Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): Estimation of pathological lesion stage from brain images.

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a disease responsible for cognitive impairment in adult humans. It is caused by mutations in the colony stimulating factor 1 receptor gene (CSF1R) or alanyl-transfer (t) RNA synthetase 2 (AARS2) gene and affects brain white matter. Settlement of stages of the pathological brain lesions (Oyanagi et al. 2017) from the findings of brain imaging will be inevitably essential for prognostication. METHODS: MRI images of eight patients with ALSP were analyzed semiquantitatively. White matter degeneration was assessed on a scale of 0 to 4 (none, patchy, large patchy, confluent, and diffuse) at six anatomical points, and brain atrophy on a scale 0 to 4 (none, slight, mild, moderate, and severe) in four anatomical areas. The scores of the two assessments were then summed to give total MRI scores of 0-40 points. Based on the scores, the MRI features were classified as Grades (0-4). Regression analysis was applied to mutual association between mRS, white matter degeneration score, brain atrophy score, the total MRI score and disease duration. RESULTS: White matter degeneration score, brain atrophy score, and the total MRI score were significantly correlated with the disease duration. MRI Grades (2-4) based on the total MRI scores and the features of the images were well correlated with the pathological lesion stages (II - IV); i.e., 'large patchy' white matter degeneration in the frontal and parietal lobes (MRI Grade 2) corresponded to pathological Stage II, 'confluent' degeneration (Grade 3) to Stage III, and 'diffuse' degeneration (Grade 4) to Stage IV. CONCLUSION: MRI Grades (2-4) resulted from the total MRI scores were well correlated with the pathological lesion Stages (II - IV).

High-Intensity Circular Dichroism of Head-To-Tail Regioregular Poly(1,4-Phenylene)s in the Aggregated State.

Circular dichroism (CD) studies on poly(1,4-phenylene)s bearing a chiral side chain in the aggregated conditions were carried out. Little CD was observed in a solution form, while addition of a poor solvent into the polyphenylene solution induced aggregation and a strong CD was observed, accordingly. Applying the controlled degree of polymerization (DP) of poly(1,4-phenylene) in the use of bidentate diphosphine Chiraphos as a ligand for the nickel catalyst, the relationship of DP with CD strength was studied to reveal to show the highest CD at the DP=84 (gabs=ca. 2×10-2). It was also found that the related aggregation was observed in good solvent 1,2-dichloroethane upon standing the solution at 4 °C for 3-23 days to observe gabs=ca. 10-1. Studies on the substituent effect of poly(1,4-phenylene) suggested that CD behaviors were dependent on the type of non-chiral substituent on the aromatic ring as well as the side-chain chirality.

How the ARCH Project Could Contribute to Strengthening ASEAN Regional Capacities on Disaster Health Management (DHM).

OBJECTIVE: The Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) developed Regional Collaboration Drills (RCDs) and is proposing an ASEAN Academic Network to strengthen capacity in disaster health management (DHM) in ASEAN Member States (AMS), as well as developing a standard training curriculum in DHM. This study aims to clarify the impacts and sustainability of the ARCH Project. METHODS: The four previous RCDs and the enhancement of academic activities were reviewed. RESULTS: The ARCH Project developed the RCDs with simulation exercises based on possible disaster scenarios in each host country to test and validate the capacity of AMS International Emergency Medical Teams (I-EMTs), the Standard Operating Procedure (SOP) for I-EMT coordination, and regional tools, as well as the relevant domestic SOPs of the host countries for receiving international assistance. Following the RCD in Thailand, three AMS: Viet Nam, Philippines, and Indonesia, all of which are considered disaster-prone, successfully hosted RCDs with significant improvements. The project also established a sub-working group (SWG) to develop a standard curriculum in DHM. Two curricula developments, the Basic Course on DHM and In-Country Course for Coordination on EMTs, are on-going as part of the project activity. The establishment of the ASEAN Academic Network and the ASEAN Institute for DHM (AIDHM) are currently in the endorsement process of the ASEAN health sector. CONCLUSION: The RCDs are very effective to test and to validate the SOP and regional tools developed, providing opportunities for AMS I-EMT to familiarize the tools, as well as for host countries to assess their coordination capacity for receiving international assistance and identifying the country's specific challenges, and verifying ASEAN regional coordination mechanism. The development of the standard curriculum can enhance regional capacity both in supporting disaster-affected countries and in receiving international assistance. A sustainable capacity development mechanism in DHM is envisaged through the establishment of the ASEAN Academic Network and AIDHM toward the goal of One ASEAN One Response.

