CJD 두 번째 사례 확인

- 추적가능한 모든 CJD 환자에 대해 뇌경막 이식 여부 확인 등

추적조사 실시 예정 -

출처 : 2011년 12월 8일 질병관리본부
http://www.cdc.go.kr/

□ 질병관리본부(본부장:전병율)는 산발성 CJD로 신고되었던 환자의 병력조사를 통해 뇌경막 이식 후 발생한 것으로 추정되는 의인성 CJD〔의인성(醫因性) 크로이츠펠트-야콥병(Iatrogenic Creutzfeldt-Jakob Disease ; 이하 iCJD〕* 사례를 추가 확인하였다고 밝혔다.

□ 금번 iCJD 사례는 수도권 소재 병원으로부터 2011년 7월 산발성 CJD로 진단되어 법정감염병신고체계를 통해 신고된 48세 남성으로, 1988년 5월 외상에 의한 뇌실질 출혈에 의해 수술한 병력이 있으며, ‘뇌경막 이식(dura-graftd)’ 및 Lyodura에 대한 기록을 의무기록에서 확인하였다.

○ 일반적으로 뇌실질 출혈에 의한 수술 시 뇌경막 이식은 매우 드문 경우이며, 동 사례에서 환자에게 이식된 뇌경막의 생산이력은 확인할 수 없었음

한림대 김윤중 교수팀이 대한의학회에서 발행하는 영문학술지 [J Korean Med Sci] 2011년
11월호에 뇌경막 이식 수술 후 23년이 지난 다음 iCJD로 사망한 한국 최초의 보고 사례인
54세 여성 사망자에 관한 case report입니다. 전문은 첨부파일을 보세요.

Dura Mater Graft-Associated Creutzfeldt-Jakob Disease: The First Case in Korea
Hye Lim Kim,1 Ju Young Do,1 Han Jeong Cho,2 Yong-Chul Jeon,2 Seok Joo Park,2 Hyeo Il Ma,1 Jun Ho Song,3 Yul Lee,4 Hyun Choi,5 Kyung Chan Choi,6 Yong Sun Kim,2,7 Inga Zerr,8 Kai Kallenberg,9 and Yun Joong Kim1,2
1Department of Neurology, Hallym University College of Medicine, Hallym University, Anyang, Korea.
2ILSONG Institute of Life Science, Hallym University, Anyang, Korea.
3Department of Neurosurgery, Hallym University College of Medicine, Hallym University, Anyang, Korea.
4Department of Radiology, Hallym University College of Medicine, Hallym University, Anyang, Korea.
5Department of Anesthesiology and Pain Medicine, Hallym University College of Medicine, Hallym University, Anyang, Korea.
6Department of Pathology, Hallym University College of Medicine, Hallym University, Chuncheon, Korea.
7Department of Microbiology, Hallym University College of Medicine, Hallym University, Chuncheon, Korea.
8Department of Neurology, National Reference Center for TSE, Goettingen, Germany.
9Department of Neuroradiology, University Medicine, Georg-August-University, Goettingen, Germany.
Address for Correspondence: Yun Joong Kim, MD. ILSONG Institute of Life Science, Hallym University, Department of Neurology, Hallym University Sacred Heart Hospital, Rm 607, ILSONG Bldg, 170 Gwanpyong-ro, Dongan-gu, Anyang 431-060, Korea. Tel: +82.31-380-1666, Fax: +82.31-381-8820, Email: yunkim@hallym.ac.kr
Received April 19, 2011; Accepted September 05, 2011.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Since 1987, dura mater graft-associated iatrogenic Creutzfeldt-Jakob disease (dCJD) has been reported in many countries. We report the first case of dCJD in Korea. A 54-yr-old woman, who underwent resection of the meningioma in the left frontal region and received a dura mater graft 23 yr ago presented with dysesthesia followed by psychiatric symptoms and ataxia. Her neurological symptoms rapidly progressed to such an extent that she exhibited myoclonus, dementia, and pyramidal and extrapyramidal signs within 8 weeks. The 14-3-3 protein was detected in her cerebrospinal fluid; however, an electroencephalogram did not reveal characteristic positive sharp wave complexes. Diffusion-weighted magnetic resonance images, obtained serially over 64 days, revealed the rapid progression of areas of high signal intensity in the caudate nucleus and cingulate gyrus to widespread areas of high signal intensity in the cortex and basal ganglia. Pathological examination of brain biopsy specimens confirmed the presence of spongiform changes and deposition of prion protein in the neurons and neuropils.

