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      Myasthenia gravis following human papillomavirus vaccination: a case report

      case-report

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          Abstract

          Background

          Myasthenia gravis (MG), an autoimmune neuromuscular disorder, occurs owing to autoantibodies against acetylcholine receptors. MG symptoms can be triggered by various vaccines. Many studies have evaluated the safety and adverse events of the human papillomavirus (HPV) vaccine. Here, we present a life-threatening case of ocular and bulbar MG symptoms after HPV vaccination and a brief literature review.

          Case presentation

          A 23-year-old woman presented with binocular diplopia, ptosis, dysarthria, and dysphagia, which occurred on the 3rd day after the second HPV vaccine administration. She was diagnosed with MG based on history, clinical features, and test results. Her symptoms deteriorated on the 3rd day after admission, and she was transferred to the intensive care unit with mechanical ventilation. On the 7th day after admission, due to discomfort in the right chest, pulmonary embolism was suspected. A tracheostomy was performed on the 14th day of mechanical ventilation. In the 4th week, the tracheostomy tube was removed; all symptoms had completely resolved at discharge. She was followed up for 5 months without recurrence or further treatment.

          Conclusion

          HPV vaccination may cause MG owing to unexpected abnormal autoimmune responses. Additional studies are needed to clarify the possible causal relationship between the HPV vaccine and neurological complications and to evaluate the safety of the vaccine.

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          Most cited references10

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          A systematic review of population based epidemiological studies in Myasthenia Gravis

          Background The aim was to collate all myasthenia gravis (MG) epidemiological studies including AChR MG and MuSK MG specific studies. To synthesize data on incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the condition and investigate the influence of environmental and technical factors on any trends or variation observed. Methods Studies were identified using multiple sources and meta-analysis performed to calculate pooled estimates for IR, PR and MR. Results 55 studies performed between 1950 and 2007 were included, representing 1.7 billion population-years. For All MG estimated pooled IR (eIR): 5.3 per million person-years (C.I.:4.4, 6.1), range: 1.7 to 21.3; estimated pooled PR: 77.7 per million persons (C.I.:64.0, 94.3), range 15 to 179; MR range 0.1 to 0.9 per millions person-years. AChR MG eIR: 7.3 (C.I.:5.5, 7.8), range: 4.3 to 18.0; MuSK MG IR range: 0.1 to 0.32. However marked variation persisted between populations studied with similar methodology and in similar areas. Conclusions We report marked variation in observed frequencies of MG. We show evidence of increasing frequency of MG with year of study and improved study quality. This probably reflects improved case ascertainment. But other factors must also influence disease onset resulting in the observed variation in IR across geographically and genetically similar populations.
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            Management of immune-related adverse events and kinetics of response with ipilimumab.

            Monoclonal antibodies directed against the immune checkpoint protein cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152)-ipilimumab and tremelimumab-have been investigated in metastatic melanoma and other cancers and have shown promising results. Recently, ipilimumab was approved by the US Food and Drug Administration for the treatment of metastatic melanoma. We review the literature on managing the adverse effects and kinetics of tumor regression with ipilimumab and provide guidelines on their management. During treatment with these antibodies, a unique set of adverse effects may occur, called immune-related adverse events (irAEs). These include rashes, which may rarely progress to life-threatening toxic epidermal necrolysis, and colitis, characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab. Early recognition of irAEs and initiation of treatment are critical to reduce the risk of sequelae. Interestingly, irAEs correlated with treatment response in some studies. Unique kinetics of response have been observed with CTLA-4 blockade with at least four patterns: (1) response in baseline lesions by week 12, with no new lesions seen; (2) stable disease, followed by a slow, steady decline in total tumor burden; (3) regression of tumor after initial increase in total tumor burden; and (4) reduction in total tumor burden during or after the appearance of new lesion(s) after week 12. We provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them, along with the unusual kinetics of response associated with ipilimumab therapy.
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              Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53

              Summary The p53 pro-apoptotic tumor suppressor is mutated or functionally altered in most cancers. In epithelial tumors induced by “high-risk” mucosal Human Papillomaviruses (hrm-HPVs), including human cervical carcinoma and a growing number of head-and-neck cancers 1 , p53 is degraded by the viral oncoprotein E6 2 . In this process, E6 binds to a short LxxLL consensus sequence within the cellular ubiquitin ligase E6AP 3 . Subsequently, the E6/E6AP heterodimer recruits and degrades p53 4 . Neither E6 nor E6AP are separately able to recruit p53 3,5 , and the precise mode of assembly of E6, E6AP and p53 is unknown. Here, we solved the crystal structure of a ternary complex comprising full-length HPV16 E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumor suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against HPV-mediated oncogenesis.
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                Author and article information

                Contributors
                time4peace@hanmail.net
                slee026@jbnu.ac.kr
                sbsoo@jbnu.ac.kr
                +82-63-250-1590 , hgkang@jbnu.ac.kr
                Journal
                BMC Neurol
                BMC Neurol
                BMC Neurology
                BioMed Central (London )
                1471-2377
                28 December 2018
                28 December 2018
                2018
                : 18
                : 222
                Affiliations
                [1 ]ISNI 0000 0000 9475 8840, GRID grid.254187.d, Department of Neurology, , Chosun University School of Medicine, ; Gwangju, 61453 Republic of Korea
                [2 ]ISNI 0000 0004 0470 4320, GRID grid.411545.0, Institute for Molecular Biology and Genetics and Department of Chemistry, , Chonbuk National University, ; Jeonju, 54896 Republic of Korea
                [3 ]ISNI 0000 0004 0470 4320, GRID grid.411545.0, Department of Neurology, , Chonbuk National University School of Medicine, ; Jeonju, 54896 Republic of Korea
                [4 ]Department of Neurology & Research Institute of Clinical Medicine of Chonbuk National University - Biomedical Research Institute of Chonbuk National University Hospital, 20 Geonji-ro, Deokjin-gu, Jeonju-si, Jeonbuk-do 54907 South Korea
                Author information
                http://orcid.org/0000-0001-5443-3635
                Article
                1233
                10.1186/s12883-018-1233-y
                6309058
                30593270
                cc9b0f7d-9794-4f5d-8646-0563877e1efa
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 4 September 2018
                : 20 December 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002701, Ministry of Education;
                Award ID: 2017R1A1A03015876
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100003621, Ministry of Science, ICT and Future Planning;
                Award ID: 2017R1C1B5017293
                Award Recipient :
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2018

                Neurology
                adverse event,human papillomavirus vaccine,myasthenia gravis,myasthenia gravis crisis,vaccination

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