Impact of the ARCH Project on National Capacity Development on Disaster Health Management among the ASEAN Member States and Japan.

OBJECTIVE: This report tries to capture the impact of the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) in each ASEAN Member State (AMS) and Japan as a result of the ARCH Project implementation since July 2016. METHODS: Impact on AMS: The analysis of the impact on AMS was based on a comparison of the impact of the project on management and coordination of Emergency Medical Teams (EMTs), and application of the project outcome in actual emergency operations compared to the previous status in each AMS.Impact on Japan: The history of the development of disaster medicine in Japan was reviewed, with an aim to analyze the impact of supporting AMS through the ARCH Project on Japan, and the possibility of bi-directional cooperation in the future. RESULTS: Impact on AMS: Since the initiation of the ARCH Project, AMS has made significant progress in WHO EMT accreditation, strengthening EMTCC capacity for receiving international assistance, as well as the development of legislation or strategic plans related to DHM, and application of the Project products such as standard operating procedures or regional tools in actual disasters/emergencies.Impact on Japan: Disaster medicine in Japan originated from the Cambodian refugees' relief mission in 1979. Since then, the management system has been strengthened including the foundation of the Japan Disaster Relief (JDR) Team, a structure with a legal foundation. The experience gained through international operations has contributed to the development of Japan's domestic disaster response system. Japan learned the operational effectiveness of the post-disaster health surveillance system through the disaster response operation in 2013 Typhoon Yolanda Disaster in Philippines and introduced a modified system in Japan for domestic disaster response, which was later refined and proposed for an international standard. CONCLUSION: ARCH Project is highly appreciated by AMS as the opportunity to share knowledge and experience among countries and thereby contributing to achieving the "One ASEAN, One Response" concept, as well as the driving force for each AMS to develop its capacity in DHM. While the ARCH Project started to support AMS to strengthen its regional capacity in disaster health management, it is important to build a bi-directional relationship between ASEAN and Japan in terms of mutual learning and support to tackle future disasters.

ARCH Project and the Global Initiatives of Disaster Health Management.

OBJECTIVE: The prime aim of Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) is to strengthen the disaster health management (DHM) capacity in the context of personal level, Emergency Medical Team (EMT), and the regional collaboration. The ARCH Project was implemented with reference to international trends of DHM and seeks to contribute to the development of global standards. METHODS: The project established the Project Working Groups that consisted of representatives of ASEAN Member States (AMS) to develop standard operating procedures (SOP) for international EMT (I-EMT) coordination. Furthermore, it aimed to organize training sessions along with implementation of the regional collaboration drill (RCD) in accordance with I-EMT minimum requirements and in line with coordination standards set by the WHO. RESULTS: The ARCH Project developed the SOP and common platform for I-EMT coordination, organized training, and conducted RCDs with reference to the WHO's EMT initiative. Furthermore, it also contributed to the development of the EMT Minimum Data Set (MDS), an international standard DHM tool that underwent testing at the RCDs before the WHO endorsement and its utilization in actual disaster response. CONCLUSION: In the process of strengthening ASEAN regional capacity in DHM, the project is constantly capturing international trends and also making significant contributions in the development of global systems and tools.

How the ARCH Project has Contributed to the Development of the ASEAN Regional Collaboration Mechanism on Disaster Health Management.

