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Neuroinfection
Research paper
Insight into the frequent occurrence of dura mater graft-associated Creutzfeldt-Jakob disease in Japan
  1. Tsuyoshi Hamaguchi1,
  2. Kenji Sakai1,
  3. Moeko Noguchi-Shinohara1,
  4. Ichiro Nozaki1,
  5. Ichiro Takumi2,
  6. Nobuo Sanjo3,
  7. Atsuko Sadakane4,
  8. Yosikazu Nakamura4,
  9. Tetsuyuki Kitamoto5,
  10. Nobuhito Saito6,
  11. Hidehiro Mizusawa3,
  12. Masahito Yamada1
  1. 1Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
  2. 2Department of Neurosurgery, Nippon Medical School Musashi Kosugi Hospital, Kawasaki, Kanagawa, Japan
  3. 3Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
  4. 4Department of Public Health, Jichi Medical University, Shimotsuke, Japan
  5. 5Department of Prion Protein Research, Division of CJD Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan
  6. 6Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  1. Correspondence to Professor Masahito Yamada, Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan; m-yamada{at}med.kanazawa-u.ac.jp

Abstract

Objective More than 60% of patients worldwide with Creutzfeldt-Jakob disease (CJD) associated with dura mater graft (dCJD) have been diagnosed in Japan. The remarkable frequency of dura mater grafts in Japan may possibly contribute to the elevated incidence of dCJD, but reasons for the disproportionate use of this procedure in Japan remain unclear. We investigated differences between dCJD patients in Japan and those elsewhere to help explain the more frequent use of cadaveric dura mater and the high incidence of dCJD in Japan.

Methods We obtained data on dCJD patients in Japan from the Japanese national CJD surveillance programme and on dCJD patients in other countries from the extant literature. We compared the demographic, clinical and pathological features of dCJD patients in Japan with those from other countries.

Results Data were obtained for 142 dCJD patients in Japan and 53 dCJD patients elsewhere. The medical conditions preceding dura mater graft transplantation were significantly different between Japan and other countries (p<0.001); in Japan, there were more cases of cerebrovascular disease and hemifacial spasm or trigeminal neuralgia. Patients with dCJD in Japan received dura mater graft more often for non-life-threatening conditions, such as meningioma, hemifacial spasm and trigeminal neuralgia, than in other countries.

Conclusions Differences in the medical conditions precipitating dura mater graft may contribute to the frequent use of cadaveric dura mater and the higher incidence of dCJD in Japan.

  • Creutzfeldt-Jakob Disease
  • Infectious Diseases

https://doi.org/10.1136/jnnp-2012-304850

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    To date, 469 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported worldwide.1 The medical procedures resulting in transmission of CJD include cadaveric dura mater graft transplantation, neurosurgery, EEG needle use, corneal transplantation, human cadaveric pituitary hormone administration and blood transfusion.1 ,2 Nearly half of the iatrogenic CJD cases are associated with dura mater grafts.1 ,2 More than 60% (142 cases) of patients worldwide with dura mater graft-associated CJD (dCJD) are from Japan.1 ,2

    Although the exact number of patients receiving a dura mater graft is unknown, it has been estimated that cadaveric dura mater was used in approximately 20 000 Japanese patients annually during the 1980s.3 The extremely frequent use of dura mater grafts in Japan was much higher than in any other country,4 although the reasons for this remain unclear. In this study, we investigated differences between patients with dCJD in Japan and elsewhere to help explain the common use of cadaveric dura mater and the high incidence of dCJD in Japan.

    Methods

    Patients with dCJD in Japan

    We obtained data on patients with dCJD in Japan from previously reported nationwide surveillance studies, including a nationwide questionnaire survey carried out by the Japan CJD Surveillance Group to identify CJD patients.3 ,5–11 More detailed information was obtained by a member of the surveillance group who visited the referral hospital or conducted a post-mortem review of the case records of patients with a history of dura mater graft transplantation.5 Between 1996 and 1999, additional dCJD patients were identified.5 In April 1999, prospective surveillance of human prion disease by the Creutzfeldt-Jakob Disease Surveillance Committee was initiated,6–10 where each case of suspected prion disease was investigated by members of the committee in cooperation with CJD specialists in each prefecture. The study protocol was approved by the medical ethics committee of Kanazawa University and Tokyo Medical and Dental University.

