Case ReportRituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus and autoimmune thyroiditis
Introduction
Stiff-person syndrome (SPS) is a rare neurological disorder characterized by progressive muscle rigidity with superimposed painful muscle spasms and gait impairment, owing to continuous motor activity. SPS is an autoimmune, predominantly encephalomyelopathic disorder resulting from B cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the glutamic acid decarboxylase (GAD) enzyme and the synaptic membrane protein amphiphysin.1 Three variants of SPS have been recognized: (i) a purely autoimmune variant that is linked to anti-GAD antibodies and commonly associated with other autoimmune diseases, mainly Type I diabetes mellitus and autoimmune thyroid disease; (ii) a less common paraneoplastic variant related to breast cancer and small-cell lung cancer that is characterized by anti-amphiphysin autoantibodies; and (iii) an idiopathic variant that has no detectable autoantibodies. While the pathogenic role of anti-GAD antibodies is uncertain,2 a convincing role of anti-amphiphysin antibodies has been established through the passive transfer of SPS to rats.3 These data taken together have prompted clinicians to treat SPS with plasmapheresis, intravenous (i.v.) immunoglobulins (Ig) or immunosuppressive agents. Treatment generally slows the course of the disease or, at best, improves muscle rigidity, but rarely achieves a total remission.4 Rituximab, by contrast, has shown promising results. Baker et al. first reported its efficacy in 2005;5 however, no subsequent publication has confirmed the findings.
We demonstrate the efficacy of rituximab in a patient with paraneoplastic SPS associated with a thymoma, who secondarily developed Type I diabetes mellitus and autoimmune thyroiditis, and who produced both anti-GAD and anti-amphiphysin autoantibodies. The patient’s condition initially showed a marked improvement after a thymectomy followed by treatment with i.v. Ig, prednisone, and mycophenolate mofetil (MM) but the disease relapsed and the patient produced a persistent high titre of anti-GAD and anti-amphiphysin antibodies. Following treatment with rituximab, the patient achieved a complete remission with suppression of anti-amphiphysin autoantibodies.
Section snippets
Case report
A 53-year-old caucasian man was admitted to our unit for painful muscle spasms affecting the neck, back, arms and legs and a stiffness of the spinal column, and muscles of the abdomen and legs. The patient was bed-bound. His muscle tone was markedly increased in all muscle groups, predominantly in the axial and proximal limb muscles, and his leg spasms were precipitated by movement, startle, and light touch. The spinal column was hyperlordotic, and the patient was unable to walk. In a standing
Discussion
SPS is an autoimmune disorder, resulting from B cell-mediated clonal production of autoantibodies against presynaptic inhibitory epitopes on the GAD enzyme and the synaptic membrane protein amphiphysin.1 Two variants have been categorized according to autoantibody types: (i) a purely autoimmune variant, characterized by anti-GAD antibodies and involvement of the DQ B1 0201 allele, and commonly associated with autoimmune diseases such as diabetes mellitus and autoimmune thyroiditis, as well as
Conclusion
Rituximab has demonstrated efficacy in the treatment of numerous autoimmune disorders, and it also has promising applications for patients with SPS. The positive correlation between the clinical improvement of the patient and the elimination of anti-amphiphysin antibodies provides additional evidence for the inhibitory role of this antibody on GABAergic neurons.
References (7)
- et al.
Paraneoplastic stiff-person syndrome: passive transfer to rats by means of IgG antibodies to amphiphysin
Lancet
(2005) - et al.
Pathological evidence of encephalomyelitis in the stiff man syndrome with anti-GAD antibodies
J Clin Neurosci
(2002) - et al.
Stiff-person syndrome
Curr Treat Options Neurol
(2007)
Cited by (37)
Treatment and Management of Disorders of Neuromuscular Hyperexcitability and Periodic Paralysis
2021, Neuromuscular Disorders: Treatment and ManagementRituximab improves not only back stiffness but also “stiff eyes” in stiff person syndrome: Implications for immune-mediated treatment
2020, Journal of the Neurological SciencesCitation Excerpt :Treatment of SPS includes GABA-enhancing drugs and intravenous immunoglobulin (IVIG) [11], but their efficacy is often partial and transient [12]. Although several small case series have reported that rituximab, which is monoclonal antibodies against CD20 cells that causes B cell depletion, is effective for treating patients with SPS [13–18], a recent double-blind placebo-controlled study in the United States did not show statistically significant efficacy of rituximab in SPS patients when a stiffness scale was used [12]. However, it is possible that rituximab is effective for other SPS symptoms such as eye movement disorders.
SPS: Understanding the complexity
2019, Journal of the Neurological SciencesCitation Excerpt :However, a large controlled trial conducted on anti-GAD ab positive SPS patients demonstrated no statistically significant difference in the efficacy measures between rituximab and placebo [170]. PERM or patients with SPS with antiamphiphysin antibodies who lack response to other immunotherapies, may benefit from a trial of rituximab [282–284]. Currently, there is limited evidence for proving the effectiveness of rituximab use in SPS [171,172].
Paraneoplastic Neurologic Syndromes
2019, Abeloff’s Clinical OncologyManagement of neuro-oncologic emergencies
2017, Handbook of Clinical NeurologyCitation Excerpt :CNS paraneoplastic disorders are usually more refractory to treatment, although anecdotal reports have demonstrated responses to corticosteroids or IVIG (Damek, 2009; Greenlee, 2010). Rituximab, an anti-CD20 monoclonal agent, has shown beneficial effects in patients with anti-Hu associated sensory neuropathy and gastric pseudo-obstruction, anti-GAD and anti-amphiphysin in stiff-person syndrome, and patients with anti-Yo antibodies (Baker et al., 2005; Shams'ili et al., 2006; Coret et al., 2009; Dupond et al., 2010; Greenlee, 2010). 3,4-Diaminopyridine for LEMS, benzodiazepines for stiff-person syndrome, and cholinesterase inhibitors such as pyridostigmine for MG have been shown to be effective as supportive treatment (Jani-Acsadi and Lisak, 2007; Greenlee, 2010).
Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials
2016, Neurotherapeutics