NR ASGC
AU Zeidler,M.
TI Human Dura Mater
QU Workshop on TSE Risks in Relation to Source Material, Processing, and End-Product Use. June 8-9, 1998, College Park, MD
IA http://www.life.umd.edu/jifsan/tse/zeidler.htm
PT Workshop
VT
Thank you very much and I'd like to start this by thanking JIFSAN for kindly inviting me here today.
I became involved in the whole issue of Creutzfeldt-Jakob disease and dura mater grafts about a year ago when I had the good fortune to be working with the World Health Organization. It was at this time that WHO had a consultation addressing the issue of safety of medicinal and other products in relation to human and animal TSEs. This meeting recommended that dura mater grafts could no longer be used, which caused some controversy and I was involved in the debate which ensued with various dura mater manufacturers.
What I'd like to do over the next 15 minutes or so, is to give a background to human dura mater; talk to you about WHO's recommendations and finally discuss FDA's recommendations. I should note that I'm not actually here as a representative of WHO, so any opinions are my own. Furthermore, I should state that I personally have no hands-on experience of the use of dura mater grafts and my knowledge of the practical use of dura mater has been gleaned from discussions with neurosurgeons in Edinburgh and elsewhere.
So, what is dura mater? Well, it's the outer covering of the meninges, this is the fibrous sheath which encircles the central nervous system. It really has two functions, first, to keep the spinal fluid in, and, second, to stop infection from getting into the central nervous system. Surgical procedures or trauma that broach the dura mater may result in a hole, that because of the fibrous, inelastic nature of dura, may not be possible shut by primary closure. If the defect is to be filled, perhaps the obvious tissue to do this is a dural graft. Since the 1950s, dura mater grafts have been utilised ; some of the first grafts came from the U.S. Navy's Medical School here in the United States. The popularity of dural grafts came to the fore in the 1970s and 1980s when they were commercially produced. It appeared that surgeons were actually very happy with these particular materials - they provided a good barrier to infection and stopped the leakage of CSF. It was in 1987 that the first case was reported of a person with CJD who had previously been known to have received a dura mater graft. The patient was a 28-year-old woman who had an operation 18 months previously to remove a cholesteatoma and she subsequently developed histologically confirmed CJD. To date I've managed to find a total of 83 case reports of dura mater related CJD cases, and I am grateful Dr Paul Brown for providing me with data. There are 3 additions to the number which Paul mentioned during his talk earlier, although these three cases are slightly questionable. Two of these were reported from France, and both had undergone embolisation procedures with dura mater rather than receiving a conventional graft. The third case is from Thailand and has not yet been pathologically confirmed.
The clinical phenotype of patients with dura mater-associated CJD is similar to that seen in the classical sporadic form of CJD: rapidly progressive dementia, myoclonus, and in the majority of patients a characteristic EEG. However, there are some differences: dura-associated cases tend to have more prominent early cerebellar symptoms and a somewhat more prolonged clinical course. In sporadic CJD the median illness duration is 4 1/2 months and this is doubled on average in dura mater cases. The age at onset is about 10-15 years younger on average than we see with sporadic CJD. I think the youngest dura mater case documented was 16 or 17. The average incubation period from the time the patient received their graft to onset of their illness is approximately 6 years, but ranges from 16 months to 16 years. Although most of these cases have arisen through the use of dura mater for cranial surgery, there are some cases which have been known to have resulted from ear, nose and throat surgery or from spinal surgery. Two cases from France, as mentioned, followed embolism procedures, in one case the patient had a nasopharyngeal tumor and dura mater was cut up into lots of little pieces and injected into the external carotid artery to embolise this, and in the other case the dura mater was inoculated into an artery in the chest to embolise an area of infection.
I would like to just go back and show you the countries which are known to have had dura mater cases of CJD. Most of the reports come from Japan, and we were rather surprised at the WHO consultation last year in Geneva, to hear reports from Dr Tateishi of a recent study conducted in Japan which had shown the presence of 43 cases of dura mater CJD. I think you will agree looking at the slide that the other cases have been reported really quite widely throughout the world. Virtually all of these patients received one particular form of dura mater graft that was commercially manufactured by a single German company. The product was called Lyodura, and most of the patients had received grafts that had been manufactured during a 4 year period between 1983 and 1987. Lyodura was pooled during this time, so there was a potential for cross contamination and the sterilization procedures used involved 10% hydrogen peroxide for 24 hours and ionizing radiation. Subsequent animal experiments have shown that this is not an adequate form of sterilization.