    Patients with dCJD in countries other than Japan

    Literature searches of PubMed and Embase were conducted to identify patients with dCJD in countries other than Japan. Search terms included ‘Creutzfeldt-Jakob disease’ and ‘dura’ or ‘dural’. We selected articles that provided clinical information about patients in the English language; conference abstracts were excluded.

    Data analyses

    We analysed sex, age and calendar year at dura mater graft transplantation, medical conditions leading to the use of dura mater grafts, age and calendar year at CJD onset, incubation period between dura mater graft transplantation and CJD onset, polymorphism at codon 129 of the prion protein gene (PrP), the source of the dura mater, and pathological data. Patients with dCJD were classified into two different types, non-plaque and plaque.6 Non-plaque type dCJD shows the classic clinicopathological features of sporadic CJD (sCJD), while plaque-type dCJD is characterised by a relatively slow progression of neurological manifestations and the presence of amyloid plaques.6

    Statistical analysis

    Differences between Japan and other countries in sex distribution, use of Lyodura (B Braun, Melsungen, Germany; the dura mater graft material used in most patients with dCJD), medical conditions requiring dura mater graft transplantation, polymorphism at codon 129 of PrP and neuropathological type were analysed with Fisher's exact probability test. Differences between Japan and other countries in age at dura mater graft transplantation, age at CJD onset and incubation period between dura mater graft transplantation and CJD onset were analysed with the Mann–Whitney U test. Differences in incubation period as regards PrP codon 129 polymorphism were analysed with one-way analysis of variance. Statistical significance was defined as p<0.05. Statistical analyses were performed using SPSS V.19 (IBM, Armonk, New York, USA).

    Results

    As of June 2012, we had identified 142 patients with dCJD in Japan, and obtained from published articles information on 53 other patients diagnosed with dCJD elsewhere (see online supplementary e-references 1–31). The numbers of patients with dCJD in each country analysed in this study are shown in online supplementary table e-1. Except for Japanese patients, most cases of dCJD were in western countries.

    The clinical, genetic and pathological features were compared between patients in Japan and elsewhere (table 1). The proportion of patients undergoing dura mater graft transplantation because of medical conditions was significantly different between Japan and other countries (p<0.001). The most frequent precipitating medical condition was tumours in both Japan and other countries. Vascular diseases and hemifacial spasm or trigeminal neuralgia were more frequent as causes in Japan (vascular diseases: 28.9% and hemifacial spasm or trigeminal neuralgia: 18.3%) compared to other countries (6.1% and 2.0%, respectively). The mean age at receiving a dura mater graft in Japan was significantly higher than in other countries (p<0.001), as was the mean age at CJD onset (p<0.001). The incubation period between dura mater graft transplantation and CJD onset was not significantly different between Japan and other countries. We identified the source of cadaveric dura mater in 130 (91.5%) patients in Japan and 38 (71.7%) patients in other countries, and found that Lyodura is used significantly more often in Japan than in other countries (p<0.05). Besides Lyodura, Zenoderm (porcine) was used for a patient in the UK,12 Tutoplast for a patient in the USA13 and non-commercial dura mater for a patient in Italy.14 We obtained the results of the polymorphic PrP codon 129 analyses for 59 (41.5%) patients in Japan and 35 (66.0%) patients in other countries. The proportion of each genotype was significantly different between Japan and other countries (p<0.01), showing a higher frequency of the methionine homozygote in Japan. The distribution of pathology type (non-plaque or plaque) was not significantly different between Japan and other countries.

