Figure. Timeline of clinical events and serological data. A, Clinical and neuromyelitis optica (NMO)–IgG titer evolution. Results of additional methods of titer evaluation for each time point are (Sep 2006) immunoprecipitation assay [IPA] = 222 nmol/L, enzyme-linked immunosorbent assay [ELISA] > 160 U/mL; (Oct 2008) IPA = 20.8 nmol/L, ELISA < 5 U/mL; (Aug 2009) IPA not tested, ELISA > 160 u/mL; (May 2010) IPA = 262.8 nmol/L, ELISA > 160 U/mL; and (Dec 2010) IPA = 19.9 nmol/L, ELISA < 5 U/mL. B, Sagittal T1-weighted image with gadolinium-enhanced T1 spinal cord magnetic resonance images (May 2010) showing abnormal enhancement from T3 through T8. IF, immunofluorescence; ON, optic neuritis; TM, transverse myelitis; qid, 4 times per day; qod, every other day; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; AHSCT, autologous hematopoietic stem cell transplantation.
Matiello M, Pittock SJ, Porrata L, Weinshenker BG. Failure of Autologous Hematopoietic Stem Cell Transplantation to Prevent Relapse of Neuromyelitis Optica. Arch Neurol. 2011;68(7):953-955. doi:10.1001/archneurol.2011.38
Author Affiliations: Departments of Neurology (Drs Matiello, Pittock, and Weinshenker) and Laboratory Medicine and Pathology (Dr Pittock), and the Division of Hematology (Dr Porrata), Mayo Clinic, Rochester, Minnesota.
Here we describe a woman with relapsing neuromyelitis optica (NMO) who was seropositive for NMO-IgG and who experienced a relapse of myelitis 4 months after autologous hematopoietic stem cell transplantation (AHSCT) for a lymphoma that developed while receiving azathioprine therapy. Analysis of serum samples obtained at key points in her disease course using 3 different serological techniques (immunofluorescence, immunoprecipitation assay, and enzyme-linked immunosorbent assay) documented marked increase in titer coinciding with the relapse.
A 64-year-old woman who had a history of optic neuritis in 1989 presented with left-sided abdominal pain accompanied by dysesthesias and severe left leg weakness and spasticity in 2006. Magnetic resonance imaging revealed three T2-hyperintense lesions in the thoracic spinal cord 4 months after the first symptom, the longest spanning 2 vertebral segments. Cerebrospinal fluid analysis revealed a cell count, total protein, IgG index, and synthesis rate in the reference range but detected 9 cerebrospinal fluid–unique oligoclonal bands. Results of testing for NMO-IgG were positive (immunofluorescence titer, 480). Following a 5-day course of intravenous corticosteroids, her condition improved and she could ambulate with a walker. She was treated with 60 mg of prednisone every other day and azathioprine 150 mg daily. On October 2008, she presented with fatigue, fever, and night sweats. Her hemoglobin level was 7.3 g/dL (to convert to grams per liter, multiply by 10.0). Adenopathy of the anterior mediastinum, epigastrium, retrocrural space, and retroperitoneum was discovered, and a bone marrow biopsy was consistent with Hodgkin lymphoma. She received six 4-week cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine, and reimaging revealed complete remission. Azathioprine use was discontinued. Serology for NMO-IgG revealed a 10-fold reduction by the immunoprecipitation assay compared with baseline and negative result by immunofluorescence at 1:120 serum dilution. At the 8-month follow-up visit, positron emission tomography revealed nodal and extranodal recurrent lymphoma and she was treated with AHSCT preceded by high-dose conditioning chemotherapy (carmustine, etoposide, cytarabine, and melphalan hydrochloride). A positron emission tomographic scan done 3 months after treatment documented a complete response. Four months after AHSCT, she presented with pain in the torso and lower abdomen associated with numbness of the right leg and increased weakness of the left leg. Magnetic resonance imaging of the spinal cord showed a transverse myelitis lesion extending from T3 through T8, with associated patchy enhancement and mild cord expansion; NMO-IgG titer increased to 7680 by immunofluorescence. Intravenous corticosteroids were administered, and 6 monthly doses of rituximab were initiated. At the last follow-up (December 2010), she had no further NMO relapses, although she had a localized recurrence of pelvic lymphoma that was managed with radiotherapy; NMO-IgG titer decreased to lower than 120 (Figure).