OBJECTIVE: This paper aims to clarify how the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project) strengthened regional collaboration mechanisms on disaster health management (DHM) in ASEAN. METHODS: The political process and the relevant documents of the ARCH Project were reviewed. RESULTS: The ARCH Project established the Regional Coordination Committee as a coordination platform for providing strategic direction to the project and strengthening the regional coordination of DHM. Also, the Project Working Groups and Sub-Working Groups were set up as implementation bodies for the project activities with representatives of ASEAN Member States (AMS). With support from DHM experts of Japan and Thailand, a series of discussions were conducted for the development of a Standard Operating Procedure (SOP) for the Coordination of International Emergency Medical Teams (I-EMTs), regional tools, and collective measures supporting AMS to overcome challenges, and thereby meeting the minimum requirements set by the WHO EMT Initiative. The progress and outputs of the ARCH Project are subsequently elevated to the ASEAN Health Sector for endorsement, the updates are further shared to the Joint Task Force to Promote Synergy with Other Relevant ASEAN Bodies on Humanitarian Assistance and Disaster Relief (JTF-HADR) for the implementation of the ASEAN Declaration on One ASEAN One Response. The initiation of the ARCH Project in July 2016 has resulted in the development of the ASEAN regional collaboration framework, including the establishment of the Regional Coordination Committee on Disaster Health Management (RCCDHM), the SOP for ASEAN I-EMT coordination, and regional tools, such as forms for Medical Record for Emergency and Disaster and Health Needs Assessment. Moreover, further discussions on ASEAN Collective Measures that aim to support AMS to meet the WHO EMT minimum standards and strengthening I-EMT coordination capacity were also conducted. As adopted by the ASEAN Health Ministers Meeting (AHMM) in 2019, the RCCDHM was established as one of the mechanisms to operationalize the Plan of Action to implement the ASEAN Leaders' Declaration on DHM. CONCLUSION: The contribution of the ARCH Project to strengthen the ASEAN regional capacity in DHM has enhanced the regional coordination platform, with a formalization of RCCDHM as ASEAN's official regional mechanism, and of the on-going integration process of the SOP for EMT coordination into the ASEAN SASOP.

Introduction to the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project).

BACKGROUND: Southeast Asia is the second biggest region in the world in terms of the total number of natural disasters since 1900. Therefore, the Association of Southeast Asian Nations (ASEAN) initiated regional challenges toward strengthening regional collaboration for disaster prevention and response since the earthquake of Sumatra in Indonesia occurred in 2004. Moreover, ASEAN Leaders signed "the ASEAN Declaration on One ASEAN, One Response" in 2016. Under these circumstances, ASEAN decided to implement the Project for Strengthening the ASEAN Regional Capacity on Disaster Health Management (ARCH Project). OBJECTIVES: The objective of the ARCH Project is to strengthen coordination on disaster health management (DHM) for rapid and effective response to disasters occurring in the ASEAN region and to enhance the capacity of each ASEAN Member State (AMS) on DHM. This article aims to overview the outline and its strategy, and review the progress of the project. METHODS: ARCH Project is an ASEAN official project supported by Japan's official development assistance. Five outputs were launched for: (1) coordination platform on DHM; (2) framework of regional collaboration practices; (3) tools for effective regional collaboration; (4) enhancement of academic network on DHM; and (5) capacity development activities for each AMS. The Project was reviewed in terms of accomplishment and evaluation criteria. RESULTS: Regional Coordination Committee on DHM was established as a coordination platform to: Oversee the implementation of the ARCH Project for the Output 1; Regional Collaboration Drill was developed and conducted for the Output 2; The standard operating procedure for coordination of emergency medical teams (EMTs) in ASEAN was developed for the Output 3; Various presentations on ARCH were made in academic conferences for the Output 4; and Several training programs and educational curricula were developed for the Output 5. The Project has accomplished its Project Purpose and satisfied all the indicators set. ARCH Project has high Relevance, Impact, Sustainability, and Effectiveness, while some improvements in Efficiency are needed. CONCLUSIONS: ARCH Project is the first-ever successful regional cooperation mechanism and standardization of DHM in ASEAN, one of the most disaster-prone regions. It also contributes to the capacity building of AMS. The ARCH Project has a remarkable impact on the resilience and flexible medical response to disasters, although continuous efforts of stakeholders to make this initiative sustainable are necessary.

A Long-Term Observation on the Possible Adverse Effects in Japanese Adolescent Girls after Human Papillomavirus Vaccination.

In Japan, a significant number of adolescent females noted unusual symptoms after receiving the human papillomavirus (HPV) vaccination, of which the vast majority of them were initially diagnosed with psychiatric illnesses because of the absence of pathologic radiological images and specific abnormalities in laboratory test results. Later these symptoms were thought to be adverse effects of HPV vaccination. However, a causal link between HPV vaccination and the development of these symptoms has not been demonstrated. Between June 2013 and March 2021, we examined 200 patients who noted various symptoms after HPV vaccination. In total, 87 were diagnosed with HPV vaccination-related symptoms based on our proposed diagnostic criteria. The clinical histories of these 87 patients were analyzed. The age at initial vaccination ranged from 11 to 19 years old (mean ± SD: 13.5 ± 1.5 years old), and the age at the first appearance of symptoms ranged from 12 to 20 years old (mean ± SD: 14.3 ± 1.6 years old). The patients received an initial HPV vaccine injection between May 2010 and May 2013, but the first affected patient developed symptoms in October 2010, and the last affected developed symptoms in October 2015. A cluster of patients with a post-HPV vaccination disorder has not appeared in Japan during the last five years. Our study shows that, in Japan, the period of HPV vaccination considerably overlapped with that of a unique post-HPV vaccination disorder development. This disorder appears as a combination of orthostatic intolerance, chronic regional pain syndrome, and cognitive dysfunction, but its exact pathogenesis remains unclear.