    View this table:
    Table 1

    Comparison of clinical, genetic and pathological features of patients with dura mater graft-associated CJD (dCJD) between Japan and other countries

    In order to clarify why age at dura mater graft transplantation in Japan was higher than in other countries, we examined each medical condition leading to the use of dura mater graft by age (table 2). Patients who underwent neurosurgery for tumours in Japan were approximately 12 years older than those in other countries. Patients who had surgery for hemifacial spasm or trigeminal neuralgia were approximately 50 years of age in both Japan and other countries.

    View this table:
    Table 2

    Age of patients in Japan and other countries with each medical condition at dura mater graft

    We analysed the types of tumours in these patients (table 3). In Japan, meningioma was the most frequent tumour requiring a dura mater graft (48.4%), followed by acoustic neurinoma (27.4%). In other countries, glioma was the most frequent tumour (34.6%), followed by meningioma (30.8%) and acoustic neurinoma (11.5%).

    View this table:
    Table 3

    Detailed diagnoses of patients who underwent neurosurgery for a tumour in Japan and in other countries

    We investigated the incubation period between dura mater graft transplantation and CJD onset in each PrP codon 129 genotype (table 4). The incubation period was not significantly different among these genotypes in the entire sample in Japan or in other countries.

    View this table:
    Table 4

    Incubation period from dura mater graft to the onset of Creutzfeldt-Jakob disease in each prion protein codon 129 genotype

    Patients in Japan received dura mater grafts from 1975 to 1993, and in other countries from 1969 to 1992 (figure 1A). The years from 1981 to 1987 were the highest risk period for dCJD following dura mater grafting in patients both in Japan and elsewhere (figure 1A). The year of CJD onset ranged from 1985 to 2009 in Japan and from 1978 to 2010 in other countries, while many patients developed dCJD from 1985 to 2006 in both Japan and elsewhere (figure 1B).

    Figure 1
    Figure 1

    Number of patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) by year of dura mater graft procedure (A) and by year of dCJD onset (B). (A) Patients in Japan underwent dura mater graft transplantation from 1975 to 1993, while patients in other countries underwent surgery from 1969 to 1992. Most patients in both Japan and other countries received dura mater grafts between 1981 and 1987. (B) Patients in Japan developed dCJD from 1985 to 2009, while those in other countries developed dCJD from 1978 to 2010. The majority of all patients developed dCJD between 1985 and 2008, while the number of diagnoses of new-onset dCJD continues to decrease in Japan and elsewhere.

    Discussion

    Our results show that patients with dCJD in Japan had several notable features compared to those in other (primarily western) countries: (i) cerebrovascular diseases and hemifacial spasm or trigeminal neuralgia were frequent reasons for dura mater graft transplantation; (ii) patients receiving a dura mater graft were older; (iii) Lyodura was more frequently used as grafted dura mater; and (iv) more patients were homozygous for methionine at PrP codon 129.

    The medical conditions precipitating dura mater graft were significantly different between Japan and other countries (table 1). The death rate from stroke was higher in Japan than in western countries, while that from coronary heart disease was lower.15 In addition, the incidence of stroke in Japan was the highest among developed countries in the 1960s.15 Although death rates from stroke in Japan decreased from 1960 to 1990, the incidence of stroke was still higher than that of coronary heart disease in Japan in 1980.15 ,16 Thus, the high incidence of stroke might have contributed to the high proportion of vascular diseases among the medical conditions leading to dura mater grafting in Japan. Hemifacial spasm or trigeminal neuralgia was also more frequent in Japan (18.3%) than in other countries (2.0%; table 1). In this diagnostic sub-group, microvascular decompression surgery was performed.17–19 According to a Japanese review of this procedure, use of Lyodura was recommended to patch the opened dura at the posterior fossa,20 which likely contributed to the frequent use of Lyodura by Japanese neurosurgeons.

