Stiff person syndrome: navigating challenges in diagnosis and treatment

Background and objectives. Stiff person syndrome (SPS) is a rare, autoimmune neurological disorder marked by progressive muscle stiffness and episodic spasms. Its low prevalence and varied presentation complicate timely diagnosis. This review synthesizes clinical, diagnostic, and therapeutic insights into SPS and its phenotypic variants, highlighting challenges in early diagnosis and management. Materials and methods. We performed a narrative review of 48 English-language publications identified through comprehensive searches of PubMed and Web of Science (up to 2025). Inclusion focused on studies addressing SPS epidemiology, clinical features, antibody associations, diagnostics, and treatments. Results. SPS affects approximately 1 in 1,000,000, predominantly women in mid-adulthood. Phenotypic variants include classic SPS (axial rigidity with anti-GAD65 antibodies in ~70–80%), focal/partial SPS, SPS-plus with ataxia (often anti-GAD or anti-GlyR), progressive encephalomyelitis with rigidity and myoclonus (PERM; frequently anti-GlyR positive), and paraneoplastic SPS (commonly anti-amphiphysin). Diagnostic challenges arise from overlap with functional, psychiatric, or movement disorders and seronegative cases (~20%). Management involves GABA-enhancing drugs for symptom relief plus immunotherapies (IVIG, plasmapheresis, rituximab), though responses are often partial. Early diagnosis and tailored immunotherapy improve function and quality of life, despite residual disability. Five summary tables detail the clinical spectrum, antibody associations, and treatment outcomes. Conclusions. SPS requires a high index of suspicion and combined symptomatic and immunotherapy for optimal management. Early recognition and treatment may improve outcomes, but residual disability is common, highlighting the need for more effective therapies. Increased awareness of phenotypes, EMG and antibody testing, and timely immunotherapy are key. Future research should develop targeted therapies to better modify disease progression.