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446 COMMENTARY Br J Ophthalmol: first published as 10.1136/bjo.2003.028373 on 18 March 2004. Downloaded from Series editor: David Taylor We analysed the surgical history of ...... sCJD and vCJD cases with specific reference to ophthalmic . Cases of CJD were identified in the current Ophthalmic surgery and Creutzfeldt- prospective UK national surveillance project (1990-October 2002) by direct Jakob disease notification or from death certificates,10 and were classified as definite, probable, P S-Juan, H J T Ward, R De Silva, R S G Knight, R G Will or possible cases of sCJD or vCJD according to published diagnostic cri- ...... teria. Only definite or probable cases Although the evidence does not suggest that contaminated were included in this analysis. All cases with a history of ophthalmic surgery ophthalmic instruments represent a risk of onward transmission of were identified from the database, sporadic CJD, this conclusion should be treated with caution which has a specific code for this type of surgery. Information on past ophthal- he occurrence of variant the anterior chamber of the in mic surgery was obtained from relatives, Creutzfeldt-Jakob disease (vCJD) guinea pigs.8 records, and/or Tand the probable causal link with Recently it has been shown that the copies of case notes. Case files were bovine spongiform encephalopathy experimental transmission of metallic examined to identify the type of surgery, (BSE) in cattle have increased interest suface bound prions is highly efficient.9 date of surgery, and in which in the search for possible environmental Steel wires in contact with the brain of the surgery had taken place. In cases in sources of sporadic CJD (sCJD). pre-symptomatic mice needed only which the surgery was carried out after Presumed iatrogenic CJD is rare. Up to 5 minutes to acquire an infectious load the onset of clinical symptoms of CJD the year 2000 there had been 267 cases equivalent to the injection of a 1% detailed information on the clinical reported worldwide: three cases second- homogenate of brain. Infected wires course was extracted. ary to human corneal grafting (one were inserted transiently into the brains The frequency of a history of eye confirmed, one probable, and one pos- of healthy mice and only 30 minutes of surgery in sCJD and vCJD was com- sible case), 114 related to human dura exposure was sufficient to result in pared with data on the frequency of past mater grafts, 139 related to human . The same wires remained eye surgery in age and sex matched growth hormone treatment, four related infective when reintroduced into control groups. During the period of the to human pituitary gonadotrophin ther- another set of healthy mice. Although, study the case-control study has apy, and seven linked to neurosurgical to our knowledge, there have been no evolved. Between 1990 and 1998 a procedures or stereotactic EEG electro- documented cases of CJD secondary to single hospital control was obtained for des.1 Because of the marked resistance ophthalmic surgery other than corneal the sCJD cases and from 1999–2002 a of the infectious agent of CJD to transplantation, there is a possibility single community based control was conventional sterilisation techniques, that ophthalmic surgery might be a risk identified. From 1996–2002 a single there is concern about the possibility of procedure for the accidental iatrogenic hospital control was obtained for vCJD cases and since 1998 attempts have been transmission of infection via surgical transmission of CJD. http://bjo.bmj.com/ instruments in contact with infected Precautions to minimise the risks of made to obtain four community based tissue, especially in or iatrogenic transmission of CJD are vital controls per case of vCJD. Because of the ophthalmic surgery. and the Department of Health has limited numbers of controls and the infrequency of past eye surgery this The presence of infection in the eye established an incidents panel to pro- study reports on unmatched compari- in sCJD was first demonstrated follow- vide advice in cases of all forms of sons of the frequency of past eye ing the intracerbral inoculation of human prion diseases in which there is the possibility for cross infection. surgery.

pooled sCJD eye tissue in non-human on September 26, 2021 by guest. Protected copyright. primates.2 Recently the infectious form However, an important question is Fifty eight cases of sCJD (11%) out of of prion protein (PrPSc) has been iden- whether the concerns raised by experi- 510 with information available had a tified in the neural , , mental work translate into an actual history of intraocular surgery, with an average of 1.34 interventions per and in retinal pigmented epithelium risk in the clinical setting. This com- patient. The types of operation (n = 78) in variant and sporadic CJD using mentary reviews the data on ophthalmic in the total of 58 cases having under- immunohistochemistry or western surgery in sCJD and vCJD from the gone any form of ocular surgery are blot,34 with comparable levels to those archives of the UK National CJD listed in table 1 and the years of found in brain. PrPSc was not detected Surveillance Unit from 1990 to 2002, including information on both sCJD and operation in figure 1. Ten cases of in other ocular tissues. Although this vCJD. sCJD underwent eye surgery during suggests that there may be a greater risk of contaminating surgical instru- ments in procedures involving the Table 1 Types of operation on cases of sporadic CJD posterior segment of the eye, infecti- vity has been demonstrated in animal Number of 5 Number of operations operations on Number of operations and human , and circumstan- on sCJD cases hospital controls on community controls tial evidence has implicated corneal (n = 78) (n = 39) (n = 20) transplantation as a mechanism of 6 Intraocular surgery* 55 (70%) 29 (74%) 17 (85%) transmission of iatrogenic CJD. Experi- Extraocular surgery 17 (22%) 6 (16%) 3 (15%) mental infection has been achieved Laser 4 (5%) 2 (5%) — following conjunctival installation of Information not available 2 (3%) 2 (5%) — scrapie infectivity in mice7 and by *, trauma, and . inoculation of an adapted agent into