    Patients receiving a dura mater graft in Japan were significantly older than those elsewhere (table 1). Tumours were the most frequent medical condition in both Japan and other countries (table 1), but age at surgery for tumours was approximately 12 years higher in Japan than in other countries (table 2). Previous epidemiological surveys indicated that the incidence of glioma in Japan was almost half of that in western countries,21 ,22 and that glioma rates were higher in white than in black, Latin and Asian subjects.23 In addition, although glioma was more frequent than meningioma in western countries, the reverse was true in Japan.21 The incidence of meningioma increased until 79 years of age, although a similar increase in the incidence of other types of tumour including glioma was not evident.21 Thus, the high incidence of meningioma in Japan may explain the older age at dura mater graft transplantation. Furthermore, the frequent use of dura mater grafting for hemifacial spasm or trigeminal neuralgia in Japan may also explain the higher age at dura mater graft transplantation, since age at surgery for these conditions was the highest among all surgeries for dura mater graft transplantation (table 2).

    Most patients (165/168 patients in total; 98.2%) in whom the source of cadaveric dura mater could be identified, received Lyodura (table 1). It was estimated that about 20 000 grafts were used each year in Japan during the 1980s,3 and only Lyodura was available for dura mater grafting in Japan from July 1973 to August 1985. The cumulative incidence rate of dCJD in Japan was 0.09% in neurosurgical patients receiving a dura mater graft between 1981 and 1987, with an incidence rate of 0.15% during the peak year of 1986.3 In contrast, less than 2500 patients received Lyodura in Australia and the cumulative risk of dCJD there was 0.20–0.23%.24 In addition, in the USA, it was estimated that less than 400 patients per year received Lyodura,4 and the cumulative incidence rate of dCJD there was 0.11% between 1981 and 1987. These results indicate that it is unlikely that the Lyodura used in Japan was more contaminated with abnormal prion protein than that used in other countries.

    Regarding the polymorphism at codon 129 of PrP in dCJD, the distribution in Japan and other countries is similar to that in sCJD, as a recent study reported.1 In the general Japanese population, the frequency of methionine homozygotes is higher and that of other genotypes lower (methionine homozygotes: 0.92; methionine/valine heterozygotes: 0.08; valine homozygotes: 0) compared to European populations (methionine homozygotes: 0.37–0.49; methionine/valine heterozygotes: 0.42–0.49; valine homozygotes: 0.08–0.15).25–31 Although homozygosity at PrP codon 129 predisposes to sporadic and iatrogenic CJD,25 ,32 ,33 the cumulative incidence rate of dCJD in Japan (0.09%) was no higher than that in Australia (0.20–0.23%)24 or the USA (0.11%), as mentioned previously. Thus, the frequent occurrence of methionine homozygotes in the general Japanese population might not explain many cases of dCJD in Japan.

    The genotype of the polymorphism at PrP codon 129 influences the clinicopathological phenotypes of dCJD, and all patients with plaque-type dCJD ever reported have been methionine homozygotes.6–8 An animal study showed that plaque-type dCJD pathology could be caused by cross-sequence transmission of sCJD-VV2 prions to individuals from patients with the methionine homozygote.34 Furthermore, another animal study showed that sCJD-MV2 prions could also induce plaque-type dCJD pathology (T Kitamoto, unpublished data, April 2013). The proportion of sCJD-VV2 and sCJD-MV2 patients among all cases of sCJD in Germany, where Lyodura was produced, is 24.3%.35 The frequency of plaque-type dCJD in Japan (45.2%) as reported in the current study seems inordinately high. One possible reason is that the number of patients in whom pathological type could be confirmed was relatively small in Japan (21.8%) and atypical cases (plaque type) underwent autopsy more frequently than typical cases (non-plaque type). In our previous reports which included clinically diagnosed cases, about one-third of patients with dCJD may have the plaque type,6 ,8 which is similar to the proportion of sCJD-VV2 and sCJD-MV2 in Germany.

