Medicine. 2015 Jun;94(23):e954.
A Case of Stiff Person Syndrome: Immunomodulatory Effect of Benzodiazepines: Successful Rituximab and Tizanidine Therapy.
From the Department of Clinical Immunology, Lower Silesian Center for Cellular Transplantation, Wroclaw, Poland.
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.
Antibody against GABA-producing enzyme: 65KDa Glutamate decarboxylase (GAD65Ab) secreted by long-lived plasma cells are describes in Stiff Person Syndrome (SPS) as a reason for rituximab therapy failure. Because of low level lymphocyte, limiting inflammation and immune-mediated injury to nervous tissues the certain immune functions were downregulated as ‘the way of immune privilege’. However, GABA is also produced in other sites; notably by pancreatic β cells and immune cells with inhibitory effects. The Latent Autoimmune Diabetes of Adults (LADA) and impaired glucose tolerance (IGT) coexist also with GAD65Ab, but with significantly lower titre. High GAD65Ab titre and temporary efficacy of plasmapheresis in SPS manifestation indicate that intrathecal synthesis of GAD65Ab is of minor importance. Contrary to SPS a causal relationship GAD65 in LADA has been evoked, although the mechanism of action has not been strictly elucidated. Although many studies show GABA-immunoinhibitory properties, the most of literature contain data from animal or in vitro studies with repeated discrepancy to jump the conclusion. Noteworthy lymphocytes appear to express only type A (GABAAR) to play immunosuppressive role: GABA blocks NF-κB activation and GABA-agonists protects against diabetes in mice(1). Contrary, other animal studies reveal that NF-κB is an important positive regulator of GAD65(2) (Figure 1) and GAD-65 expression do not correspond with insulin secretion under influence of TNFα, but high dose of IL-1 block both (3). For clinicians GABA-derived immunosuppresion may be source of (1)higher immunoreactivity (autoimmune profile) in patients with GAD-65Ab (known as overlap in GAD65Ab-positive patients –for example autoimmune polyendocrinopathy) (4,11) and (2)protective role of GABA-agonistic therapy. The autoimmune profile in our case is not observed, neither ancrestral nor LADA susceptibility haplotype. Mooving on to letter issue, the risk for antipsychotic-related IGT is low, but investigation unfortunately was provided after therapy initiation (5). The big picture of our case report is that BDs are used in long-lasting manner, decrease of therapeutic effects was observed (tachyphylaxis) while GAD65Ab remained high: probably higher expression of GAD65 persists to enhance antigen stimulation (Figure 1). The observation may be clue for epidemiologic studies and explain increase of incidence LADA: BZ represented 18.1 mean DDD-10,000 inhabitants-day of the usage. Increasing consumption, frequent overdose may be source of observed tachyphylaxis in immunosuppressive and antidiabetic actions of benzodiazepines. In the case reports long-term and very high dosage of diazepam (100mg/24h) coexists by far with very high GAD65Ab titre and its clinical implications (SPS, IGT). Prolonged benzodiazepines therapies induce adoptive neuronal reaction, but for the immune response such phenomena has not been described. It is first observation. Interstingly highly prevalence of prediabetes in adults treated with antipsychotic drugs was observed elsewhere (6). Further: GABA-receptor agonist –zolpidem shows higher risk of diabetes mellitus than benzodiazepines that are allosteric effector GABAAR (7), contrary to the animal models. Tachyphylaxis and lack of GABAAR -derived effect prompt GABABR (Figure 1) and again neuronal hiperpolarization and IL-1,TNFα blockade(8). Immunomodulatory properties of benzodiazepines may be also GABA-independent i.e. by Peripheral benzodiazepine receptor (PBR): protein mainly found on the outer mitochondrial membrane to transport cholesterol into mitochondria and prompt steroidogenesis. Glucocorticoid steroid hormones show prodiabetic as well as antiinflammatory properties. The report corresponds with other observation showing that in microglia PBR ligands by increased reactive oxygen species (ROS) production and small but detectable increase in IL-1β release (9)(Figure 1). Further,under the influence of ROS,IL-1 and TNFα PBR is highly expressed in testicular, adrenocortical, and brain glial tumor cells , whose proliferation can be regulated by its ligands –benzodiazepines (10)(vicious circle, Figure 1).
Figure 1.Immunomodulatory GABA-BZ axis after long-lasting use.
