STIFF-PERSON syndrome (SPS) is a rare and disabling autoimmune disorder that presents evolving diagnostic challenges for clinicians. Increased awareness of SPS among patients and physicians due to recent public attention has increased anxiety around diagnosis, misdiagnosis, and treatment of the disorder.
In a recently published review, Marinos C. Dalakas, Professor of Neurology and Director of the Neuromuscular Division at Thomas Jefferson University School of Medicine in Philadelphia, Pennsylvania, highlighted diagnostic difficulties, misdiagnoses, and discussed overlapping glutamic acid decarboxylase (GAD) antibody spectrum disorders such as cerebellar ataxia, encephalitis, and autoimmune epilepsy.
Characterized by stiffness in the limbs and axial muscles, stiff gait with uncontrolled falls, and episodic painful muscle spasms triggered by anxiety, task-specific phobias, and startle responses, SPS collectively leads to disability. It is associated with glutamic acid decarboxylase (GAD) antibodies, which interfere with GABAergic inhibition, contributing to neuronal hyperexcitability. Dalakas underscores the need for GAD antibody titres for SPS diagnosis and, if titres are low, the presence of GAD antibodies in the cerebrospinal fluid is required.
The pathophysiology of SPS involves impaired GABA production and cortical hyperexcitability, but evidence on whether GAD antibodies are directly pathogenic remains inconclusive. Dalakas suggested other mechanisms may include environmental triggers, familial and immunogenetic susceptibility, and potential T cell cytotoxicity. Therapeutically, the review emphasizes include targeting of GABAergic inhibition with GABA-enhancing antispasmodic drugs, including baclofen, gabapentin, and diazepam as frontline treatments for managing symptoms. This is followed by immunotherapies such as intravenous immunoglobulin and rituximab, with promising novel therapies on the horizon.
As interest in SPS grows, this review provide valuable direction for clinicians, offering a clearer understanding of the disorder’s mechanisms and emerging therapeutic strategies.
Reference: Dalakas MC. Stiff-person syndrome and related disorders — diagnosis, mechanisms and therapies. Nat Rev Neurol. 2024.
Anaya Malik | AMJ
