The quadrivalent human papillomavirus (HPV) vaccine Gardasil (Merck & Co., Whitehouse Station, NJ) (qHPV-vac) was recently approved for immunization of adolescent girls to prevent cervical cancer.1 Recently, 5 cases of multiple sclerosis (MS) were reported following qHPV-vac vaccination.2 We report 4 patients who developed symptoms of neuromyelitis optica (NMO)3 within months after qHPV-vac inoculation.
Cases.
Medical records from patients at HHU Düsseldorf (case 1) and UCSF (case 2) were reviewed by T.M. and B.C. Both patients provided informed consent for anonymously reporting their cases. The Vaccine Adverse Events Reporting System (VAERS) database was searched for the term “neuromyelitis optica” entered between 2006 and 2009.
Case 1 (VAERS-ID 440761-1).
A 17-year-old girl was vaccinated with qHPV-vac in May 2007, December 2007, and April 2008. In August 2008, she presented with back pain followed by right leg monoparesis and a T6 Brown-Sequard syndrome. Spinal MRI showed a T2-hyperintense cervicothoracic lesion with mass effect extending over more than 3 vertebral segments. NMO–immunoglobulin G (IgG) was detected. In January 2009, she developed rapidly progressing spastic paraparesis, right arm weakness, and left eye visual loss. The cord lesion progressed to the medulla on MRI. Brain MRI was normal apart from a T2-hyperintense left optic nerve lesion. NMO was diagnosed, and the patient treated with IV methylprednisolone, plasma exchange, and rituximab.4
Case 2 (VAERS-ID 332160-1).
A 14-year-old girl received qHPV-vac vaccination in March, May, and September 2007. In February 2008, she was diagnosed with left optic neuritis. Brain and spinal MRI were normal; NMO-IgG was detected. In June 2008, she experienced right thigh dysesthesias followed by back pain. MRI revealed an extensive T2-hyperintense lesion in the thoracic spine. The patient was diagnosed with NMO and treated with IV methylprednisolone and rituximab.4 Ongoing relapsing disease activity eventually subsided with mycophenolate mofetil and prednisone.
Case 3 (VAERS-ID 289027-1).
A 13-year-old girl experienced transverse myelitis with flaccid paraplegia after her second qHPV-vac vaccination (time interval unknown). An optic nerve lesion and spinal MRI lesions were noted, prompting the diagnosis of NMO. The condition was unresponsive to steroids and plasma exchange, and rituximab was started.
Case 4 (VAERS-ID 342495-1).
An 18-year-old woman developed back pain and leg weakness in October 2008 after her second qHPV-vac injection in May 2008. In November 2008, she experienced hip and back pain and reported almost complete loss of monocular vision in January 2009, leading to the diagnosis of NMO. Data on MRIs, NMO-IgG, or treatment were not available.
Discussion.
We regard these 4 cases of NMO occurring in temporal association with qHPV-vac vaccinations noteworthy. The prevalence of NMO is rare (0.25–1/100,000) and may be even rarer in adolescents, given a median age at onset of 39 years.3 Until September 2009, approximately 9 million subjects were vaccinated with qHPV-vac in the United States and Europe. Thus, the reported NMO cases are unexpected and may not simply reflect the natural disease prevalence. The specificity of our observation is corroborated by the fact that other rare, but about 10-fold more prevalent antibody-mediated autoimmune diseases are not similarly frequently reported in the VAERS database for HPV vaccinations: 2 cases of scleroderma (prevalence 5–25/100,000); 5 cases of Wegener granulomatosis (prevalence 2.4–15.6/100,000); 9 cases of myasthenia gravis (prevalence 4–10/100,000).
Additionally, in aggregate only 8 NMO cases were retrieved from the entire VAERS database; in addition to the cases presented here, 2 were reported in association with hepatitis B virus vaccinations (age 47 and unknown); 1 case each occurred after influenza and DTP vaccinations (age 53 and 18). This suggests that the HPV vaccination might be overrepresented given that qHPV-vac was approved only recently and has been applied substantially less frequently than the other vaccines.
We could not confirm humoral immunologic crossreactivity between NMO and HPV, despite theoretically shared T-cell epitopes (tables 1 and 2). Additionally, the intervals between vaccinations and symptom onset (4–5 months) were consistently longer than in the 5 published MS cases (9.2 days on average),2 yet symptom onset of up to 2 years postvaccination has been reported.5 An alternative pathogenetic concept may be induction of bystander lymphocyte activation by upregulating both the adaptive and innate immune system as was shown for HPV vaccines.6
Assessment of immunologic cross-reactivity between AQ4 and L1 capsid proteins of HPVa
Serum antibody reactivities and seroprevalences against HPV 6, 11, 16, and 18 in NMO, MS, and controlsa
NMO may have been triggered by a recent HPV vaccination, although the data currently available cannot establish a pathogenic link. Hence, as of yet, the prevention of cervical cancers outweighs the low adverse event profile of qHPV-vac, and postmarketing pharmacosurveillance remains crucial to assess the vaccination's long-term safety.
Footnotes
Author contributions: T. Menge had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and drafted the manuscript. B. Cree proved a patient's case history and drafted the manuscript. A. Saleh provided the radiologic expertise reviewing the MRI data. T. Waterboer performed the HPV serologic studies and helped draft the manuscript. A. Berthele provided the NMO sera and helped draft the manuscript. S.R. Kalluri characterized the NMO sera. B. Hemmer provided the NMO sera and reviewed the manuscript draft. O. Aktas helped compile the case history and draft the manuscript. H.-P. Hartung drafted the manuscript. A. Methner helped compile the case history and draft the manuscript. B.C. Kieseier helped draft the manuscript.
Study funding: The MS Center at the Department of Neurology, Heinrich Heine University, Düsseldorf, is supported in part by the Walter-and-Ilse-Rose-Stiftung and the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis,” KKNMS-BMBF).
Disclosure: T. Menge has received honoraria and travel support from Bayer Schering Pharma, Biogen Idec, Teva, and Merck Serono. B. Cree received grant support from Genentech for a clinical trial of rituximab in NMO. A. Saleh and T. Waterboer report no disclosures. A. Berthele receives grant support from Bayer Healthcare for studies on NMO. S.R. Kalluri reports no disclosures. B. Hemmer received honoraria and grant support from Bayer Schering, Merck Serono, Biogen Idec, Teva, Roche, Genzyme, Genentech, and Novartis. O. Aktas has received consultancy fees/honoraria and travel grants from Bayer HealthCare, Merck Serono, and Novartis. H.-P. Hartung received honoraria, with approval of the rector of Heinrich Heine University and the CEO of Heinrich Heine University Hospital, for consulting and speaking from Bayer Schering pharma, Biogen Idec, Merck Serono, Genzyme, Novartis, Roche, and Teva Sanofi Aventis. A. Methner reports no disclosures. B.C. Kieseier received honoraria for lecturing and travel expenses for attending meetings and received financial research support from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, and Teva Pharmaceuticals. He has served or serves as consultant for Biogen Idec, Medac, Sanofi-Aventis, and Teva. Go to Neurology.org for full disclosures.
Acknowledgment: The authors thank the patients for consenting to the publication of their medical histories. NMO serum samples used in the HPV seroprevalence analysis were collected as part of the activities of the German Neuromyelitis Optica Study Group (NEMOS; www.nemos-net.de). The Departments of Neurology at the Heinrich Heine University Düsseldorf and at the Technische Universität München are members of NEMOS.
- Received June 16, 2011.
- Accepted October 18, 2011.
- Copyright © 2012 by AAN Enterprises, Inc.
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