    Although age at dura mater graft transplantation and the distribution of the PrP codon 129 polymorphism were different between patients in Japan and in other countries, the incubation period between dura mater graft transplantation and CJD onset was similar among all patients (table 1). Interestingly, although the incubation period was not significantly different among the three codon 129 genotypes in dCJD patients in the current study (table 4), homozygosity has been reported to be associated with a shorter incubation period in human growth hormone-associated CJD.36

    In both Japan and other countries, dura mater graft transplantation from 1981 to 1987 was associated with the highest risk of dCJD (figure 1A). Until May 1987, cadaveric dura mater was treated with 10% H2O2 for 24 h and irradiated with gamma rays (25 kGy). However, after May 1987, when the first case of dCJD was reported, the manufacturer included treatment with 1N NaOH for 1 h to reduce the risk of CJD transmission.37 ,38 Nevertheless, a small number of patients with dCJD received a dura mater graft in or after 1988 in both Japan and other countries (figure 1A). Most patients developed CJD between 1985 and 2006, while the number of new-onset dCJD cases has decreased since approximately 2002 in Japan and elsewhere (figure 1B).

    The high incidence of stroke and the frequent use of a dura mater graft for hemifacial spasm or trigeminal neuralgia may both play a role in the markedly higher use of dura mater graft procedures in Japan compared to elsewhere. In addition, patients in Japan may have received Lyodura more frequently as it was covered by national health insurance.39 Furthermore, results from the present study show that patients with dCJD in Japan received a dura mater graft more often for non-life-threatening conditions than patients in other countries. Although surgery for a tumour was the most frequent reason for a dura mater graft in Japan and elsewhere (table 1), the proportions of meningioma and acoustic neurinoma were higher and that of glioma lower in Japan compared to other countries (table 3). Meningioma and acoustic neurinoma normally have a good prognosis, while glioma is sometimes fatal. Furthermore, in Japan many patients received a dura mater graft following microvascular decompression surgery for hemifacial spasm or trigeminal neuralgia (table 1), and most survived until they developed CJD in old age.

    Several limitations should be considered when reviewing the results of this study. First, data on patients with dCJD in other countries was limited to information available in the extant literature. Second, the method of obtaining patient information differed in Japan from that in other countries. However, information from most journal articles was detailed enough for comparison of data on patients from Japan with data from other countries.

    In conclusion, this study elucidated several important differences in the dura mater graft patient population in Japan compared to other countries. The different medical conditions precipitating dura mater graft transplantation might have increased the use of Lyodura in Japanese patients, and patients in Japan may be more likely to have survived until CJD developed because they received a dura mater graft more often for non-life-threatening conditions than patients in other countries.

    Acknowledgments

    The authors thank members of the Creutzfeldt-Jakob Disease Surveillance Committee in Japan and Creutzfeldt-Jakob disease specialists and physicians in the prefectures as well as the patients with Creutzfeldt-Jakob disease and their families for providing important clinical information. We would also like to thank Dr Takeshi Sato for insightful comments.

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    Supplementary materials

    • Supplementary Data

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    Footnotes

    • Contributors TH: study concept and design, analysis and interpretation of data, statistical analysis, drafting/revising the manuscript; KS, MN-S, IN, AS: drafting/revising the manuscript; IT, NSan, YN, TK, NSai: acquisition of data, drafting/revising the manuscript; HM: acquisition of data, drafting/revising the manuscript, study supervision; MY: study concept and design, acquisition of data, drafting/revising the manuscript, study supervision.

    • Funding This work was supported by a grant-in-aid from the Research Committee of Prion Disease and Slow Virus Infection, the Ministry of Health, Labour and Welfare of Japan (TH, KS, NSai, HM, MY), and a grant-in-aid from the Research Committee of Surveillance and Infection Control of Prion Disease, the Ministry of Health, Labour, and Welfare of Japan (IT, NSan, YN, TK, NSai, HM, MY).

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the institutional ethics committee at Kanazawa University and Tokyo Medical and Dental University.

    • Provenance and peer review Not commissioned; externally peer reviewed.