Pathologic basis of the preferential thinning of thecorpus callosum in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

BACKGROUND: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and "focal lesions" of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017). METHODS: Seven autopsied brains of ALSP and five controls were neuropathologically examined. RESULTS: Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the "focal lesions" were identical with those of centrum semiovale. CONCLUSION: Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, "focal lesions" were formed in connection with the lesions in centrum semiovale.

Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.

Sjögren syndrome-related plasma cell disorder and multifocal nodular AL amyloidosis: clinical picture and pathological findings.

Background: Localized nodular deposits of AL amyloid are seen in different tissues/organs; however, the pathogenesis of this form of amyloidosis remains unclear. Recently, Sjögren syndrome combined with localized nodular AL amyloidosis has been noted. Here, we report Sjögren syndrome cases showing multifocal nodular AL amyloidosis and the followed benign course. Materials and methods: We investigated the clinical pictures and histopathological findings of three cases with both presence of Sjögren syndrome and localized nodular AL amyloidosis, paying a special attention to the distribution of amyloidoma. Results: All three cases were middle-aged females. In two of three cases localized deposits of AL amyloid preceded Sjögren syndrome. Amyloidoma was detected in scalp, eyelid, cheek, larynx, trachea, lung and breast, and around these amyloid-deposited lesions infiltration of plasma cells was seen. Pulmonary amyloidosis was consistently accompanied with parenchymal cystic lesions, but this amyloidosis did not produce any significant respiratory symptoms. Some of large pulmonary amyloidomas showed cavity formation and subsequent shrinkage. In two cases amyloid deposition was found on gastric mucosa. Two cases received small doses of oral prednisone, with no further appearance of amyloidoma. Conclusion: Sjögren syndrome-related plasma cell disorder may be responsible for the formation of this unique multifocal nodular AL amyloidosis.

Discriminative clinical and neuroimaging features of motor-predominant hereditary diffuse leukoencephalopathy with axonal spheroids and primary progressive multiple sclerosis: A preliminary cross-sectional study.

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. METHODS: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. RESULTS: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. CONCLUSIONS: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.

[A 36-year-old woman with primary central nervous system lymphoma diagnosed by twice brain biopsies, showing relapsing and remitting brain lesions].

A 36-year-old woman visited a local hospital suffering from acute onset dizziness. Brain MRI revealed multiple white matter lesions without gadolinium enhancement in the both hemispheres. Although she began to receive a treatment under a clinical diagnosis of multiple sclerosis, she developed newly emerging brain lesions and was referred to our hospital. Neurological examination detected intention tremor, right-sided dysdiadochokinesis, and gait ataxia. Both blood and cerebrospinal fluid tests were unremarkable but follow-up brain MRIs showed rapidly relapsing and remitting lesions. The first brain biopsy ended up showing non-specific changes but the second biopsy with five months interval confirmed primary central nervous system lymphoma (PCNSL). The patient was treated by chemotherapy and showed partial response. It is important to consider sequential brain biopsies if needed because PCNSL may present diverse brain lesions on MRI including non-neoplastic early lesions.

Suspected adverse effects after human papillomavirus vaccination: a temporal relationship.

In Japan, a significant number of adolescent girls complained unusual symptoms after human papillomavirus (HPV) vaccination, and the vast majority of them were initially diagnosed as having psychiatric illness because of the absence of pathologic findings, radiological images and specific abnormalities in laboratory test results. Later, these symptoms were supposed to be adverse effects after HPV vaccination, and the recommendation for HPV vaccination was withdrawn by Japanese Ministry of Public Health, Labour and Welfare 4 years and 9 months ago. However, a causal link has not been demonstrated between HPV vaccination and the development of these symptoms. Our study has shown that the period of HPV vaccination considerably overlapped with that of unique postvaccination symptom development, adding that new patients with possible HPV vaccine-related symptoms have not appeared during our recent 28-month follow-up period. This social episode has now subsided in Japan.

