A Case of Stiff Person Syndrome: Immunomodulatory Effect of Benzodiazepines: Successful Rituximab and Tizanidine Therapy

Abstract

Stiff person syndrome (SPS) is a rare autoimmune disease. Most patients have high-titer antibodies against glutamate decarboxylase (GADAb), which is without practical value in disease monitoring. Benzodiazepines are the first line drugs, but long-term use is not well characterized. This report demonstrates ineffective benzodiazepine therapy of SPS that prompts tachyphylaxis, loss of responsiveness, and finally benzodiazepine withdrawal syndrome. Convulsion and anxiety correlate with high level of creatine phosphokinase (CK). Although tonus and spasm attacks were successfully controlled by tizanidine, glutamate release inhibitor, the immune response, and autoimmune diabetes development require the plasmapheresis, mycophenolat mofetil, and rituximab therapy that results in a significant decrease of GADAb, impaired glucose tolerance (IGT), lactate dehydrogenase (LDH), and CK normalization. Unfortunately, reintroduction of benzodiazepine was a source of rapid and high increase of CK, LDH, GADAb titer (up to 1:15,000), IGT, and SPS relapse. Contrary to previous publications, we observed IGT that correlated with high anti-GAD level, but without high immunogenetic susceptibility to haplotype human leukocyte antigens-DR3, DQw2. This preliminary observation and the last finding of immunomodulatory properties of peripheral benzodiazepine receptor suggest that increased antigenic stimulation during benzodiazepine therapy and glutamatergic hyperactivity could account for convulsions observed in SPS. Benzodiazepine withdrawal prompted alternative muscle relaxant therapy (tizanidine). Muscular and brain abnormalities observed in SPS indicate that noncardiac CK level may be a useful tool in SPS therapy monitoring.

FIGURE 1

Immunomodulatory effect of benzodiazepines. The effect of diazepam (DZ) withdrawal and plasmapheresis treatment followed by immunosupprression on serum anti-GAD antibody (GADAb) titer, glucose intolerance, and noncardiac creatine kinase (CK) (CK-MM + CK-BB) in SPS patient. Single course of rituximab (375 mg/m² infusions on day 1 and 8) followed by mycophenolate mofetil (1 g b.i.d.) and tizanidine (4–6 mg t.i.d.).

FIGURE 2

Tizanidine therapy in stiff person syndrome (SPS). The inhibitory and excitatory equilibrium disturbance in SPS and long-term benzodiazepine (BZ) therapy. Red font: points of tizanidine therapy. Anti-GAD65Ab = antibodies against glutamate decarboxylase 65 kDa, GABA = γ-amino butyric acid; Glu-glutamate, NMDA = N-methyl-D-aspartate, VOCC = voltage-operated Ca(2+) channels.