension and treatment, SPS has not been adequately diagnosed and is not substantiated by sufficient data on high-quality clinical trials. There is a need for early identification, proper diagnostic stewardship, and multidisciplinary care to enhance functional outcomes and quality of life. Future studies should address standard diagnostic criteria, phenotyping based on biomarkers, and specific immunotherapeutics.