Therapies in Stiff-Person Syndrome: Advances and Future Prospects Based on Disease Pathophysiology

Abstract

Among the glutamic acid decarboxylase (GAD)-antibody-spectrum disorders, the most common phenotypic subset is the stiff-person syndrome (SPS), caused by impaired GABAergic inhibitory neurotransmission and autoimmunity characterized by very high titers of GAD antibodies and increased GAD-IgG intrathecal synthesis. If not properly treated or untreated because of delayed diagnosis, SPS progresses leading to disability; it is therefore fundamental to apply the best therapeutic schemes from the outset. This article is focused on the rationale of specific therapeutic strategies based on the SPS pathophysiology targeting both the impaired reciprocal GABAergic inhibition to symptomatically improve the main clinical manifestations of stiffness in the truncal and proximal limb muscles, gait dysfunction, and episodic painful muscle spasms and the autoimmunity to enhance improvement and slow down disease progression. A practical, step-by-step therapeutic approach is provided, highlighting the importance of combination therapies with the preferred gamma-aminobutyric acid-enhancing antispasmodic drugs, such as baclofen, tizanidine, benzodiazepines, and gabapentin, that provide the first-line symptomatic therapy, while detailing the application of current immunotherapies with intravenous immunoglobulin (IVIg) plasmapheresis, and rituximab. The pitfalls and concerns of long-term therapies in different age groups, including children, women planning pregnancy, and especially the elderly considering their comorbidities are emphasized, also highlighting the challenges in distinguishing the conditioning effects or expectations of chronically applied therapies from objective meaningful clinical benefits. Finally, the need for future targeted immunotherapeutic options based on disease immunopathogenesis and the biologic basis of autoimmune hyperexcitability are discussed, pointing out the unique challenges in the design of future controlled clinical trials especially in quantifying the extend and severity of stiffness, episodic or startle-triggered muscle spasms, task-specific phobias, and excitability.

Figure 1. Reciprocal Inhibition and Its Electrophysiology

(A) When the brain sends a message to the alpha motor neurons of the agonist to contract (1), its antagonist (2) automatically relaxes because the inhibitory GABAergic gamma interneurons of the antagonist muscle do not discharge, preventing the opposing alpha motor neurons from firing. Originally published in Dalakas M. Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies. Neurotherapeutics 2022;19:832. (B) Electrophysiologically, the normal muscle at rest does not fire and no motor unit action potentials (MUPs) are recorded from the agonist (a) and its antagonist (b). During voluntary muscle contraction of the agonist (c), no MUPs are recorded from the antagonist (d) because this muscle is silenced by its inhibitory GABAergic interneurons. (C) Impaired reciprocal GABAergic inhibition in SPS. In SPS, the a-motor neurons fire continuously, even at rest and in spite of relaxation efforts, with MUP electrophysiologically recorded in both the agonist and its antagonist (a, b). When the agonist muscle contracts (c), its antagonist is not silenced or relaxed but contracted with firing MUP (d) leading to simultaneous contraction of the agonist and its antagonist. GABA = gamma-aminobutyric acid; SPS = stiff-person syndrome.

Figure 2. Characteristic Hyperlordosis, Thoracolumbar Stiffness With S-Shape Formation and Typical Spastic Foot in Patients With SPS

(A, B) Concurrent hypercontraction of thoracolumbar paraspinals [agonists (A)] and abdominal [antagonists (B)] muscles due to impaired reciprocal inhibition in a woman with stiff-person syndrome. In chronic and severe cases, the hypercontracted thoracolumbar region resembles an S-shape formation, as depicted in 2 other patients, clinically (C) and with X-rays of the spine (D). On palpation, the paraspinal and abdominal muscles feel stiff or hypertrophic. Another common region of simultaneous cocontraction of opposing muscles is at the foot, as shown in the left foot of a patient (E, F), where the tibialis anterior, tibialis posterior, and gastrocnemius variably cocontract, resulting in a painful spastic foot inversion with either toe extension (E) or claw-toe formation (F) and swollen foot that prevents patients for full-step initiation. Figures 2, A and B are republished with permission from Dalakas MC, Fuji M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 2000;55:1,531. The Creative Commons license does not apply to this content. Use of the material in any format is prohibited without written permission from the publisher, Wolters Kluwer Health, Inc. Please contact permissions@lww.com for further information. GAD = glutamic acid decarboxylase.

Figure 3. Antigenic Targets in the Inhibitory Synapses of Patients With SPS-SD

The targeted presynaptic antigens in SPS-SD are GAD (1), the enzyme that synthesizes GABA, and amphiphysin (2), a synaptic vesicle protein responsible for endocytosis of plasma membranes after GABA release. The postsynaptic targets are glycine receptor (3), a ligand-binding ion channel that allows the passage of chloride ions; gephyrin (4), a tubulin-binding protein needed for clustering both GABA-A and glycine receptors; and GABA-A receptor–associated protein (GABARAP) (5), a linker protein which promotes the organization of the GABAA receptors (2,4). Originally published in Dalakas M. Stiff-person Syndrome and GAD Antibody-spectrum Disorders: GABAergic Neuronal Excitability, Immunopathogenesis and Update on Antibody Therapies. Neurotherapeutics 2022;19:832. GABA = gamma-aminobutyric acid; GAD-SD = glutamic acid decarboxylase–spectrum disorders; SPS = stiff-person syndrome.

Figure 4. Response to IVIg or Rituximab in 2 Representative Patients Who Participated in the Double-Blind Placebo Control Trials With IVIg (A and B) or Rituximab (C and D)

(A, B) Before therapy, this patient who participated in the controlled study was very stiff, unable to bend down or walk unassisted requiring a walker (A). After 3 monthly infusions of IVIg, she had an impressive improvement, not requiring any more assistive devices, being able to bend down and walk independently (B). (C, D) Before rituximab, this patient who participated in the large controlled study was very stiff and unable to walk independently requiring 2 walking canes (C). He was randomized to rituximab and started to improve after 3 months; by the 6th month after the infusion, he had become independent in his walking abilities to the point of even went skiing (D). His improvement lasted several months thereafter.