www.bjophthalmol.com COMMENTARY 447 Br J Ophthalmol: first published as 10.1136/bjo.2003.028373 on 18 March 2004. Downloaded from the prodromal (within 3 months of onset) or early symptomatic phase of the disease, the majority cataract opera- tions. Four out of these 10 patients had the Heidenhain variant of sCJD, with visual onset and early development of cortical blindness (table 2). Figure 2 shows the time interval between last eye surgery and the onset of symtoms in sCJD patients. The frequency of past eye surgery was compared with the control groups in sCJD (table 3) and vCJD. In the hospital control group for sCJD, 31 (14%) out of 226 had a history of ophthalmic surgery, with an average of 1.26 procedures per Figure 1 Year of eye surgery in sCJD. patient and in the community control group for sCJD 14 (13%) out of 106, with an average of 1.43 procedures per patient. Eight patients with vCJD (6%) out of 125 with information available Table 2 sCJD patients with ophthalmic surgery after clinical onset had a history of eye surgery and all were squint corrections in childhood, with Heidenhain Case Date of surgery Intervention variant Diagnosis the exception of one case with a history of open surgery for 1 1992 Cataract Definite carried out 15, 17, and 20 months before 2 1992 Laser therapy * Definite 3 1992 Cataract * Definite the development of symptoms (this case 4 1993 Cataract Definite predated the establishment of the CJD 5 1996 Cataract Definite incidents panel). In the hospital control 6 1998 Definite group for vCJD (15%) 10 out of 67 had a 7 1998 Cataract Definite 8 1999 Cataract * Definite history of ophthalmic surgery and in the 9 1999 Laser therapy * Definite community control group for vCJD five 10 2000 Cataract Definite (3%) out of 155 had had eye surgery. There were no significant (at the 5% * Heidenhain variant: cases with isolated cortical visual symptoms at onset. level) differences between the frequen- cies of past eye surgery in the cases and any of the control groups. Details of the year and hospital of each surgical procedure were listed and in the great majority there was no http://bjo.bmj.com/ temporal or geographic link between operations. A group of six cases of sCJD had been operated on in one hospital and in two pairs of cases the procedures had been carried out in the same year. Inquiry about the specific dates of these

procedures, however, indicated that the on September 26, 2021 by guest. Protected copyright. operations had been carried out months apart. The aim of this article is to document the frequency of past eye surgery in CJD and to determine whether there is evidence of transmission of CJD through contaminated ophthalmic instruments. About 10% of cases of sCJD have a history of eye surgery, of Figure 2 Interval between last eye surgery and onset of symptoms in sCJD (n = 54). which about 70% involved open surgery on the anterior chamber of the eye. In the great majority of cases the surgical instruments were reused on subsequent Table 3 Past ophthalmic surgery in sCJD compared with control groups patients, usually because CJD developed years after the original procedure. Cases Hospital controls Community controls Despite this, the evidence in this paper (n = 510) (n = 226) (n = 106) does not suggest that there is onward Patients with eye operations 58 (11%) 31 (14%) 14 (13%) iatrogenic transmission of sCJD through Total number of operations 78 39 20 eye surgery, a finding consistent with Average per patient 1.34 1.26 1.43 some previous studies.11 12 An important question is whether cases of CJD caused by this type of

