Stiff Person Syndrome (SPS) is a rare neurological disorder that primarily affects the ability to relax musculature. This results in affected muscle groups remaining in constant contracture, leading to painful spasms that have significant morbidity and impact the patient's quality of life. Disease prevalence is one to two persons in a million, and as a result, very few randomized controlled studies have examined the efficacy of various treatment regimens. One notable study examined intravenous immunoglobulin (IVIG) and its efficacy in the treatment of SPS. This study found that using IVIG was of significant benefit in improving stiffness in SPS. However, beyond this, immune modulating therapy is limited by lack of peer-reviewed evidence. The use of rituximab has been reported in cases of SPS that are refractory to treatment with IVIG and has had mixed outcomes. Our search of the literature involved examining case reports of patients with diagnosed SPS, who had been initially treated with the standard of care and were then placed on treatment with rituximab. Our review of the available case reports demonstrates an increase in SPS remission correlating with the frequency of dose. However, the limited number of case reports available limits conclusions related to the treatment of SPS. More studies are needed to assist in guiding therapy for SPS.
Introduction & Background
Stiff Person Syndrome (SPS) is a rare neurological movement disorder that occurs at the rate of one to two persons per million. The hypothesized mechanism of SPS is a dysregulation of neuronal firing, leading to sustained muscular contraction, stiffness, and rigidity. However, the details of the exact pathogenic mechanism has yet to be elucidated. Evidence exists that implicates an underlying autoimmune process potentially involving both the B-cell and T-cell mechanisms. The autoimmune process is further supported by the occurence of other autoimmune conditions along with SPS. Examples of this include diabetes mellitus, hypothyroidism, pernicious anemia, and vitiligo . There is also evidence of a paraneoplastic variant of SPS.
The autoimmune nature of SPS has been illustrated by the presence of anti-glutamic acid decarboxylase (anti-GAD) antibodies and/or anti-amphiphysin antibodies in the serum of patients with SPS. High titers of anti-GAD are highly specific for the disease. However, up to 30% of patients with SPS are negative for anti-GAD antibodies. It is thought that these antibodies interfere with the inhibitory effects of gamma-aminobutyric acid (GABA) in the central nervous system (CNS), leading to constant muscle contractions . Antibodies of the post-synaptic GABA-A receptor have also been found in approximately 70% of patients with SPS, which may also have pathogenic implications. A T-cell-based mechanism has been considered becaise of the 30% rate of co-occurrence of type 1 diabetes mellitus (T1DM) in patients with SPS. It is thought that microglia could become sensitized to a form of glutamic acid decarboxylase (GAD) protein and then present the protein to T-cells, leading to neural damage via a T-cell mediated mechanism . This is supported by the understood role of T-cells in the pathogenesis of T1DM and the documented rates of T1DM and other autoimmune conditions in SPS patients.
With a pathogenesis that is poorly understood, the management options available for SPS mainly involve symptomatic treatment with baclofen, diazepam, and other similar neuromuscular drugs that work to reduce muscle rigidity and spasms. The argument for the autoimmune basis of the disease is further strengthened by the documented effectiveness of various first-line treatments in other autoimmune conditions, including intravenous immunoglobulin (IVIG), steroids, and plasmapheresis . Another treatment option that has been explored in SPS case reports is rituximab because of its ability to target and destroy B-cells. Rituximab binds to the CD20 antigen on mature B-cells, leading to B-cell lysis, while sparing the precursor B-cells. Rituximab has been shown to be useful in delaying the progression of disease in other neurological autoimmune disorders and may show a similar benefit in SPS . This review seeks to examine the reported efficacy of rituximab in treating SPS when it is refractory to other forms of treatment.
To be included in this review, the patients in the case report literature had to have a clinical presentation consistent with a diagnosis of SPS and a positive serology (anti-GAD or anti-amphiphysin) or an electromyography (EMG) consistent with SPS (as seen in Table 1). The outcomes of the treatments involved were evaluated based on EMG changes, anti-GAD titers, and clinical mobility. Table 1 references each of the nine cases of rituximab use in patients with reported SPS.
Of the case reports that were reviewed, clinical improvement was seen in seven of the nine patients. However, the dose and schedule of rituximab varied among those patients. Patients 1 through 5 and 9 received 375 mg/m2 with variable dosing intervals and total number of doses. Remission was seen with fewer doses in several patients. It is important to note that clinical improvement was seen in all six patients, though some required an additional dose because of the recurrence of symptoms several months after the original dose. Patient 5 did relapse in her disease after experiencing remission; however, it is important to note that she received the fewest number of doses of the patients who received 375 mg/m2 doses of rituximab. No comment was made with reference to repeat dosing following a relapse or after the initial duration of remission. Patient 6 received two doses of 500 mg/m2 14 days apart and clinical improvement was observed despite the difference in dose size and frequency compared with the patients mentioned earlier. Finally, in a double-blind crossover study, a 1,000 mg dose of rituximab was given to a monozygotic set of twins with SPS. This study gave doses at intervals of 2 weeks and compared with the use of saline. These patients were given a follow-up two-week treatment at 54 weeks of 1,000 mg. No clear benefit was shown upon functional analysis; however, the authors suggested that it may have prevented a worsening of the disease.