Update: Creutzfeldt-Jakob disease associated with cadaveric dura mater grafts–Japan, 1978-2008.

출처 : http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5248a3.htm

In 1997, a nongovernment surveillance group for Creutzfeldt-Jakob disease (CJD) in Japan supported financially by the Ministry of Health and Welfare* (MHW) reported 43 cases of CJD associated with receipt of cadaveric dura mater grafts (1). In all but one case, the most probable vehicle of transmission was a single brand of dural graft (LYODURA^® [B. Braun Melsungen AG, Melsungen, Germany]) produced before May 1987. As of March 2003, ongoing surveillance in Japan had identified an additional 54 dura mater graft–associated cases. This report summarizes the investigation of the 97 cases, which indicated that during 1983–1987, the estimated minimum risk for CJD within 17 years of receipt of the implicated product in Japan was approximately one case per 1,250 grafts. No cases have been reported among patients who received their first dural graft after 1991; however, because of the long latency period between graft placement and symptom onset, additional cases of graft-associated CJD are likely to be reported.

During 1996–2003, cases of CJD were identified in Japan by using 1) a mail survey of neurologic, psychiatric, and neuropathologic institutions (overall response rate: 74%) (1) and 2) subsequent reporting of CJD patients by clinicians to MHW. During this period, 97 cadaveric dura mater graft–associated CJD cases were identified. A case of dura mater–associated CJD was defined as a case in which a patient received a cadaveric dura mater graft and subsequently had CJD diagnosed by a physician and reviewed and accepted as CJD by a surveillance panel of neurologists.

The 97 CJD patients had illness onset during September 1985–April 2002 (Figure 1). Median age at onset was 58 years (range: 15–80 years); mean age was 55 years. Mean age at onset was younger than that reported for sporadic CJD in Japan (66 years). A total of 58 (60%) patients were female. Neuropathologic confirmation of CJD diagnosis was obtained for 20 (21%) patients; 65 (84%) of the other 77 patients with physician-diagnosed CJD had an electroencephalogram with a periodic synchronous discharge pattern consistent with CJD.

All 97 patients received dura mater grafts during 1978–1991 (Figure 2). Three patients received more than one dural graft during this period, including one patient reported previously (1). In all three cases, the first graft was considered to be the source of infection. Medical conditions leading to the use of dural grafts in these patients included tumor (n = 46), brain hemorrhage (n = 14), Jannetta procedure for facial palsy (n = 13) and for trigeminal neuralgia (n = six), intracranial aneurysm (n = eight), unspecified anomalies (n = five), hematoma (n = three), injury (n = one), and ossification of the spinal posterior longitudinal ligament (n = one).

Latency periods ranged from 14 months (receipt in 1987 and onset in 1989) to 275 months (receipt in 1978 and onset in 2001). The median and mean latency periods were 122 and 125 months, respectively. A total of 93 patients received dural grafts during 1978–1987. In 1987, the manufacturer revised collection and processing procedures for the implicated product to reduce the risk for CJD transmission. Four patients received grafts during 1988–1991. No cases have been reported among patients who received their first dural graft after 1991. A total of 86 (89%) patients were documented to have received LYODURA^®; the brand name of dural graft was unknown for 11 patients. A total of 81 (84%) of the 97 patients received their dural grafts during 1983–1987, during which time an estimated 100,000 patients received LYODURA^® grafts in Japan. All 81 patients died from CJD within 17 years after receipt of the grafts. Lot numbers of the dura mater grafts used for the 97 patients could not be identified. As of September 2003, five additional cases were under investigation in Japan for suspected dural graft–associated CJD.