www.bjophthalmol.com 448 COMMENTARY Br J Ophthalmol: first published as 10.1136/bjo.2003.028373 on 18 March 2004. Downloaded from transmission would be identified by this clinical illness and this is particularly CJD, this conclusion should be treated study. The clinicopathological features true of cases with isolated cortical visual with caution. The eye contains signifi- and incubation period of iatrogenic CJD symptoms (the Heidenhain variant of cant levels of infection in sCJD and vary according to the route of transmis- sCJD), which affected four of these 10 vCJD, and even limited exposures can sion with, for example, a cerebellar cases. The presence of confusion, mem- result in the iatrogenic transmission of syndrome and only limited cognitive ory impairment, or other neurological CJD.17 impairment in human growth hormone signs may raise the suspicion of a This paper confirms that ophthalmol- related CJD. In CJD caused by corneal neurodegenerative disorder. ogists may be involved in treating transplantation the clinical and patho- The data on vCJD are limited and the patients in the early stages of CJD and logical phenotype is similar to sCJD and period of observation is shorter than in it is essential to follow current guide- the incubation periods in the three cases sCJD. Although there is currently no lines in relation to surgical, including reported to date were 15 months, evidence of transmission of vCJD ophthalmic and neurosurgical, instru- 18 months, and 30 years.613 The sur- through contaminated ophthalmic ments used in suspect cases of CJD of all veillance system for CJD in the United instruments, this possibility cannot be types.18 Such instruments should be Kingdom is efficient at identifying cases excluded, not least because the incuba- destroyed or quarantined until a defini- as judged by annual incidence rates of tion period in vCJD is unknown. tive diagnosis is available and the sCJD of around one case per million, Furthermore, in vCJD the presence of development of single use devices and and it is likely that cases with a typical prion protein (PrP) immunostaining in instruments in eye surgery has been phenotype would be identified. The systemic lymphoreticular tissues sug- advocated,19 provided these do not pre- period of observation of CJD from 1990 gests that the risk from contaminated judice clinical outcome. All cases of to 2002, with additional information surgical instruments may be greater suspect CJD should be reported to the from 1980–9, suggests that there is the than in sCJD, in which these tissues local consultant in communicable dis- potential to identify case to case trans- do not stain for PrP, using comparable ease control in order that appropriate mission through past eye surgery, with methods. measures to protect the assumption that the incubation The data from our case-control study are instituted, including a review of period of such cases would be months show no significant risk related to a previous surgery. Advice on specific or years rather than decades. It is, history of eye surgery in sCJD in cases which raise concern is available however, important to emphasise that comparison with two control groups. from the CJD incidents panel (www.doh. a significant proportion of the eye The methodology of the case-control gov.uk/cjd/incidentspanel.htm), which operations were carried out relatively study in our analysis is not ideal. There has published a consultation document recently and, if the incubation period is a deficit in the numbers of controls in (www.doh.gov.uk/cjd/consultation). were extended, onward transmission comparison with the numbers of cases may not have been identified by this and an unmatched analysis was under- ACKNOWLEDGEMENTS study. taken. The results of our study are, We would like to thank Dr JF Geddes and Evidence of transmission of sCJD however, consistent with the results of Miss Gillian Adams, FRCS, for their help in through contaminated neurosurgical a previous case-control study in confirming some of the clinical details. PS-J instruments rests on the close temporal Europe,12 but contrast with the results was supported by the postMIR grant Wenceslao Lopez Albo from the IFIMAV relation between operations carried out of an Australian study in which previous Institute of the Fundacio´n Pu´blica Marque´s on CJD cases and unaffected individuals cataract/eye surgery was associated with de Valdecilla. The National CJD Surveillance 14 15 http://bjo.bmj.com/ who subsequently developed CJD. a more than sixfold increase in the risk Unit is funded by the Department of An analysis of the dates and sites of of sCJD.16 The studies used different Health and the Scottish Executive Health eye operations in cases of sCJD in this types of control group, the European Department. study showed no such relation. The study hospital controls and the Br J Ophthalmol 2004;88:446–449. elegant experiments by Weismann et Australian study community controls. doi: 10.1136/bjo.2003.028373 al9 raise the possibility that surgical However, in a reanalysis of the instruments contaminated during neu- European data using a community con- ...... rosurgery might pose a significant risk trol group, eye surgery was again found Authors’ affiliations on September 26, 2021 by guest. Protected copyright. of iatrogenic transmission. In this con- not to increase the risk of sporadic P S-Juan, H J T Ward, R S G Knight, R G Will, text it is of interest that a number of CJD.11 The disparity in outcome in the The National CJD Surveillance Unit, Western cases of sporadic (and iatrogenic) CJD two studies relates primarily to the General Hospital, Edinburgh EH4 2XU, UK have undergone brain surgery (12/400 frequency of previous eye surgery in R De Silva, Oldchurch Hospital, Romford, UK cases in the European study), but there the control groups (European studies is no evidence from case-control studies 34/406, 8% , 37/325, 11%: Australian 24/ Correspondence to: R G Will, The National CJD that previous neurosurgery increases the 784, 3%) rather than the cases Surveillance Unit, Western General Hospital, Edinburgh EH4 2XU, UK; [email protected] risk of developing sporadic CJD. This is (European studies 33/401, 8%, 37/328, despite the fact that potentially con- 11%: Australian 24/241, 10%). Although Accepted for publication 19 August 2003 taminated neurosurgical instruments this type of study cannot exclude the have inadvertently been reused on other possibility of rare instances of iatro- patients on a number of occasions. genic transmission of CJD through eye REFERENCES The 10 cases of sCJD undergoing eye surgery, the balance of evidence does 1 Brown P, Preece M, Brandel JP, et al. Creutzfeldt- Jakob disease at the millennium. surgery in the early clinical stages of the not support the hypothesis that expo- 2000;55:1075–81. illness may represent the greatest risk of sure to potentially contaminated 2 Brown P, Gibbs CJ, Rodgers-Johnson P, et al. onward transmission of infection, ophthalmic instruments has, hitherto, Human spongiform encephalopathy: The because there are probably higher levels been associated with the risk of devel- National Institutes of Health Series of 300 cases of experimentally transmitted disease. Ann Neurol of infection in the eye late in the oping CJD. 1994;35:513–29. incubation period as a result of centri- Although the evidence in this paper 3 Wadsworth JD, Joiner S, Hill AF, et al. Tissue fugal spread of infection along the optic does not suggest that contaminated distribution of protease resistant prion protein in 4 variant Creutzfeldt-Jakob disease using a highly nerve. The diagnosis of sCJD can be ophthalmic instruments represent a sensitive immunoblotting assay. Lancet very difficult in the early stages of the risk of onward transmission of sporadic 2001;358:171–80.

