Correspondence
High-Dose Intravenous Immune Globulin for Stiff-Person Syndrome
N Engl J Med 2002; 346:1747-1748May 30, 2002
- Article
To the Editor:
Dalakas et al. (Dec. 27 issue)1 report the efficacy of high-dose intravenous immune globulin for the treatment of stiff-person syndrome. Stiff-person syndrome is a devastating disorder, and evidence of the associated immunologic impairment began to emerge in the 1980s.2 Over the next decade, it was confirmed that stiff-person syndrome was caused, in particular, by damage by an autoimmune mechanism.
Intravenous immune globulin is extraordinarily costly; thus, the current focus of interest among clinicians is not on the efficacy of this approach but, rather, on the timing of the treatment and its long-term outcome, including the duration of the effect and any adverse consequences. Dalakas et al. failed to address this issue, because they terminated their comparative observation one month after the end of the double-blind study, even though in the group that received immune globulin first, titers of antibodies against glutamic acid decarboxylase (GAD65) had increased significantly four months after the completion of the study, whereas in the group given placebo first, the titers were monitored for only one month. We believe that the authors should provide further follow-up information.
2 ReferencesKazumasa Sudo, M.D.
Yasutaka Tajima, M.D.
Akihisa Matsumoto, M.D.
Sapporo City General Hospital, Sapporo 060-8604, Japan
sudo@med.hokudai. ac. jp 1
Dalakas MC ,Fujii M ,Li M ,Lutfi B ,Kyhos J ,McElroy B . High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med 2001;345:1870-1876
Full Text | Web of Science | Medline2
Piccolo G ,Cosi V ,Zandrini C ,Moglia A . Steroid-responsive and dependent stiff-man syndrome: a clinical and electrophysiological study of two cases. Ital J Neurol Sci 1988;9:559-566
CrossRef | Medline
To the Editor:
Dalakas et al. report the efficacy of intravenous immune globulin for treating stiff-person syndrome. They did not report whether cerebrospinal fluid was analyzed in order to determine whether anti-GAD65 antibodies were being synthesized intrathecally. As shown recently by Dalakas et al. in another study,1 the production of antibodies within the central nervous system seems to have an important role in the pathogenesis of the disorder, by affecting the synthesis of a neurotransmitter, γ-aminobutyric acid (GABA),2 within the central nervous system. Immune globulin should work in the periphery, since its hypothesized mechanism of action is to reduce the levels of circulating antibody against an antigen target that accelerates IgG catabolism or to induce an anti-idiotypic antibody response. Does the activity in the periphery reflect what is happening in the cerebrospinal fluid?
Dalakas et al. also report that the reduction in anti-GAD65 antibody titers after immune globulin therapy did not correlate with the degree of clinical improvement. Can we suppose that a correlation exists between the clinical outcome and the level of the antibodies in cerebrospinal fluid or the anti-GAD65 antibody index in cerebrospinal fluid?
2 ReferencesClaudio Solaro, M.D.
Ospedale P.A. Micone, 16153 Genoa, Italy
csolaro@neurologia.unige. it 1
Dalakas MC ,Li M ,Fujii M ,Jacobowitz MD . Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780-784
Web of Science | Medline2
Dinkel K ,Meinck HM ,Jury KM ,Karges W ,Richter W . Inhibition of gamma-aminobutyric acid synthesis by glutamic acid decarboxylase autoantibodies in stiff-man syndrome. Ann Neurol 1998;44:194-201
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Dalakas replies:
To the Editor: Contrary to the contentions of Sudo et al., the main concern of clinicians caring for patients with stiff-person syndrome is not when to treat but how best to treat the disease; hence, the need for controlled studies to determine the efficacy of the various proposed therapies. My colleagues and I demonstrated that intravenous immune globulin improves or reverses even the long-standing disabling symptoms in most patients with stiff-person syndrome. Furthermore, we monitored the anti-GAD65 antibody titers not for one month, as Sudo et al. suggest, but for up to three months. Immune globulin is an immunomodulating (not an immunosuppressive) agent that modifies but does not permanently suppress various immune factors. Consequently, the rebound in the antibody titers after the end of treatment is not unexpected. Although the purpose of our study was to establish the efficacy of immune globulin and not to assess its long-term effectiveness, we reported long-term follow-up data that were collected for at least two years after the completion of the study.
Dr. Solaro refers to our previous study of the intrathecal synthesis of IgG antibodies1 and wonders whether immune globulin acts in the periphery or directly within the central nervous system to suppress antibody production. This pertinent question also relates to the pathogenic role of anti-GAD65 antibodies. GAD65 is a cytoplasmic antigen that may not be easily recognized by the immune system, and the antibody titers do not correlate with disease severity. Thus, the relation between the suppression of anti-GAD65 antibody titers and the magnitude of clinical benefit after immune globulin therapy is unclear. Immune globulin probably suppresses anti-GAD65 antibodies in the periphery through an idiotypic–anti-idiotypic interaction.2,3 However, the IgG molecules within the immune globulin cross the blood–cerebrospinal fluid barrier4 and may enter the brain; whether they also exert an effect in situ is unknown. Although high titers of anti-GAD65 antibodies in serum and cerebrospinal fluid are highly specific for stiff-person syndrome, another target antigen or surface receptor, in conjunction with GAD65, may be more directly involved in GABAergic transmission and may correlate better with the severity of symptoms. Our search for other target antigens in affected patients continues.
4 ReferencesMarinos C. Dalakas, M.D.
National Institutes of Health, Bethesda, MD 20892-1382
dalakasm@ninds.nih. gov 1
Dalakas MC ,Li M ,Fujii M ,Jacobowitz DM . Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780-784
Web of Science | Medline2
Kazatchkine MD ,Kaveri SV . Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 2001;345:747-755
Full Text | Web of Science | Medline3
Dalakas MC . Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999;22:1479-1497
CrossRef | Web of Science | Medline4
Sekul EA ,Cupler EJ ,Dalakas MC . Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-262
Web of Science | Medline