Reported by: Y Nakamura, MD, M Watanabe, MD, K Nagoshi, MD, Dept of Public Health, Jichi Medical School, Minamikawachi; T Kitamoto, MD, Dept of Neuropathology, Tohuku Univ School of Medicine, Sendai; T Sato, MD, Kohnodai Hospital, National Center for Neurology and Psychiatry, Ichikawa; M Yamada, MD, Dept of Neurology, Kanazawa Univ Graduate School of Medical Science, Kanazawa; H Mizusawa, MD, Dept of Neurology, Tokyo Medical and Dental Univ School of Medicine, Tokyo, Japan. R Maddox, MPH, J Sejvar, MD, E Belay, MD, LB Schonberger, MD, Div of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC.

Editorial Note:

Dural graft–associated CJD cases continue to be identified in Japan. The estimated minimum risk within 17 years after receipt of LYODURA^® is approximately one case per 1,250 recipients. The precise number of dura mater grafts used in Japan is unknown, but an estimated 20,000 grafts per year might have been used during 1983–1987. The widespread use of LYODURA^® during neurosurgical procedures in Japan is the most probable source of the unusually high number of dural graft–associated CJD cases in Japan (2). Dural graft recipients have symptom onset at a younger age compared with age at onset in sporadic cases of CJD in Japan. The identification of additional cases over time has resulted in an expected increase in the latency period between dural graft placement and symptom onset. The mean and range for this latency of CJD from contaminated grafts is unknown, but the upper limit now exceeds 22 years. The occurrence of new cases, the increase in the mean and range of the latency period, and the identification of suspected cases under investigation all suggest that this outbreak is ongoing.

No cases in Japan were reported to be related to receipt of a dural graft other than LYODURA^®. For 11 cases, the manufacturer brand name was unknown. Although LYODURA^®, or in one case either LYODURA^® or a dural graft from another manufacturer (Tutoplast^® [Pfrimmer-Viggo GmbH & Co., Erlangen, Germany]), was suspected in these cases, documentation of a specific source was unavailable. Four patients received dural grafts after collection and processing procedures were revised by the manufacturer in 1987, but whether the implicated dural grafts were LYODURA^® produced before 1987 is unknown. That all LYODURA^®-associated CJD cases to date occurred among patients who received grafts before 1992 suggests that all implicated grafts likely were processed before 1987; the implicated product’s expiration date is 5 years after processing.

LYODURA^® never was produced by the manufacturer for distribution in the United States, and relatively few LYODURA^® grafts were used in this country. In May 1987, after identification of the first dural graft–associated CJD case in a U.S. patient who had received the implicated product, the manufacturer revised its procedures for collecting and processing dura mater grafts to reduce the risk for CJD transmission (e.g., by discontinuing the commingling of dura and disinfecting them with sodium hydroxide) (3,4). Subsequently, numerous other dura mater graft–associated cases were identified worldwide; nearly all patients had received the implicated product, including one additional U.S. patient. In 1997, the report of 43 cases of dura mater graft–associated CJD in Japan represented the largest cluster of such cases in any one country (1).

In one of the CJD cases reported in Japan, the implicated graft was used in a spinal (not an intracranial) procedure. This case suggests that transmission from contaminated dura might occur in areas of the neuraxis outside of the cranial vault.

In 1997, the Food and Drug Administration’s Transmissible Spongiform Encephalopathy Advisory Committee (TSEAC) recognized that the use of human dura mater in the United States carries an inherent risk for transmitting CJD. However, the committee recommended that the use of such grafts be left to the discretion of the treating neurosurgeon, provided that the human dura mater is procured and processed according to appropriate safety measures (5). In 1997, an estimated 4,500 dural grafts were distributed for use in the United States (6). After the TSEAC recommendations were issued, the number of dural grafts distributed for use in the United States declined to an estimated 900 grafts in 2002 (B.E. Buck, M.D., Miami Tissue Bank, personal communication, 2003).