Binding of benzodiazepines to this GABAAR receptor complex does not alter binding of GABA, but induce higher GABA inhibitory signal. While BD therapeutic effects disappear with tolerance the GAD65-expression increase. GABAAR -derived lymphocyte inhibition usually observed in vitro may be blocked by strong antigenic stimulation, again tachyphylaxis and PBR pleiotropic properties. SMS patients show high GAD65Ab and the main titers were orders of magnitude higher than in LADA patients The high level of GAD65Ab provide the sufficient concentration in CNS for clinical manifestation SPS
Abbreviations: reactive oxygen species (ROS); Glucocorticoids GKS; Peripheral benzodiazepine receptor (PBR); γ-Aminobutyric acid (GABA); type A or B GABA receptor GABAAR and GABABR respectively; 65KDa Glutamate decarboxylase (GAD65Ab); benzodiazepine –BZ; Stiff Person Syndrome (SPS); Impaired glucose tolerance -IGT
A number of target therapies was approved for the treatment of LADA, but autoimmune phenomena observed in LADA has not been described as a standard therapeutic regimen.
As shown in the case description GAD-65Ab may be temporary eliminated by plasmapheresis, but unusually 2h-capilary blood glucose was significantly decreased: (from 161 to 108mg/dl) in 75 g oral glucose tolerance test. Although plasmapheresis is suitable for urgent therapy and conventional immunosuppressive therapy was commenced, it also has advantage of removing of overused benzodiazepines. The observation shows that autoimmune process in LADA may reversible and antibody-dependent cytotoxicity is not strict patomechanism of LADA. GAD65Ab results in allosteric inhibition of GAD65 activity rather, that may be unblocked by GAD65Ab removal. In the case report the prolonged benzodiazepines induce predictable (neurological tolerance) and unpredictable (autoimmune) adverse drug reaction. Rituximab in combination with mycophenolate may be successful therapeutic option for SPS and LADA if the prodiabetic drug will be withdrawn. The imunosuppresive therapy did not block the LADA and SPS relapse as well as significant GAD65Ab increase after reintroduction of BD (Figure 2). The SPS is serious illness with different degree and monitoring in nominal scale is problematic because GAD65Ab level do not correspond with disease severity. The SPS is autoimmune disease with central nervous system and muscles involvement; therefore non-cardiac creatine phosphokinase (CK) isoenzymes may be useful tool.
The conclusions based on SPS/IGT course and the therapeutic intervention are:
1. for clinical use
a. The tizanidine therapy show promising results:
i, block the major excitatory signal – -N-methyl-D-aspartate (NMDA) and may be used in autoimmunity against NMDA in SPS
ii, It is Glutamate (GLU) release inhibitor (GLU is the most abundant excitatory neurotransmitter). Fortunately Glu is substrat for GAD65 in intracellular GABA production: the blocking Glu release may be indirect source of GABA increase: inhibitory properties GABAR on neuronal cells and leukocytes may be beneficial for all autoimmune CNS illness with hyperspastic symptoms (as in SM)
b. Plasmapheresis may be used for initial SPS and LADA immunotherapy
c. Rituximab therapy together with MMF may be therapeutic option for both GAD65Ab-dependent illness: SPS and LADA, probably for other autoimmune cerebellar too (Figure 2), but after BZ withdrawal. BZ overuse and first-line therapy in SPS is probably source of rituximab therapy failure.
2. for further evaluation and investigation:
- The critical balance between inhibitory and excitatory signal was controlled by GAD65 activity: high prompt Glu decarboxylation and GABA-derived inhibition, but low activity are source increased Glu excitatory signal.
- Long-term benzodiazepine use is source of tolerance and low GABAAR signal in central nervous system and probably in peripheral tissues (immune system)
- Role of benzodiazepines overuse and tachyphylaxis in pathogenesis LADA/SPS.
- Creatine phosphokinase isoenzyme CK-BB usefulness in brain autoimmune diseases, as CK-MM in autoimmune myositides.
FIGURE2. Immuofluorescence oon on cerebellum after rituximab and mycophenolate therapy. The significant increase GAD65Ab after reintroduction of diazepam coexist with higher autoimmune reactivity in CNS as shown in immunofluorescence. Noteworthy the immunofluorescence staining on cerebellum indicate that in SPS cerebellar dysfunction may be significant. GAD65Ab are reported in patients with cerebellar ataxia too (11).
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