Dosages of rituximab show a trend toward increased doses being effective in this limited population size. Patients 1 and 2 received five doses of rituximab, with four given over four weeks, and they demonstrated lasting clinical improvement. Patient 9 received four doses of rituximab over the course of three months, prompting lasting remission that was still present one year later. The double-blind crossover study with Patients 7 and 8 also reported four doses; however, these were spaced out over the course of one year and very little clinical improvement was observed. Patient 3 was administered three doses, with one initial dose and two more doses three months later, with a month separating the final two doses. This patient remained in “good neurologic condition at 23 months” following the rituximab treatment per the case report . Patient 4 was administered rituximab 15 days apart and showed clinical improvement. Patient 6 received two doses 14 days apart with sustained improvement; however, the paper did not list a duration of improvement. Patient 5 was given two doses of rituximab seven days apart and improvement was initially seen but followed by relapse. It is important to note that Patient 5 was complicated by benzodiazepine withdrawal syndrome.
Based on this review of the dosing schedule and quantity of rituximab administered, it would seem that a treatment plan involving frequent doses of 375 mg/m2 over a shorter period of time was the most-effective treatment for SPS. To draw any conclusions, the limited sample size warrants more research in this area.
At this time, there is limited evidence for proving the effectiveness of rituximab use in SPS. The case-based evidence presented in this literature review includes anti-GAD positive patients who have failed symptomatic therapy. No cases have been reported of rituximab use in seronegative or paraneoplastic etiologies. A phase II clinical trial conducted by the National Institute of Health was recently completed and may help to further delineate the role of rituximab in SPS. Further, several of these case reports failed to define or quantify complete remission (i.e., no more pain, regained muscle function, lack of muscle spasms, and so on). A definition of remission and a means of quantifying treatment response is necessary to not only monitor outcomes but also to determine the usefulness of various treatments relative to each other. Additionally, because of the various pathogenic mechanisms that may be involved in SPS, criteria that may make rituximab a first-line treatment for selected patients with SPS need to be determined. For example, a patient with a T-cell based mechanism for their disease pathogenesis would be a poor candidate for rituximab treatment given the confounding disease process when compared to the mechanism of action of rituximab. The varied nature of SPS pathogenesis may be the enigma behind the differing responses to treatment not only with rituximab, but also with IVIG and other treatment modalities.
- Ali F, Rowley M, Jayakrishnan B, et al.: Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun. 2011, 37:79–87.
- Holmøy T, Geis C: The immunological basis for treatment of stiff person syndrome. J Neuroimmunol. 2011, 231:55–60. 10.1016/j.jneuroim.2010.09.014
- Dalakas MC, Fujii M, Li M, et al.: High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med, 2001. 345:1870–1876. 10.1056/NEJMoa01167
- Kosmidis ML, Dalakas MC: Practical considerations on the use of rituximab in autoimmune neurological disorders. Sage Journals. 2010, 3:93–105. 10.1177/1756285609356135
- Baker MR, Das M, Isaacs J, et al.: Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005, 76:999–1001. 10.1136/jnnp.2004.051144
- Dupond JL, Essalmi L, Gil H, et al.: Rituximab treatment of stiff-person syndrome in a patient with thymoma, diabetes mellitus and autoimmune thyroiditis. J Clin Neurosci. 2010, 17:389–391. 10.1016/j.jocn.2009.06.015
- Katoh N, Matsuda M, Ishii W, et al.: Successful treatment with rituximab in a patient with stiff-person syndrome complicated by dysthyroid ophthalmopathy. JSIM. 2010, 49:237–241. 10.2169/internalmedicine.49.2821
- Lobo ME, Araujo ML, Tomaz CA, et al.: Stiff-person syndrome treated with rituximab. BMJ Case Reports. 2010, 10.1136/bcr.05.2010.3021
- Zdziarski P: A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful rituximab and tizanidine therapy. Wolters Kluwer. 2015, 94:954. 10.1097/md.0000000000000954
- Fekete R, Jankovic J: Childhood stiff-person syndrome improved with rituximab. Case Rep Neurol. 2012, 4:92–96.
- Venhoff N, Rizzi M, Salzer U, et al.: Monozygotic twins with stiff person syndrome and autoimmune thyroiditis: rituximab inefficacy in a double-blind, randomised, placebo controlled crossover study. Ann Rheum. 2009, 68:1506–1508. 10.1136/ard.2008.103721
- Qureshi A, Hennessy M: Stiff person syndrome (SPS) complicated by respiratory failure: successful treatment with rituximab. J Neurol. 2012, 259:180–181. 10.1007/s00415-011-6123-9
Evaluation of Treatment Outcomes in Patients with Stiff Person Syndrome with Rituximab vs. Standard of Care
Ethics Statement and Conflict of Interest Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.
We would like to thank Dr. David Lebowitz for his review of the content and advice related to it.
Cite this article as:
Rineer S, Fretwell T (June 24, 2017) Evaluation of Treatment Outcomes in Patients with Stiff Person Syndrome with Rituximab vs. Standard of Care. Cureus 9(6): e1387. doi:10.7759/cureus.1387
Received by Cureus: April 14, 2017
Peer review began: May 02, 2017
Peer review concluded: June 13, 2017
Published: June 24, 2017
© Copyright 2017
Rineer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 3.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.