The cases described in this report indicate that recipients of contaminated dura mater grafts might remain at risk for CJD for >22 years after receiving grafts. CDC continues to conduct surveillance for cases of CJD in the United States. Patients with a rapidly progressive dementia consistent with CJD and a history of dural graft implantation should be reported through local or state health departments to CDC, telephone 404-639-3091.

References

1. CDC. Creutzfeldt-Jakob disease associated with cadaveric dura mater grafts—Japan, January 1979–May 1996. MMWR 1997;46:1066–9.
   
2. Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55:1075–81.
   
3. Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob disease probably acquired from a cadaveric dura mater graft. J Neurosurg 1988;69:766–9.
   
4. CDC. Epidemiologic notes and reports update: Creutzfeldt-Jakob disease in a patient receiving a cadaveric dura mater graft. MMWR 1987;36:324–5.
   
5. U.S. Food and Drug Administration. Class II Special Controls Guidance Document: Human Dura Mater; Draft Guidance for Industry and FDA. Rockville, Maryland: U.S. Food and Drug Administration, 2002.
   
6. Solomon R. Methods used in human cells, tissues, and cellular and tissue-based product (HCT/P) establishments. Available at http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3969t2.pdf.

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Page converted: 12/4/2003

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About CJD and CJD Support Network in Japan February of 2006

CJD Support Network in Japan


http://www.cjd-net.jp/EnglishPage.htm

Creutzfeldt-Jakob Disease (CJD) is one of intractable and fatal diseases caused by an infectious agent called prion. There are four types of CJD: Sporadic, Familial, Variant and Iatrogenic. Sporadic CJD is said to occur in one out of one million people. Variant CJD is thought to occur in relation to Bovine Spongiform Encephalopathy(BSE). Outbreak of BSE and Variant CJD is reported from many countries, especially the UK.

Japanese government researched whether there was Variant CJD in Japan in 1996. Consequently, in Japan, however, none of variant CJD has yet been reported from 1996 until 2004. Instead, until February 2006, 117 iatrogenic CJD patients due to human dura mater grafts have been reported. This figure of dura mater victims is abnormally high in comparison with other countries.

The main reason for this is thought to be the results of using many prion contaminated human dura mater named Lyodura produced by B.Braun in Germany between 1973 and 1996. B.Braun had been adopting gamma radiation for the sterilisation of Lyodura since 1973. This method, however, was found to be ineffective for the sterilisation of CJD agent by Gibbs, Gajdusek and others in 1978. In spite of this fact, this company continued to produce Lyodura. In addition to adopting ineffective sterilisation method and not identifying CJD donor, B.Braun produced Lyodura by “pooling”. This was primarily due to the packaging technique by B. Braun. In this process, 600 sheets of duras were packaged together in one plastic bag regardless of the duras condition. As the results, healthy duras were thought to be contaminated with prion-infected duras.

In 1987, the FDA in the US prohibited the use of Lyodura because the first CJD patient was reported after using Lyodura. However the Japanese government did not follow this measure and did not take any step to prohibit selling Lyodura.

In Japan, CJD victims filed suits against the Japanese government, B.Braun and BSS, the importer in Ohtsu and Tokyo since 1996. In March 2002, after 6 years of litigations, an historical out- of-court settlement was reached. The defendants apologised to CJD victims. By 2006, 71% of plaintiffs have received compensation from the settlement. The litigation is not yet finished as of February 2006.


The CJD Support Network(CS Net) of Japan was established on June 2002. Volunteers and victims themselves, medical workers, researchers, lawyers support this Network. CS Net provides information, support and assistance for any forms of CJD to patients and their families in Japan. CS Net also promotes research, education and awareness concerning CJD problems. CS Net has been getting financial support by the Japanese Government from the fiscal year of 2003 as one of the results of the settlement. In Japan, there has been 22 cases of BSE reported as of January 2006, and regrettably, one Variant CJD case has been reported in February 2005.