An important question is whether any of the dura mater cases were recipients of grafts that were treated with more thorough and adequate sterilisation. By this, I mean treatment with 1N sodium hydroxide, which is in the standard step which was introduced in the treatment of Lyodura after 1987. There are four cases out of this series of 83 which perhaps I'll talk about in a little bit more detail. Two cases were clearly not Lyodura. These were locally procured grafts, one from Italy and the other from the United Kingdom - these were used between 1969 and 1981. Furthermore, there was the a recently reported case from America which we heard about yesterday. Perhaps the case of most interest is one from the Japanese series. This was a lady in her mid-60s who received a graft in 1991 and later developed clinically probable CJD, but this was not histologically confirmed. The hospital records did not note whether or not her graft was Lyodura or the other form of dura used in that hospital at that time. It was concluded in the report of the Japanese cases that it was unlikely that this patient had received Lyodura produced before 1987. So the possibility exists that this patient had received a form of dura which was considered to be adequately sterilised. It is important to note two points, first, as this case did not undergo histological examination the diagnosis of CJD is not 100% certain, and second, we can not be absolutely sure that in this or some of the of other 82 cases that the history of receiving a dural mater graft is coincidental. In none of these cases is there data which tells if the graft donor had CJD.
Following the announcement of the first case here in the United States, doctors in the United Kingdom, Australia and New Zealand decided that they were going to use alternatives to cadaveric dura homografts, and here in the States I believe there was an importation ban on Lyodura. So what alternatives are there to cadaveric-derived dura? There are several - I'll just run through these. One of the most popular is fascia lata, this is the fibrous covering of the lateral thigh muscle. The removal of this can add about 30 minutes to the length of the operation and of course leaves a wound which, as with all wounds, can potentially become infected or have other complications. Other alternatives include pericranium (the covering of the skull bone), temporalis fascia (the membrane which surrounds the temporalis muscle at the side of the head) and synthetic materials - a number of such materials have been tried over the years including gold foils, cellophane, and dacron grafts. However, there has been some concern about the safety of synthetic materials and neurosurgeons have felt that these were rather inferior, although I think with the newer materials that's not so clearly the case. I should note that there is no controlled trial that has ever been conducted to answer the question as to whether or not these substitutes are better or worse than cadaveric-derived dura. I think there are two key questions that need to be addressed, first, are there situations where cadaveric dura is better than available alternatives? If the answer is no then we need to question why we are using cadaveric dural grafts at all. If the answer is yes, then the next question is how can dura be made as safe as possible? I'd like to show you some of the report from the WHO meeting over a year ago. I'll read it to you. "Because over 50 cases of CJD have resulted from cadaveric dura mater grafts, the group strongly recommended that dura mater no longer be used, especially in the case of neurosurgery, unless no alternative is available. If dura mater is to be used, only material which is from non-pooled sources originating from carefully screened donors subjected to validated inactivated treatment should be considered." Following this recommendation the Japanese authorities decided that they were no longer going to issue a license for the use of dura mater and the TSE Advisory Committee here in the States met again to discuss the issue of dura mater. I just want to run through their recommendations, there were some differences from WHO's: although they also discouraged use of dura mater, the final decision on its usage was left up to the individual physicians, but certain additional safeguards were put into place. For instance, it was felt mandatory that for every donor a full brain autopsy should be performed and examined histologically and with immunocytochemistry, which is probably the most sensitive method that we have, other than transmission studies. It was further recommended that a sample of the dura and the brain should be kept for further testing as needed. Additionally, standard protocols for determining donors eligibility and tissue procurement were recommended, and dura should be collected