Stiff Person Syndrome Spectrum Disorders: Knowledge Gaps and Future Research Considerations

A recent review provides updates on the clinical spectrum and diagnostic criteria for stiff person syndrome spectrum disorders (SPSD), a group of rare neuroimmunological disorders characterized by rigidity and painful spasms.

The clinical manifestations of SPSD are heterogeneous, with patients experiencing varying levels of symptom severity and disability. There are multiple phenotypes that may have varied underlying immune mechanisms, but there is a lack of awareness surrounding these conditions and misdiagnosis early in the course of SPSD is common. Delayed diagnosis can have a significant impact on patient quality of life and future disability as the disease progresses.

The review, published in the Journal of Neuroimmunology, describes updates on the expanding clinical spectrum of SPSD, considers potential updates to diagnostic criteria by phenotype, and summarizes prognostic markers, potential immunopathology, and SPSD treatment. The authors also suggest future research directions for SPSD.

Stiff person syndrome (SPS) was first described in 1956, with classic clinical characteristics that include painful spasms, rigidity, and excessive lower spine curvature known as lyperlordosis. In the classic phenotype, patients typically experience muscle stiffness in the trunk and abdomen, and later legs and other muscle groups.

Since its description, additional phenotypes have been designated, including partial SPS that is limited to the extremities or just a single limb, SPS-plus involving classic symptoms and cerebellar or brainstem findings, pure cerebellar ataxia lacking musculoskeletal signs, and progressive encephalomyelitis with rigidity and myoclonus. However, physician opinions differ regarding the characteristics of these phenotypes and some patients do not fit into any of the described phenotypes. The classical phenotype is the most common in clinical practice, accounting for approximately 70% of patients with SPSD. Recent studies suggest the clinical spectrum of SPSD may be broader than currently thought.

Regardless of phenotype, studies show that most patients end up waiting several years for a diagnosis. There is no standard test or marker, making diagnosis challenging—especially because the symptoms of SPSD may be mimicked by other conditions. However, a patient’s symptoms at presentation and phenotype designation may provide prognostic markers.

The presence of a high-titer autoantibodies targeting GAD65 or amphiphysin has historically helped guide SPS diagnosis, but there are no established clinical or paraclinical SPSD markers correlating with disease severity or long-term prognosis. The condition is both rare and heterogeneous, making it difficult to determine whether certain phenotypes, symptoms, or immune markers hold prognostic value. Recent studies have provided some insight into factors and symptoms affecting disease burden and outcomes, but further research is needed in this area.

SPSD treatment typically includes a combination of pharmacological treatment with symptomatic and immune therapies, as well as nonpharmacological interventions. Most patients eventually require symptomatic treatment with γ-aminobutyric acid (GABA)-ergic (GABAergic) agonists, and immune-based treatments are also commonly used. The go-to symptomatic GABAergic agonists for SPSD are benzodiazepines such as diazepam, alone or in combination with other therapies such as clonazepam, baclofen, tizanidine, or botulinum toxin.

Depending on patient needs, nonpharmacological approaches include targeted physical therapy, heat therapy, aqua therapy, massage and/or myofascial techniques, osteopathic or chiropractic manipulation, acupuncture, and acupressure therapy.

When symptomatic interventions are ineffective, immune therapies are another course of action. Intravenous immunoglobulin, subcutaneous immunoglobulin, and therapeutic plasma exchange have all been shown to benefit patients with SPSD to some degree. Rituximab is a potential option for escalation of therapy when these interventions are unsuccessful. Early initiation of immunomodulatory therapy may alter SPSD progression, although more studies are needed to confirm their potential benefits in this context.

More research is also needed to understand the underlying mechanisms of SPSD. Although studies have identified certain autoantigens that are associated with SPSD overall and in subtypes of patients, knowledge gaps remain and more immune characteristics are likely to be discovered. “Further characterizing immune specificities in SPSD may be beneficial for understanding disease mechanism as well as for prognosis, diagnosis, and guiding therapeutic interventions,” the authors wrote.

Overall, they conclude that crucial unmet needs in SPSD are present in both the clinical and scientific research realms. Further exploration of the immunopathogenesis of SPSD and identification of relevant biomarkers are both important goals in SPSD research, and more refined diagnostic criteria are needed to assist clinicians in timely diagnosis and treatment initiation when appropriate. The optimal timing of therapy initiation is also a question that remains unanswered and one that could improve outcomes for patients across SPSD phenotypes.

Reference

Newsome SD, Johnson T. Stiff person syndrome spectrum disorders; more than meets the eye. J Neuroimmunol. Published online August 15, 2022. doi:10.1016/j.jneuroim.2022.577915