Public Health

출처 : http://www.mja.com.au/public/issues/180_04_160204/bro10566_fm.html

Creutzfeldt–Jakob disease (CJD) is a fatal, transmissible, neurodegenerative disorder belonging to the group known as the transmissible spongiform encephalopathies (TSEs). CJD can occur without explanation (sporadic), secondary to mutations in the prion protein gene (PRNP), or as a complication of medical treatment using contaminated therapeutic agents or equipment (iatrogenic). Although corneal grafts and neurosurgical equipment have been associated with disease transmission, the most common causes of iatrogenic CJD have been treatments involving human-derived cadaveric pituitary hormones or dura mater.1

Creutzfeldt–Jakob disease and Lyodura

The first identified case of CJD in a dura mater recipient was reported in the United States in early 1987.2 In response, the US Food and Drug Authority issued a safety alert in April 1987, seeking immediate discontinuation of use of the identified dura mater batch (Lyodura batch #2105).3 A second patient with CJD linked to Lyodura was detected in New Zealand in 1988,4 but the specific batch could not be identified. This has remained a frequent difficulty when tracing contamination sources.

As of January 2003, over 120 CJD cases related to dura mater use had been detected globally, with 97 in Japan.5 These cases were predominantly associated with Lyodura, a commercial product produced since 1969 by B Braun Melsungen AG (based in Germany). Only a few reports suggest the possibility of CJD after use of dura mater from other commercial or non-commercial sources.6-8

Lyodura consists of lyophilised, irradiated human dura mater sourced post mortem. Additional processing with immersion in a solution of sodium hydroxide (1 M) was instituted in 1987, with a noticeable reduction in Lyodura-related cases thereafter.9 Lyodura has been used in a number of countries, including Australia, Japan, Canada, the United States and the United Kingdom, mainly in neurosurgery, but also in orthopaedic, otological, dental, urological, gynaecological and cardiac procedures (Box 1) (Dr L Schonberger, Assistant Director, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga, USA, personal communication).

Most cases of CJD associated with dura mater have occurred in Japan. In 1996, in response to the growing incidence, a survey was undertaken of Lyodura use in almost 3000 Japanese healthcare institutions. This estimated that up to 100 000 people received Lyodura grafts between 1983 and 1987,9,10 and up to 220 000 between 1979 and 1991 (out of a total of 260 000 who received dura mater grafts). Use of these grafts greatly declined after 1991 but may have continued until 1997.11,12 Assuming that all cases of CJD associated with dura mater were a consequence of Lyodura use, the overall risk of Lyodura-associated CJD in Japan is approximately 0.04%.5

Estimating Lyodura use and risk in Australia

Lyodura was approved by the Australian Therapeutic Goods Administration for importation and use in Australia in 1972. The product licence was withdrawn in early May 1987, shortly after recognition of the first case of CJD linked to Lyodura use.

To date, five cases of CJD have been epidemiologically linked to neurosurgical use of Lyodura in Australia. Their clinical features have already been described13-15 and are summarised in Box 2. Patient 1 presented in 1987, about 5 years after implantation of Lyodura. The longest incubation period was in Patient 4, who presented in 1999 after an incubation period of almost 17 years.14 The most recent (fifth) patient died in 2000. Patients 1, 2 and 4 were exposed in 1982, while Patients 3 and 5 were exposed in 1985 and 1986, respectively.

A number of studies have attempted to determine the number of people exposed to Lyodura in Australia. We collated the available information and undertook further enquiries, as a basis for estimating the risk of Lyodura-associated CJD in this country (Box 3).

Implications for Australia

Quantifying past use of Lyodura in Australia relies on data that cannot be fully confirmed. Initial estimates by the Commonwealth Department of Health and Ageing in discussion with the Therapeutic Goods Administration placed an upper limit of between 5000 and 10 000 individuals potentially exposed to Lyodura. However, from the results reported here, the true number is likely to be much smaller — probably fewer than 2500. If so, the risk of Lyodura-associated CJD is higher in Australia (0.20%–0.23%) than in other countries that have undertaken similar investigations, such as Japan.

