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  • Review Article
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Stiff-person syndrome and related disorders — diagnosis, mechanisms and therapies

Nature Reviews Neurology volume 20, pages 587–601 (2024)Cite this article

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Abstract

Stiff-person syndrome (SPS) is the prototypical and most common autoimmune neuronal hyperexcitability disorder. It 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. Increased awareness of SPS among patients and physicians has created concerns about diagnosis, misdiagnosis and treatment. This Review addresses the evolving diagnostic challenges in SPS and overlapping glutamic acid decarboxylase (GAD) antibody spectrum disorders, highlighting the growing number of overdiagnoses and focusing on the progress made in our understanding of SPS pathophysiology, antibodies against GAD and other inhibitory synaptic antigens, and the fundamentals of neuronal hyperexcitability. It considers the role of impaired GABAergic or glycinergic inhibition in the cortex and at multiple levels in the neuraxis; the underlying autoimmunity and involvement of GAD antibodies; immunopathogenic mechanisms beyond antibodies, including environmental triggers; familial and immunogenetic susceptibility; and potential T cell cytotoxicity. Finally, the mechanistic rationale for target-specific therapeutic interventions is presented along with the available therapeutic approaches, including enhancers of GABA signalling drugs and immunotherapies.

Key points

  • Stiff-person syndrome (SPS) is the most common form of glutamic acid decarboxylase (GAD) antibody spectrum disorder; others include cerebellar ataxia, encephalitis and autoimmune epilepsy.

  • SPS is characterized by stiffness, muscle spasms and task-specific phobias; GAD antibody titres are essential for diagnosis and, if titres are low, the presence of GAD antibodies in the cerebrospinal fluid is required.

  • Stiffness and task-specific phobias are explained by impaired reciprocal GABAergic inhibition, reductions in brain levels of GABA, and cortical hyperexcitability.

  • GAD antibodies have some effects on GABAergic neurons and GABA production in vitro and in vivo, but convincing evidence that GAD antibodies are pathogenic is lacking.

  • Intrathecal GAD antibody synthesis occurs in SPS, and circulating GAD-reactive B cells can differentiate into antibody-producing cells in the peripheral blood and bone marrow.

  • Therapeutic approaches to SPS include targeting of GABAergic inhibition with GABA-enhancing antispasmodic drugs, such as baclofen, gabapentin and diazepam, followed by immunotherapy, such as intravenous immunoglobulin or rituximab. Novel immunotherapies are in the offing.

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Fig. 1: Timeline of the major milestones in the field of stiff-person syndrome.
Fig. 2: Clinical manifestations of stiff-person syndrome.
Fig. 3: Pathophysiology and electrophysiology of reciprocal inhibition in health and stiff-person syndrome.
Fig. 4: Known antigenic targets involved in inhibitory synaptic transmission in glutamic acid decarboxylase antibody spectrum disorders.

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  1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA

    Marinos C. Dalakas

  2. Neuroimmunology Unit, National and Kapodistrian University of Athens Medical School, Athens, Greece

    Marinos C. Dalakas

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Dalakas, M.C. Stiff-person syndrome and related disorders — diagnosis, mechanisms and therapies. Nat Rev Neurol 20, 587–601 (2024). https://doi.org/10.1038/s41582-024-01012-3

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