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ARTICLES: Beth B. Murinson and Joseph B. Guarnaccia Stiff-person syndrome with amphiphysin antibodies: Distinctive features of a rare disease Neurology 2008; 71: 1955-1958 [Abstract] [Full text] [PDF]

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Stiff-person syndrome with amphiphysin antibodies: Distinctive features of a rare disease

Andrew McKeon, MB, MRCPI, Sean J Pittock, MD, Vanda A. Lennon, MD, PhD   (26 May 2009)

Reply from the authors

Beth B. Murinson, Joseph B. Guarnaccia (New Haven, CT)   (26 May 2009)

Stiff-person syndrome with amphiphysin antibodies: Distinctive features of a rare disease 26 May 2009
Andrew McKeon, MB, MRCPI, Mayo Clinic College of Medicine Department of Neurology, 200 1st St SW, Rochester, MN, 55905, Sean J Pittock, MD, Vanda A. Lennon, MD, PhD Send Correspondence to journal: Re: Stiff-person syndrome with amphiphysin antibodies: Distinctive features of a rare disease mckeon.andrew{at}mayo.edu Andrew McKeon, MB, MRCPI, et al.	Drs. Murinson and Guarnaccia convincingly demonstrate different patterns of stiffness in glutamic acid decarboxylase (GAD65) autoimmunity (stiff-person syndrome) and amphiphysin autoimmunity. [1] All of the 11 patients seropositive for amphiphysin antibody were women and 10 had breast adenocarcinoma. The authors state that “testing for the relevant antibodies is no longer performed by immunocytochemistry, a labor intensive method that could identify multiple antigens in a single serum sample” and “antibodies are now measured by immunoassay, using purified antigen and detecting only the antibody specifically requested.” In our experience with amphiphysin-IgG seropositive patients, the detection of this antibody predicts the presence of small-cell lung carcinoma or breast adenocarcinoma but does not further refine the cancer search. [2] Cancer diagnosis and definitive treatment are expedited by a comprehensive serological evaluation by: immunofluorescence to screen for neuronal and glial nuclear and cytoplasmic autoantibodies; radioimmunoprecipitation to detect plasma membrane cation channel antibodies; and ELISA and Western blotting, permitting detection of autoantibody profiles that predict a specific neoplasm. [3] Using this screening protocol on a service basis (1990-2008), the Mayo Clinic Neuroimmunology Laboratory has identified 58 amphiphysin antibody seropositive patients with histologically-confirmed small-cell lung carcinoma (33 patients; 22 men and 11 women) or breast adenocarcinoma (25 patients; all women). Amphiphysin autoantibody was detected in all patients by immunohistochemical characteristics and was confirmed by reflexive Western blot using recombinant full-length human amphiphysin protein. [2] Of 33 patients with small-cell lung carcinoma, 27 had one or more coexisting neural-specific autoantibodies predicting that cancer type (82%). Immunohistochemistry identified collapsin response mediator-protein (CRMP)-5-IgG in 11 patients; anti-neuronal nuclear antibody type 1 (ANNA-1) in nine patients; Purkinje cell antibody (PCA) type 2 in two patients; and anti-glial/neuronal nuclear antibody, type 1 (AGNA-1) in one patient. Radioimmunoprecipitation assays identified coexisting P/Q-type voltage-gated calcium channel antibodies in 11 patients; N-type calcium channel antibodies in four patients; and muscle acetylcholine receptor binding antibody in one patient. None of 30 patients with breast adenocarcinoma or other cancer type had a coexisting autoantibody predictive of small-cell lung carcinoma. Only 15 of 58 patients presented with signs of stiff-man syndrome or limb stiffness (26%); the majority (12) had breast carcinoma (80%). Contrary to the authors’ recommendation [1], our data do not support the practice of nominating a single or limited number of individual autoantibodies for testing. This practice often leads to failure in detecting diagnostically important paraneoplastic autoantibodies. Optimal serological evaluation of patients with suspected paraneoplastic neurologic disorders mandates comprehensive screening for cancer-specific autoantibody profiles. [3] References 1. Murinson BB, Guarnaccia JB. Stiff-person syndrome with amphiphysin antibodies. Distinctive features of a rare disease. Neurology 2008;71:1955-1958. 2. Pittock SJ, Lucchinetti CF, Parisi JE, et al. Amphiphysin autoimmunity: paraneoplastic accompaniments. Ann Neurol 2005;58:96-107. 3. Pittock SJ, Kryzer TJ, Lennon VA. Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol 2004;56:715-719. Disclosure: Drs. Lennon, Pittock and McKeon have no intellectual property related to the tests referenced in the related correspondence. Drs. Pittock, McKeon and Lennon receive no royalties from the sale of these tests when used for patients. Mayo Collaborative Services, Inc. does receive revenue for conducting these tests. Dr. Lennon and Mayo Clinic have a financial interest in the following intellectual property, the technologies have been licensed to commercial entities, and Dr. Lennon has received royalties for: "NMO-IgG: A Marker Autoantibody of Neuromyelitis Optica”; "Collaboration with Theraclone Sciences, Inc., ( f.k.a. Spaltudaq) for Human Monoclonal Antibody Production Specific for Surface Membranes of Cancer Cells and Astrocytes and Related Know-How"; and "BAP31-Specific IgG Monoclonal Antibodies (CC-1 and CC-4)". Dr. Lennon and Dr. Pittock have a potential financial interest in the technologies: "Aquaporin-4 Autoantibody as a Cancer Marker". A non-provisional patent application has been filed by Mayo Clinic for the following technology, it has been licensed by Mayo Clinic to a commercial entity, and no royalties have accrued from this license for:"Aquaporin-4-Binding Autoantibodies in Patients with Neuromyelitis Optic Impair Glutamate Transport by Down-Regulating EAAT2". Dr. McKeon has no financial interest in any of the technologies listed.
Reply from the authors 26 May 2009
Beth B. Murinson, Johns Hopkins School of Medicine Baltimore, MD, Joseph B. Guarnaccia (New Haven, CT) Send Correspondence to journal: Re: Reply from the authors bmurins1{at}jhmi.edu Beth B. Murinson, et al.	The authors thank Drs. McKeon, Pittock and Lennon for their comments on our recent article. [1] It is understood that a large majority of patients with antibody-associated SPS will have antibodies to glutamic acid decarboxylase 65 (GAD65), and that for the most part, testing for these relevant antibodies is no longer performed using immunocytochemistry. The data of Dr. McKeon et al. may be constrained by the presence of ascertainment bias. [4] For the data they have presented, the ascertainment of cases is through a laboratory test that is offered for all neurological syndromes with suspected co-morbid cancer. The acquisition of cases in this manner necessarily limits the application of such data to more general clinical scenarios. In our case, study inclusion criteria sought to examine patients who were referred with symptoms suggestive of Stiff-person syndrome. This is reflected in the high probability of a positive result associated with our (GAD65) antibody testing which approached 25%. [5] In the case of our amphiphysin antibody testing, probability was still relatively high at 2%, compared with an estimated .01% for the Mayo group. One additional point is that McKeon et al. are describing the neurological accompaniments of amphiphysin antibodies, findings that are firstly of interest to those working in serological testing labs or conducting research on amphiphysin, and secondarily of interest to clinicians who may order paraneoplastic antibody testing as part of 'casting a wide net'. Our report focused on the clinical characterization of Stiff-person syndrome associated with these antibodies, information that we believe will be of great utility to clinicians at the bedside of patients with this often devastating disorder. We conclude that our study represents a significant advance in the understanding of Stiff-person syndrome that we have previously described more broadly. [6] References 4. Bogenschutz MP, Nurnberg HG. Theoretical and methodological issues in psychiatric comorbidity. Harv Rev Psychiatry. 2000;8:18-24. 5. Murinson BB, Butler M, Marfurt K, Gleason S, De Camilli P, Solimena M. Markedly elevated GAD antibodies in SPS: effects of age and illness duration. Neurology. 2004;63:2146-2148. 6. Murinson BB. Stiff-person syndrome. Neurologist. 2004;10:131-137. Disclosures: Dr. Murinson receives or has received support from the MayDay Fund (principal investigator) and The Milbank Fund for Rehabilitation (principal investigator), has the following patent pending for a device for Prevention of Ulnar Neuropathy (U.S. Provisional Application Serial Number 60/640,691), served as a section co-editor for the Journal of Neuropathic Pain and Symptom Management, receives support from NINDS grant 1K08NS048146 (principal investigator), and has received honoraria for the VAMC Regional Pain Leadership Conference Lecture, American Pain Society Course Director, and AAN Meeting Course Director. Dr. Guarnaccia reports no disclosures. This work was supported in part by 'The Johns Hopkins School of Medicine, Fund for SPS Research'. This fund was endowed by a deceased patient and donations in his memory. This fund has received no support directly or indirectly from the pharmaceutical or biomedical industries.