Although the risk of Lyodura-associated CJD in Japan has appeared to fluctuate over time, two relatively stable features are a peak in contaminated grafts between 1983 and 1987, and the paucity of Lyodura-associated cases after 1987, when the manufacturer instituted effective decontamination of the tissue with a 1 M solution of sodium hydroxide.1,5,9 Ninety-seven cases associated with dura mater had been recognised to 2003,5 with predictions that further cases are likely until 2020, and that final numbers may reach 160.12 Acknowledging a total of 220 000 people exposed to Lyodura, and assuming all CJD associated with dura mater was associated with Lyodura (which is reasonable based on evidence published to date),11 then the cumulative overall risk of CJD from Lyodura in Japan is currently around 0.04% (95% CI, 0.03%–0.05%) (Box 4). Estimated risk in Australia is much higher — 0.20% to 0.23% (95% CIs, 0.06%–0.47% and 0.07%–0.53%, respectively). With the same assumptions, the risk of CJD in the higher-risk period in Japan (1983–1987) is about 0.08% (95% CI, 0.06%–0.10%), while that in Australia (1982–1986) is 0.43% (95% CI, 0.14%–0.99%). Notwithstanding the need for certain assumptions to facilitate these comparisons, the risk in Australia appears about five times greater than the analogous point estimates of risk in Japan. The reality of the differences is further supported by the lack of overlap between the confidence intervals of the calculated estimates.

Nevertheless, the risk of CJD associated with Lyodura in Australia is well below the risk associated with exposure to human-derived pituitary growth hormone (hGH) in France (Box 4). As of 1999, 55 cases of CJD had been linked to French-derived hGH, from a cohort of 1361 patients, representing an attack rate of about 1 in 25 recipients (4.0%).17 A more recent report suggested the risk could be much higher, at 81 per 1361 (about 6.0%).18

The reason for the higher estimated risk of Lyodura-associated CJD in Australia compared with Japan is not known. Perhaps most likely is chance receipt of a relatively high percentage of contaminated batches of Lyodura and use of multiple pieces of Lyodura per patient in Australia, although the latter is contrary to anecdotal recollections of Australian neurosurgeons. Alternatively, the difference may reflect better case ascertainment in Australia, which, in contrast to Japan, had an established comprehensive, prospective, national surveillance program for CJD, with international comparisons of incidence rates for sporadic CJD attesting to the adequacy of case ascertainment.14

Another potential explanation is genetic difference between the populations of the two countries. For example, homozygosity for methionine at codon 129 of the PRNP gene appears to predispose to iatrogenic CJD.1 However, contrary to expectations, this homozygosity appears more common in the Japanese population (about 92%) than in occidental populations (about 37%).19

Finally, the differences in risk may reflect greater use of Lyodura in Japanese patients with malignancies, whose survival was shorter than the lengthy incubation periods typical of TSEs, or in non-neurosurgical applications, with attendant lower transmission efficiency. Japanese studies suggest that Lyodura-related transmissions have been essentially restricted to neurosurgical procedures,10,11 and our comparative risk analysis was predicated on the assumption that most Lyodura was used in these procedures in both countries. Although some Lyodura was most likely used in non-neurological procedures, the proportion is impossible to quantify in different countries, leaving uncertainty about our risk comparisons.

In addition to neurosurgery and the non-neurological applications identified by Australian surveys, additional uses of Lyodura have been reported in the US (Box 1). Cases of CJD have been linked epidemiologically to Lyodura used in the embolisation of the external carotid artery for treating a nasopharyngeal angiofibroma,20 as well as dura mater used to embolise intercostal arteries before thoracic surgery.7 This reinforces the likelihood that non-neurosurgical use of Lyodura can result in transmission.10 Therefore, risk of Lyodura-associated CJD linked to non-neurosurgical uses appears a genuine possibility, which may be very difficult to identify epidemiologically, given the often deficient state of medical records.

