Skip to main content

Advertisement

Log in

The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies

  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Introduction

High-titre anti-GAD antibodies are characteristically seen in patients with stiff person syndrome (SPS). Other CNS disorders, rarely associated with high anti-GAD antibody titres, include: a) SPS-plus, a syndrome characterised by SPS and cerebellar ataxia; b) Batten’s disease; and c) rare patients with epilepsy and idiopathic cerebellar ataxia. Currently, high-titre anti- GAD antibodies serve only as markers of an autoimmune process within the CNS because their pathogenic role in the afore-mentioned disorders has not been established. In SPS, there is evidence of autoimmune pathogenesis based on: the association of the disease with other autoimmune disorders or autoantibodies; immunogenetic background; presence of oligoclonal IgG bands in the CSF with increased intrathecal anti-GAD antibody synthesis and response to immunotherapies. SPS is the only GAD-positive CNS disease where a controlled study with immunotherapy has been conducted.

Methods

Sixteen anti-GAD antibody-positive patients were randomised to receive IVIg or placebo for 3 months. After a washout, they crossed to the alternative therapy for another three months. Efficacy was based on the difference in scores of the distribution of stiffness index and heightened sensitivity (spasms) from baseline to the second and third month of the infusions. Direct treatment and carry-over effect were compared for both groups.

Results

The stiffness scores in the IVIg-randomised patients declined significantly from month 1 through 4, but rebounded when they crossed to placebo. In contrast, the scores in the placebo-randomised group remained constant from month 1–4 but dropped significantly after crossing to IVIg. Eleven patients who received IVIg became able to walk unassisted, stopped falling and assumed household or work duties. The duration of benefit varied from 6–12 weeks or up to a year. The anti-GAD65 antibody titres declined after IVIg, but not after placebo.

Conclusion

Based on a controlled study, IVIg is a safe and effective therapy for SPS in patients unresponsive to other agents. Whether IVIg has a role in the other GAD-positive patients with neurological disease, or in SPS patients without GAD antibodies, remains unknown.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Ellis MT, Atkinson AM (1996) The clinical significance of an autoimmune response against glutamic acid decarboxylase. Nature Medicine 2:148–153

    Article  CAS  PubMed  Google Scholar 

  2. Daw K, Ujihara N, Atkinson M, Powers AC (1996) Glutamic acid decarboxylase autoantibodies in stiff-man syndrome and insulin-dependent diabetes mellitus exhibit similarities and differences in epitope recognition. J Immunol 156:818–825

    CAS  PubMed  Google Scholar 

  3. Solimena M, Folli F, Aparisi R, Pozza G, De Camilli P (1990) Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-man syndrome. N Engl J Med 322:1555–1560

    CAS  PubMed  Google Scholar 

  4. Dalakas MC, Fujii M, Li M, McElroy B (2000) The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology 55:1531–1535

    CAS  PubMed  Google Scholar 

  5. Dalakas MC (1999) Autoantibodies and immunopathogenesis of the stiffperson syndrome. In: Levy LM moderator: The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med 131:522–530

    PubMed  Google Scholar 

  6. Dalakas MC, Li M, Fujii M, Jacobowitz DM (2001) Stiff-person syndrome: quantification, specificity and intrathecal synthesis of GAD65 antibodies. Neurology 57:780–785

    CAS  PubMed  Google Scholar 

  7. Murinson BB, Butler M, Marfurt K, Gleason S, De Camilli P, et al. (2004) Markedly elevated GAD antibodies in SPS: effects of age and illness duration. Neurology 63:2146–2148

    CAS  PubMed  Google Scholar 

  8. Peltola J, Kulmala P, Isojarvi J, Saiz A, Latvala K, et al. (2000) Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology 55:46–50

    CAS  PubMed  Google Scholar 

  9. Honnorat J, Saiz A, Giometto B, Vincent A, Brieva L, de Andres C, et al. (2001) Cerebellar ataxia with antiglutamic acid decarboxylase antibodies: study of 14 patients. Arch Neurol 58:225–230

    Article  CAS  PubMed  Google Scholar 

  10. Pearce DA, Atkinson M, Tagle DA (2004) Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders. Neurology 63:2001–2005

    CAS  PubMed  Google Scholar 

  11. Vernino S, Lennon VA (2004) Autoantibody profiles and neurological correlations of Thymoma. Clin Cancer Res 10:7270–7275

    CAS  PubMed  Google Scholar 

  12. Dalakas MC (1999) Therapeutic considerations of patients with stiff-person syndrome. In: Levy LM (moderator) The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of γ-aminobutyric acid. Ann Intern Med 131:523–524

    Google Scholar 

  13. Vasconcelos OM, Dalakas MC (2003) Therapies for stiff person syndrome. Curr Treat Options Neurol 5:79–90

    PubMed  Google Scholar 

  14. Barker RA, Revesz T, Thom M, Marsden CD, Brown P (1998) Review of 23 patients affected by the stiff man syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 65:633–640

    CAS  PubMed  Google Scholar 

  15. Dalakas MC, Fujii M, Li M, Lutfi B, Kyhos J, McElroy B (2001) High-dose intravenous immunoglobulin for stiff-person syndrome. N Engl J of Med 345:1870–1876

    Article  CAS  Google Scholar 

  16. Meinck HM, Ricker K, Hulser PJ, Solimena M (1995) Stiff man syndrome: neurophysiological findings in eight patients. J Neurol 242:134–142

    Article  CAS  PubMed  Google Scholar 

  17. Dinkel K MH, Jury KM, et al. (1998) Inhibition of gama-aminoutric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 44:194–201

    Article  CAS  PubMed  Google Scholar 

  18. Ishida K, Mitoma H, Song Si-y, et al. (1999) An elective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase. Ann Neurol 46:263–267

    Article  CAS  PubMed  Google Scholar 

  19. Amato AA, Cornman EW, Kissel JT (1994) Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology 44:1652–1654

    CAS  PubMed  Google Scholar 

  20. Barker RA MC (1997) Successful treatment of stiff-man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry 62:426

    CAS  PubMed  Google Scholar 

  21. Dalakas MC (2004) Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA 291:2367–2375

    Article  CAS  PubMed  Google Scholar 

  22. Dalakas MC (2004) The use of intravenous immunoglobulin in the treatment of autoimmune neurological disorders: Evidence-based indications and safety profile. Pharmacol Therapeutics 102:177–193

    Article  CAS  Google Scholar 

  23. Weinberger DR (2001) Anxiety at the frontier of molecular medicine. N Engl J Med 344:1247–1249

    Article  CAS  PubMed  Google Scholar 

  24. Rakocevic G, Raju R, Dalakas MC (2004) Anti-glutamic acid decarboxylase antibodies in the serum and cerebrospinal fluid of patients with stiff-person syndrome: correlation with clinical severity. Arch Neurol 61:902–904

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marinos C. Dalakas MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalakas, M.C. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 252 (Suppl 1), i19–i25 (2005). https://doi.org/10.1007/s00415-005-1105-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-005-1105-4

Key words

Navigation