www.thetinman.org Copyright © All rights reserved.
Disclaimer: The material presented in this site is intended for public educational purposes only. The author is not offering medical or legal advice. Accuracy of information is attempted but not guaranteed. Before undertaking any diet, or health improvement program, you should consult your physician. The author is in no way liable or responsible for any bodily harm, physical, mental or emotional state of any patient reacting to any of the content on this site. Thetinman.org has not examined, reviewed or tested any product or service mentioned herein. We are not being paid to advertise or promote any product or service mentioned herein. The links are offered strictly as examples of resources available. The site assumes no responsibility or liability of any kind related to the content of external sites or the usage of any product or service referenced. Links to external sites were live at the time of creation of the link. Thetinman.org does not create content for or manage external sites. The information can be changed or removed by the external site’s administrators at any time and they are responsible for the veracity of their information. Links are provided to support our data and supply additional resources. Please report broken links to administrator@thetinman.org. Thetinman.org is not a charitable foundation. It neither accepts nor distributes donations or funds of any kind.
References (may require membership or payment to view)
1. Amato AA, Cornman EW, Kissel JT. Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology. 1994 Sep;44(9):1652-4.
“The recent successful use of intravenous immunoglobulin (IVIG) in treating various autoimmune neuromuscular disorders led us to try IVIG in an uncontrolled pilot study on three patients. All three showed subjective and objective improvement.”
2. Baizabal-Caravallo, JF, Jankovic J ed, Stiff-person syndrome. Parkinson's Disease Center and Movement Disorders clinic at Baylor College of Medicine. 1994, updated April 2013. Link to article
IVIG has been shown to benefit patients in a controlled trial.
3. Barker RA, Marsden CD. Successful treatment of stiff man syndrome with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):426-7. Link to article
A study of one patient treated with IVIG saw an improvement in startle and falls. Baclofen and benzodiazepines were reduced and continuous motor activity on EMG resolved. Interestingly, some of the patients in these studies responded to IVIG having only had partial or no response to steroid treatment or plasma exchange.
4. Dalakas M. IVIG in other autoimmune neurological disorders: current status and future prospects. J Neurol. 2008 Jul;255 Suppl 3:12-6. doi: 10.1007/s00415-008-3004-y. Review. Link to article
In a controlled study in patients with stiff person syndrome IVIg was effective, with improvements in the distribution of stiffness index and heightened sensitivity scores.
5. Dalakas MC , Fujii M, Li M , et al. High-Dose Intravenous Immune Globulin for Stiff-Person Syndrome. New England Journal of Medicine 2001;345:26, 1870-1876. Link to article
Eleven patients who received immune globulin became able to walk more easily or without assistance, their frequency of falls decreased, and they were able to perform work-related or household tasks. The duration of the beneficial effects of immune globulin varied from six weeks to one year. Anti-GAD65 antibody titers declined after immune globulin therapy but not after placebo administration.
6. Dalakas MC The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. Journal of Neurology 2005;252:S1, i19-I25. Link to article
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-GAD(65) antibody titres declined after IVIg, but not after placebo.
7. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immunoglobulin in treatment of neurological diseases. Eur J Neurology 2008;15:893-908. Link to article
The need for more effective therapies and the encouraging results from pilot or uncontrolled studies have prompted the need to perform controlled studies to examine the therapeutic efficacy of high-dose intravenous immune globulin (IVIg), an immunomodulating drug with prohibitive cost but minimal toxicity.
8. Dalakas MC. Intravenous immunoglobulin in patients with anti-GAD antibody-associated neurological diseases and patients with inflammatory myopathies: effects on clinicopathological features and immunoregulatory genes. Clin Rev Allergy Immunol. 2005 Dec;29(3):255-69. Link to article
In patients with SPS and DM, the scores changed positively and significantly from months 1 through 3, but returned to baseline when the patients crossed to placebo. In contrast, the scores in the placebo-randomized group remained constant or worsened from months 1 to 3, but improved significantly after crossing to IVIg.
9. Dalakas MC. Role of IVIg in autoimmune, neuroinflammatory and neurodegenerative disorders of the central nervous system: present and future prospects. J Neurol. 2006 Sep;253 Suppl 5:V25-32. Review. Erratum in: J Neurol. 2008 Feb;255(2):308. Link to article
IVIg is effective in anti-GAD-positive patients with SPS. Whether it is also effective in other GAD-positive CNS disorders such as epilepsies, cerebellar degenerations or Batten's disease need to be studied in control trials. Emerging data suggest that IVIg, by suppressing proinflammatory cytokines, may exert a beneficial effect in patients with Alzheimer's disease, postpolio syndrome, chronic pain syndromes, fibrotic disorders and narcolepsy. Controlled studies are being planned or conducted to substantiate the benefit of IVIg in neurodegenerative disorders.