The inability to clearly identify surgical uses of Lyodura, especially non-neurosurgical uses, also raises the possibility of secondary iatrogenic transmissions from Lyodura-treated patients during an extended preclinical or incubation phase. Animal models clearly support the possibility of lengthy presymptomatic periods (which may even exceed the lifespan of hosts) during which transmission is possible.21-24 Generally, infection control and other guidelines focus on the need to limit transmission risk through identifying patients who received Lyodura during neurosurgery, and do not include guidance on risk associated with other surgical applications. This approach may need to be reconsidered based on studies such as ours.

1: Non-neurosurgical uses of Lyodura in the United States*

• 
  

  Development of ligaments to stabilise shoulder joints



• 
  

  Replacement of the tracheal wall



• 
  

  Covering pleura defects



• 
  

  Securing bronchial stumps



• 
  

  Repair of pericardium



• 
  

  Repair of diaphragm defects (traumatic or congenital)



• 
  

  Arthroplasties of the elbow



• 
  

  Reinforcement of fascia in abdominal hernias



• 
  

  Reinforcement of tendons or ligaments



• 
  

  Plastic enlargement of the urinary bladder



• 
  

  Other miscellaneous surgical uses

---

* Based on information from the US National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga.

2: Features of the five Australian cases of Creutzfeldt–Jakob disease associated with Lyodura