Nationwide Survey of 741 Patients with Systemic Amyloid Light-chain Amyloidosis in Japan.

Objective To retrospectively investigate the clinical manifestations of systemic amyloid light-chain (AL) amyloidosis in Japanese patients and the treatment strategy for the condition. Methods We conducted a survey of Japanese AL amyloidosis patients, who were treated between January 1, 2012, and December 31, 2014. Results A total of 741 AL amyloidosis patients were included in this study (436 men and 305 women; median age: 65 years old, range: 31-93). The most frequently affected organ was the kidneys (n=542), followed by the heart (n=252), gastrointestinal (GI) tract (n=164), autonomic nervous system (n=131), liver (n=71), and peripheral nervous system (n=71). Diagnostic findings were most commonly detected in the GI tract (upper GI tract: 350 cases, lower GI tract: 167 cases), followed by the bone marrow and kidneys. An abdominal fat-pad biopsy was only conducted in 128 patients. Autologous stem cell transplants (ASCTs) and bortezomib were used to treat 126 and 276 patients, respectively. Conclusion The clinical features of Japanese patients with systemic AL amyloidosis are similar to those reported previously for cases in the US and Europe. Regarding treatment, a significant number of ASCTs were performed in Japan as well as in Western countries. Surprisingly, a marked number of patients received bortezomib as a treatment for AL amyloidosis.

Protein-losing Gastroenteropathy Related to Mixed Connective Tissue Disease: A Case Report of a Successful Outcome and Literature Review.

We herein report the case of a 44-year-old woman who developed protein-losing gastroenteropathy (PLGE) with hypoalbuminemia as the first manifestation of mixed connective tissue disease (MCTD). Albumin leakage from the stomach and intestinal tract was demonstrated by 99mTc-labeled human serum albumin scintigraphy. The patient's response to prednisolone therapy was insufficient; therefore, additional cyclosporin A (CsA) treatment was administered, and clinical remission was achieved. We concluded that although PLGE is a rare complication of MCTD, it may manifest as an initial clinical episode of MCTD. Furthermore, CsA can be a useful treatment option for refractory PLGE related to MCTD.

Markers for Guillain-Barré syndrome with poor prognosis: a multi-center study.

Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and ΔIgG in GBS are clinically relevant in Japan.

Suspected Adverse Effects After Human Papillomavirus Vaccination: A Temporal Relationship Between Vaccine Administration and the Appearance of Symptoms in Japan.

INTRODUCTION: In Japan, after receiving human papillomavirus vaccination, a significant number of adolescent girls experienced various symptoms, the vast majority of which have been ascribed to chronic regional pain syndrome, orthostatic intolerance, and/or cognitive dysfunction. However, a causal link has not been established between human papillomavirus vaccination and the development of these symptoms. OBJECTIVE: The aim of this study was to clarify the temporal relationship between human papillomavirus vaccination and the appearance of post-vaccination symptoms. METHODS: Between June 2013 and December 2016, we examined symptoms and objective findings in 163 female patients who had received human papillomavirus vaccination. We used newly defined diagnostic criteria for accurate inclusion of patients who experienced adverse symptoms after human papillomavirus vaccination; these diagnostic criteria were created for this study, and thus their validity and reliability have not been established. RESULTS: Overall, 43 female patients were excluded. Among the remaining 120 patients, 30 were diagnosed as having definite vaccine-related symptoms, and 42 were diagnosed as probable. Among these 72 patients, the age at initial vaccination ranged from 11 to 19 years (average 13.6 ± 1.6 years), and the age at appearance of symptoms ranged from 12 to 20 years (average 14.4 ± 1.7 years). The patients received the initial human papillomavirus vaccine injection between May 2010 and April 2013. The first affected girl developed symptoms in October 2010, and the last two affected girls developed symptoms in October 2015. The time to onset after the first vaccine dose ranged from 1 to 1532 days (average 319.7 ± 349.3 days). CONCLUSIONS: The period of human papillomavirus vaccination considerably overlapped with that of unique post-vaccination symptom development. Based on these sequential events, it is suggested that human papillomavirus vaccination is related to the transiently high prevalence of the previously mentioned symptoms including chronic regional pain syndrome and autonomic and cognitive dysfunctions in the vaccinated patients.