Immunobiology and immunotherapies in stiff-person syndrome and glutamic acid decarboxylase antibody-spectrum disorders: Present and future therapeutic prospects.

Stiff-person syndrome (SPS) is increasingly recognized as the prototypic and most common autoimmune neuronal hyperexcitability disorder that presents with 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, collectively leading to disability. Recent publicity has increased SPS awareness among patients and physicians, generating concerns about diagnosis, misdiagnoses, pathomechanism, and the most successful or promptly applied therapies. The paper addresses the evolving diagnostic challenges within the overlapping SPS-spectrum disorders, focusing on the progress made in SPS pathophysiology and the underlying autoimmunity; addresses the significance of antibodies against glutamic acid decarboxylase or other inhibitory synaptic antigens and the fundamentals of autoimmune neuronal hyperexcitability; and elaborates on the rationale of target-specific therapeutic interventions based on γ-aminobutyric acid -enhancing drugs and immunotherapies, stressing the need for early immunotherapy initiation to halt disability progression. The challenges of current therapies in late-onset SPS are also highlighted and an updated therapeutic scheme is provided for present and upcoming immunotherapeutic interventions for refractory disease. Finally, the challenges of applying suitable therapeutic scales in capturing the fundamentals of SPS symptomatology and objectively assessing responses to novel therapeutic trials are discussed.