3: Studies of Lyodura use in Australia

Survey of hospitals in Victoria In 1987, after notification of the first patient with Lyodura-associated Creutzfeldt–Jakob disease (CJD), the Victorian Department of Community Services and Health surveyed use of Lyodura in all private and public hospitals in Victoria. Five hospitals responded, out of an uncertain total number. They reported use of 40 Lyodura grafts in 1985–1986 and 36 in 1986–1987, all in neurosurgical procedures (unpublished data). Survey of neurosurgeons In 1995, the Neurosurgical Society of Australasia surveyed 100 neurosurgeons (comprising all practising neurosurgeons and retired surgeons still on their register) about use of Lyodura or other dura mater during their practice lifetimes.13 This survey was also used to assess the feasibility of tracing recipients. Sixty-five neurosurgeons responded (response rate, 65%); 35 of these (54%) had used dura mater grafts in cranial or spinal procedures at some time, with 34 having used Lyodura. Eleven of the 34 (32%) believed that they could identify over 90% of recipients from their records, nine (27%) that they could identify 50%–90%, and 14 that they could identify fewer than 50%. The survey could not determine the precise amount of Lyodura or specific batches used, nor the number of procedures involving Lyodura. However, all three cases of Lyodura-related CJD recognised before the survey were in patients of respondents who reported using Lyodura. The remaining two confirmed cases presented after this survey. Survey of non-neurosurgical use In 2001, the Department of Health and Aged Care (DHAC) undertook a survey through the Royal Australasian College of Surgeons (RACS) to assess non-neurosurgical use of Lyodura. Over 5000 practising and retired surgeons across 15 surgical specialties were asked about use of dura mater grafts (and specifically Lyodura) over their practice lifetimes. Responses were received from 172 surgeons (response rate, 3.4%). This very poor response rate precluded meaningful analysis. However, the survey confirmed that Lyodura had been used in otorhinolaryngological procedures, such as tympanoplasty, myringoplasty and mastoidectomy, with respondents reporting use of about 100 grafts in such applications. Given the poor response rate, time elapsed since the product was withdrawn, recall bias and retirement of surgeons during this time, this may be a significant underestimate of use in non-neurosurgical applications. This possibility is supported by the US Centers for Disease Control and Prevention report that up to 20% of Lyodura use in the US was in non-neurosurgical applications (Dr L Schonberger, personal communication). Quantification study In 2002, the Department of Health and Ageing, in conjunction with the Australian National Creutzfeldt–Jakob Disease Registry, undertook a study to quantify Lyodura use in Australia and to determine the types of procedures in which it was used, as a basis for estimating the risk of Lyodura-associated CJD. Methods: The Registry has ethical approval for its surveillance methods and activities from the University of Melbourne Human Research Ethics Committee. As well as collating results of previous surveys, we asked the manufacturer of Lyodura, B Braun Melsungen AG, about supplies of Lyodura to Australia, including batch numbers and the total quantity of Lyodura imported into and distributed within the country. We also contacted other potential sources of information on Lyodura use, including the Australian Therapeutic Goods Administration and the Health Insurance Commission. Results: Braun Melsungen indicated that: Before 1978, about two to five packs of Lyodura per month were distributed nationally. Between 1978 and 1982, 600 packs were distributed in mainland Australia. Between 1983 and 1987, 1278 sheets were distributed for use in mainland Australia. According to the 1985 Braun catalogue for Australia, Lyodura was available in a range of sizes, with some packs containing up to 6 pieces. The manufacturer indicated that packs sold in Australia contained either one large sheet or two smaller sheets. Its information suggests that generally the larger sheets were used for neurosurgery, and smaller sheets for other surgical applications. The single-sheet packs outsold the double-sheet packs by about three to one. Braun did not supply documentary verification of this information. Neither the Australian Therapeutic Goods Administration nor the Health Insurance Commission could furnish further information on Lyodura use. Based on the manufacturer’s information, and assuming that all distributed product was used, then a maximum of 750 sheets may have been used in Australia between 1978 and 1982. Before 1978, assuming the same distribution of pack sizes, then 180–450 sheets may have been distributed. These data suggest a total use in Australia of 2208 to 2478 Lyodura grafts. Assuming maximum and equal annual use, then about 1172 Lyodura grafts were used in the higher-risk period 1982–1986. Risk estimation: Risk estimates for Lyodura-associated CJD were based on data from the manufacturer alone, as survey results were very incomplete, and Lyodura use reported in the surveys was likely to be encompassed by the manufacturer’s information. Risk estimates were calculated from the total number of individuals exposed and the number of CJD cases detected over defined periods, with 95% confidence intervals calculated using the Poisson distribution. Based on the five Lyodura-associated CJD cases detected to 2003, the attack rate ranged from 1 in 496 patients who received Lyodura (0.20%) to 1 in 442 (0.23%) (Box 4), depending on whether a higher or lower estimate of pre-1978 use was used. In the higher-risk period (1982–1986), the attack rate may have been as high as 1 in 234 (0.43%). These calculations were based on exposure through any surgical application of Lyodura, assuming that only one sheet was used per patient and that all distributed product was used. The latter fact cannot be verified, and previous reports suggest that not all distributed Lyodura was necessarily used.16 These attack rates are therefore likely to be underestimates. The attack rates after neurosurgery in Australia may be even higher, depending on the proportion of Lyodura that was used in this type of surgery. Should the proportion be close to 60% of the total product used (as suggested by the manufacturer) or 80% (as found in the US), the overall neurosurgical attack rate may be as high as 1 in 397 (ie, 80% of 496) to 1 in 265 (ie, 60% of 442), or 0.25% to 0.38%. The CJD Registry also recently reviewed all records to determine whether any patients on the CJD register might have been exposed to Lyodura through non-neurosurgical applications. No potential cases were identified.

4: Risks of Creutzfeldt–Jakob disease (CJD) related to iatrogenic exposures in different countries

Country	Period	Deaths from CJD*	Recipients†	Risk (95% CI)
Lyodura
Japan	Overall (1979–2003)	97	220 000	0.04% (0.03%–0.05%)
	Higher-risk (1983–1987)	81	100 000	0.08% (0.06%–0.10%)
Australia	Overall (pre-1978–2003)	5	2 208‡	0.23% (0.07%–0.53%)‡
			2 478‡	0.20% (0.06%–0.47%)‡
	Higher-risk (1982–1986)	5	1 172	0.43% (0.14%–0.99%)
Human growth hormone
France	To 1999	55	1 361	4.04% (3.04%–5.26%)
* Based on cases of CJD with a history of recognised iatrogenic exposure during the defined period. † Based on estimated total national use of Lyodura or human cadaveric pituitary growth hormone during the defined period. ‡ A range exists for the number of Australian Lyodura recipients because of uncertainty about use before 1978.