Neuromyelitis optica is an autoimmune disease of the central nervous system characterized by the disease-specific aquaporin-4 reactive autoantibodies that activate complement and lead to inflammatory demyelination and necrosis.1
Use of AHSCT is being explored as a treatment for autoimmune diseases that are unresponsive to conventional treatments; its use permits the administration of potent immunosuppressive drugs in an effort to permanently eliminate autoreactive immune cells and establish a new immune repertoire. No series of AHSCT for NMO have been published; however, recruitment is ongoing for a trial of AHSCT in NMO (www.clinicaltrials.gov; NCT00787722) in which 10 patients will be treated with high-dose cyclophosphamide and rabbit antithymocyte globulin/rituximab followed by AHSCT.
Because AHSCT is costly (generally ranging from $50 000 to $100 000, www.nbmtlink.org) and risk for morbidity and mortality are substantial, the expectations that it would prolong disease-free survival should be more rigorous than for less aggressive immunosuppression. Data on the efficacy of AHSCT for antibody-mediated autoimmune disease are scarce. In the evaluation of AHSCT success in 473 patients with severe autoimmune diseases, patients with idiopathic thrombocytopenic purpura had lower success rates (sustained response in 2 of 7 patients, or 29%) than other diseases that are not mediated by antibodies.2 De novo antibody-mediated autoimmune syndromes have been reported after AHSCT.3,4 In a study of pre- and post-AHSCT vaccination, immunological memory of a T-cell–dependent neoantigen was eradicated but humoral response persisted in 60% of juvenile patients with idiopathic arthritis or patients with systemic lupus erythematosus.5 Oligoclonal bands persisted in the cerebrospinal fluid of 5 of 6 inpatients with multiple sclerosis who were treated with AHSCT.6
This article raises concerns about the efficacy of AHSCT for NMO, and data from an ongoing clinical trial may determine whether some patients experience a benefit. In the reported case, it is uncertain whether inadequate reset of immune tolerance or sustained autoimmunity to aquaporin 4 autoantigen was responsible for such treatment failure. This case further suggests that an association between NMO disease activity and titer of aquaporin 4 autoantibodies may exist, but routine testing for this purpose is not yet indicated.
Correspondence: Dr Weinshenker, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (email@example.com).
Published Online: March 14, 2011. doi:10.1001/archneurol.2011.38
Author Contributions:Study concept and design: Matiello and Weinshenker. Acquisition of data: Matiello and Porrata. Analysis and interpretation of data: Matiello, Pittock, Porrata, and Weinshenker. Drafting of the manuscript: Matiello. Critical revision of the manuscript for important intellectual content: Pittock, Porrata, and Weinshenker. Administrative, technical, and material support: Matiello and Pittock. Study supervision: Pittock, Porrata, and Weinshenker.
Financial Disclosure: Dr Pittock and Mayo Clinic have a financial interest in the technology entitled “Aquaporin-4 Autoantibody as a Cancer Marker.” This technology has been licensed to a commercial entity but no royalties have been received. In addition, Dr Pittock is an inventor of technology entitled “Aquaporin-4 Binding Autoantibodies in Patients with Neuromyelitis Optic Impair Glutamate Transport by Down-Regulating EAAT2.” Mayo Clinic has filed a nonprovisional patent application for this technology. Dr Pittock has received a research grant from Alexion pharmaceuticals for his investigator-initiated study entitled “An Open Label Study of Eculizumab in NMO” and is a consultant in the Department of Laboratory Medicine and Pathology. In his role as Codirector of the Neuroimmunology Laboratory, Dr Pittock has no additional intellectual property related to any tests performed on a service basis in the laboratory; he receives no royalties from the sale of these tests when used for patients. Mayo Collaborative Services, Inc, does receive revenue for conducting these tests. Dr Weinshenker has intellectual property associated with the discovery of NMO-IgG, which has been licensed to a commercial entity.
Funding/Support: This study was supported by the Guthy-Jackson Charitable Foundation; and a postdoctoral fellowship from the National Multiple Sclerosis Society (Dr Matiello).
Additional Contributions: We thank John Schmeling for technical assistance.