before the brain at autopsy - which obviously makes sense to avoid contamination of the graft. Furthermore, decontamination with 1N sodium hydroxide for one hour should be used. This had previously been confirmed by Paul Brown and colleagues to be an effective decontamination procedure. There should be no pooling of grafts, to prevent cross-contamination and there should be documentation to allow tracking from the donor to the recipient and from the recipients to the donor. I think there can be little doubt that if these recommendations are adopted, then the safety of dura mater grafts will be dramatically improved. However, I would like to just play the devil's advocate here and to mention a few cautions. We know from animal experiments that infectivity can predate any pathological changes and this includes immunocytological changes as well. We also know that standard decontamination procedures using sodium hydroxide, as David Taylor mentioned yesterday, may not completely be effective. I think we have to remember that dura is a potentially high-risk material, and that studies also performed by David Taylor have shown that dura mater can have 106 ID50 per gram. Perhaps through the use of current decontamination procedures we will produce grafts which are much safer than those previously used, with but with low-level residual infectivity which may lead to disease with a potentially long incubation period. (For TSE agents it is known that dose administered is inversely proportional to incubation period)
So, to conclude, I think there is now very strong evidence that dura homografts cause CJD, I don't think there is much doubt about that. Secondly, I think that recommendations, such as those which are being produced by the US TSE Advisory Committee and backed by the FDA, will clearly reduce the risks associated with these grafts. However, these are, as I understand it, just recommendations and it could be argued that there should be regulations which are enforced. Finally, I think surgeons really need to consider, for any given procedure, if the use of cadaveric derived dura is really better than any available alternative. If this is the case, they should ask themselves if the benefit of dura really outweighs the risk associated with this material. Thank you very much for your attention.
Last modified Monday, February 22, 1999 04:45:20
IN Dura mater wird seit den 50er Jahren transplantiert, verstärkt aber erst seit in den 70er und 80er Jahren ihre komerzielle Produktion begann. Seit 1987 wurden 83 Fälle von Creutzfeldt-Jakob-Krankheit bekannt bei denen der Patient zuvor eine fremde dura mater erhalten hatte. Bei diesen Fällen ist die durchschnittliche Krankheitsdauer etwa doppelt so lang wie bei den sporadischen Fällen. Außerdem ist diese Patientengruppe 10-15 Jahre jünger als die Gruppe der sporadischen Fälle. Zwischen der Implantation der dura mater und der Erkrankung liegen 16 Monate bis 16 Jahre, im Durchschnitt 6 Jahre. Fast alle dem Autor bekannten Fälle waren verbunden mit meist zwischen 1983 und 1987 von der Firma Braun Melsungen unter dem Produktnamen Lyodura produzierter dura mater. Diese Firma verabeitete damals jeweils viele Präparate gleichzeitig und sterilisierte nur 24 Stunden in 10% Wasserstoffperoxid und durch Bestrahlung. Erst nach 1987 wurde die Lyodora mit 1 N Natronlauge behandelt. Es gab aber auch je einen Fall in Italien und England, die vor 1982 lokal gewonnene dura mater erhalten hatten. Bei einem aktuellen Fall in Amerika war ebenfalls keine Lyodura von Braun Melsungen beteiligt. Eine 1991 transplantierte Japanerin hatte entweder eine japanische oder eine bereits nach dem sichereren Verfahren von Braun Melsungen produzierte erhalten. Bei dieser Japanerin wurde CJD aber nicht histopathologisch bestätigt. In keinem der bekannten Fälle wurde CJD auch bei einem Spender festgestellt. Nach dem ersten möglicherweise auf eine Transplantation von dura mater zurückzuführenden CJD-Fall haben Mediziner der Common-Wealth-Staaten beschlossen, Alternativen für dura mater von Verstorbenen zu suchen. Eine populäre Alternative ist die Hülle des seitlichen Oberschenkelmuskels, aber die Entnahme beim Patienten ist natürlich auch nicht unproblematisch. Weitere Alternativen sind das den Schädelknochen bedeckende Pericranium, die den Temporalis-Muskel an der Kopfseite umhüllende fascia temporalis und synthetische Materialien wie Goldfolie, Cellophan und Dacron. Die WHO empfiehlt dura mater nur zu verwenden, wenn es keine Alternative gibt und die dura mater von einem gründlich histologisch und immunocytochemisch untersuchten Spender gewonnen und einzeln mit einer anerkannten Methode sterilisiert wurde. In Japan ist die Verwendung von dura mater inzwischen verboten.
ZR 0
AD Martin Zeidler, M.D., Department of Clinical Neurology, Western General Hospital, Edinburgh, UK
SP englisch