10. Gerschlager W, Brown P. Effect of treatment with intravenous immunoglobulin on quality of life in patients with stiff-person syndrome. Mov Disord. 2002 May;17(3):590-3. Link to article
Six patients with the classic form of SPS completed a generic QoL instrument, the SF-36, and a Visual Analogue Scale (VAS) before treatment as well as 2 weeks after completion of a course of IVIG. There was significant improvement in the SF-36 subscores for pain, social functioning, general mental health, and energy-vitality with treatment. The VAS also improved significantly.
11.Hao W, Davis C, Daniels, et al. Epitope-specific glutamic acid decarboxylase-65 autoantibodies in intravenous immunoglobulin preparations. Transfusion Medicine 1999;9:4, 307-310
It can therefore not be excluded that GAD65 autoantibodies may be present in IVIG, which is prepared from multiple blood donors. We report here that GAD65 but not IA-2 autoantibodies were present in commercial IVIG preparations. The presence of autoantibodies may affect the outcome of IVIG treatment and screening commercial preparations of IVIG for GAD65 autoantibodies is therefore recommended before treating patients.
12. Karlson EW, Sudarsky L, Ruderman E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis & Rheumatism 1994;37:6, 915-918. Link to article
An open, unblinded study of 3 patients with active disease and/or disease refractory to treatment with diazepam and/or corticosteroids. All 3 bedridden patients improved substantially shortly after infusion with IVIG and regained function.
13. Khanlou H, Eiger G. Long-term remission of refractory stiff-man syndrome after treatment with intravenous immunoglobulin. Mayo Clin Proc. 1999 Dec;74(12):1231-2. Link to article
We present a case of refractory stiff-man syndrome, in which the symptoms were successfully controlled by the administration of intravenous immunoglobulin (IVIg). This case gives evidence that IVIg can be a safe and an efficient treatment of refractory stiff-man syndrome.
14. Mikaeloff Y, Jambaque I, Mayer M, et al.: Benefit of intravenous immunoglobulin in autoimmune stiffperson syndrome in a child. J Pediatr 2001, 139:340. Link to article
15. Molina JA, Porta J, Garcia-Morales I, et al.: Treatment with intravenous prednisone and immunoglobulin in a case of progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry 2000, 68:395–396. Link to article
A patient with SPS plus PERM was treated with diazepam, gabapentin, and valproate without response. She developed severe muscle spasms and a confusional state. Five days after starting IVIG with prednisone the patient reached a normal level of consciousness and the leg cramps disappeared, although she had moderate loss of strength in her hands and mild memory loss. She was discharged 4 weeks later on prednisone. When the prednisone was decreased, the crams came back and the prednisone had to be increased. Another IVIG course obtained a positive response. She reported being free of cramps since then. (Time line uncertain).
16. Piotrowicz A, Thümen A, Leite MI, Vincent A, Moser A. A case of glycine-receptor antibody-associated encephalomyelitis with rigidity and myoclonus (PERM): clinical course, treatment and CSF findings. J Neurol. 2011 Dec;258(12):2268-70. doi: 10.1007/s00415-011-6078-x. Epub 2011 May 4. Link to article
The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. Stiff man syndrome: clinical and laboratory findings in eight patients.
17. Sevrin C, Moulin T, Tatu L, et al.: “Stiff-man” syndrome treated with intravenous immunoglobulins. Rev Neurol (Paris) 1998, 154:431.
18. Souza-Lima CF, Ferraz HB, Braz CA, Araüjo AM, Manzano GM. Marked improvement in a stiff-limb patient treated with intravenous immunoglobulin. Mov Disord. 2000 Mar;15(2):358-9. DOI: 10.1002/1531-8257(200003)15:2<358::AID-MDS1032>3.0.CO;2-L
19. Sudo K, Tajima Y, Matsumoto A. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2002 May 30;346(22):1747-8; author reply 1747-8. Link to article
(Question) 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.
(Dalakas reply) 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. However, the IgG molecules within the immune globulin cross the blood–cerebrospinal fluid barrier 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.
ARTICLES ON IVIG THERAPY
Treatment options GABAergic drugs GABA A Agonists GABA Modulators GABA B Agonists GABA P Agonists
GABA Transaminase GABA RUI GABA Analogues GABA Supplement Muscle Relaxers Corticosteroids
Antiseizure Opiate Analgesics Experimental IVIG Plasmapheresis Immunotherapy Stem Cell Therapy PT
Disclaimer: The material presented in this site is intended for public educational purposes only. The author is not offering medical or legal advice. Accuracy of information is attempted but not guaranteed. Before undertaking any diet, or health improvement program, you should consult your physician. The author is in no way liable or responsible for any bodily harm, physical, mental or emotional state of any patient reacting to any of the content this site. Thetinman.org has not examined, reviewed or tested any product or service mentioned herein. We are not being paid to advertise or promote any product or service mentioned herein. The links are offered strictly as examples of resources available. The site assumes no responsibility or liability of any kind related to the content of external sites or the usage of any product or service referenced. Links to external sites were live at the time of creation of the link. Thetinman.org does not create content for or manage external sites. The information can be changed or removed by the external site’s administrators at any time and they are responsible for the veracity of their information. Links are provided to support our data and supply additional resources. Please report broken links to administrator@thetinman.org.