www.bjophthalmol.com COMMENTARY 449 Br J Ophthalmol: first published as 10.1136/bjo.2003.028373 on 18 March 2004. Downloaded from 4 Head MW, Northcott V, Rennison K, et al. Prion 10 Cousens SN, Zeidler M, Esmonde TF, et al. 15 Foncin JF, Gaches J, Cathala F, et al. Transmis- protein accumulation in of patients with Sporadic Creutzfeldt-Jakob disease in the United sion iatrogene interhumaine possible de maladie sporadic and variant Creutzfeldt-Jakob disease. Kingdom: analysis of epidemiological de Creutzfeldt-Jakob avec atteinte des grains de Invest Ophthalmol Vis Sci 2002;44:342–6. surveillance data for 1970–76. BMJ cervelet. Rev Neurol (Paris) 1980;136:280. 5 Lueck CJ, McIlwaine GG, Zeidler M. Creutzfeldt- 1997;315:389–95. 16 Collins S, Law MG, Fletcher A, et al. Surgical Jakob disease and the eye. I Background and 11 Ward HJT, Everington D, Croes EA, et al. treatment and risk of sporadic Creutzfeldt-Jakob patient management. Eye 2000;14:263–90. Sporadic Creutzfeldt-Jakob disease and surgery: disease: a case-control study. Lancet 6 Hogan RN, Brown P, Heck E, et al. Risk of prion a case control study using community controls. 1999;353:693–7. disease transmission from ocular donor tissue Neurology 2002;59:543–8. 17 Croes EA, Roks CMAA, Jansen GH, et al. transplantation. Cornea 1999;18:2–11. 12 Van Duijn CM, Delasnerie-Laupreˆtre N, Creutzfeldt-Jakob disease 38 years after 7 Scott JR, Foster JD, Fraser H. Conjunctival Masullo C, et al. Case control study of risk factors diagnostic use of human growth hormone. instillation of scrapie in mice can produce disease. of Creutzfeldt-Jakob disease in Europe during J Neurol Neurosurg 2002;72:792–3. Vet Microbiol 1993;34:305–9. 1993–95. Lancet 1998;351:1081–5. 18 Department of Health. Transmissible spongiform 8 Manuelidis EE, Angelo JN, Gorgacz EJ, et al. 13 Heckmann JG, Lang CJG, Petruch F, et al. encephalopathy agents: safe working and the Experimental Creutzfeldt-Jakob disease Transmission of Creutzfeldt-Jakob disease via prevention of infection: publication of revised transmitted via the eye with infected cornea. corneal transplant. J Neurol Neurosurg Psychiatry ACDP/SEAC guidance. London: DoH, June 2003 N Eng J Med 1977;296:1334–6. 1997;63:388–90. (www.doh.gov.uk/cjd/tseguidance). 9 Weissmann C, Enari M, Klohn P-C, et al. 14 Will RG, Matthews WB. Evidence for case-to- 19 Tullo A. Creutzfeldt-Jakob disease and eye Transmission of prions. J Infect Dis case-transmission of Creutzfeldt-Jakob disease. surgery—new disease, old disease. J Cataract 2002;186:S157–65. J Neurol Neurosurg Psychiatry 1982;45:235–8. Refract Surg 2003;29:629–31.

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EMichael Balis.

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