Ophthalmic surgery in prion diseases.

Eleven (1.8%) of 597 patients underwent ophthalmic surgery within 1 month before the onset of prion disease or after the onset. All ophthalmologists reused surgical instruments that had been incompletely sterilized to eliminate infectious prion protein. Ophthalmologists should be aware of prion diseases as a possible cause of visual symptoms and use disposable instruments whenever possible.

**********

Visual impairment occurs in 10% to 20% of patients with sporadic Creutzfeldt-Jakob disease (sCJD) during an early stage of the disease (Heidenhain variant) (1,2). Some patients with prion diseases may visit ophthalmologists with visual impairment due to prion diseases or with coexisting age-related eye diseases (3,4).

Infectious prion protein ([PrP.sup.Sc]) was identified in the retina and optic nerve in patients with variant CJD (vCJD) and sCJD (5,6), and CJD has been transmitted by corneal transplantation (7,8). In the World Health Organization (WHO) guidelines, eyes were classified as highly infectious tissues (9).

Secondary transmission of [PrP.sup.Sc] through ophthalmic surgery could possibly be prevented around the onset of prion diseases, although surgery that is performed long before the onset of prion diseases would not have that potential. It is important to understand the current status of ophthalmic surgery for patients with prion diseases and to clarify the clinical features of the patients with prion diseases who undergo ophthalmic surgery. Here, we describe the relevant data from CJD surveillance in Japan.

The Study

We analyzed the patients with prion diseases who had been registered by the CJD Surveillance Committee in Japan from April 1999 through March 2005. We prospectively investigated each patient with a surveillance protocol that assembled information about life history, previous medical history, clinical history, laboratory data, and results of molecular genetic and pathologic analyses. Written consent, approved by the Institutional Ethics Committee, was obtained from all the patients' families; members of the Surveillance Committee examined the patients and collected the data.

We classified the patients into 4 categories: sCJD, infectious prion diseases, inherited prion diseases, and unclassified prion diseases, sCJD was diagnosed according to the classical criteria established by Masters et al. (10). Infectious prion diseases included CJD associated with cadaveric dura mater graft (dCJD) or other iatrogenic opportunities for prion infection, in which the criteria for sCJD were applied for the diagnosis, and vCJD, in which the diagnosis was based on WHO criteria (2001) (11). Regarding the accuracy of the diagnosis of inherited prion diseases, cases verified by pathology report were defined as definite, and cases with mutations in the prion protein gene and neuropsychiatric manifestations compatible with prion diseases were defined as probable.

Among patients with a history of ophthalmic surgery, we directed special attention to the patients who had a history of eye surgery within 1 month before the obvious onset of prion disease or after the onset. Because the onset of prion diseases often overlaps with various kinds of prodromal symptoms, determining the precise time point of onset is difficult; therefore, we included the period of 1 month before the obvious onset. To gather information about the ophthalmic surgery, we mailed questionnaires to the ophthalmologists who operated on these patients, requesting the following information: diagnosis of ophthalmologic diseases, surgical procedures performed, changes in the symptoms after the surgery, whether the instruments were reused, and methods of cleaning reused instruments.

To ascertain the clinical features of prion diseases, we analyzed the patient's age at onset and duration of disease course, which was calculated as the interval between the onset and the appearance of the akinetic mutism state or death in the patients who died without akinetic mutism. Among early clinical manifestations of prion diseases, dementia and visual disturbance are major determinants that would influence the indication for ophthalmic surgery, so we grouped the patients according to whether they had dementia or visual impairment within 2 months after onset of symptoms.

The sex distribution of the patients who had ophthalmic surgery around the time of onset of clinical symptoms and those who did not was compared by Fisher exact tests, and differences in age at onset and disease duration were compared by Mann-Whitney U tests. We used [chi square] tests to compare the distribution of the patients with or without dementia or visual impairment within 2 months of onset. Statistical significance was defined as p<0.05.

We found 597 patients with definite or probable diagnosis of prion diseases: 468 (78.4%) with sCJD; 78 (13.1%) with inherited prion diseases; 48 (8.0%) with infectious prion diseases, including 47 cases of dCJD; and 1 patient with vCJD and 3 patients with unclassified CJD.

Thirty-seven patients (6.2%) had a history of ophthalmic surgery at some time in their lives. Among them, 11 patients (1.8%) underwent ophthahnic surgery within 1 month before the obvious onset of prion disease or after the onset. Except for 1 patient with Gerstmann-Straussler-Scheinker disease, all of these patients had sCJD. There have been no reports of the development of prion diseases in patients who underwent ophthalmic surgery after the ophthalmic surgery of patients with prion diseases.

Ten patients with sCJD underwent ophthalmic surgery within 14 months of symptom onset, and 8 of them had ophthalmic surgery within 4 months of symptom onset (Table 1). At clinical onset, 4 patients exhibited visual symptoms, 5 had dementia, and 1 patient had a gait disturbance. All patients underwent surgery for cataracts, except for 1 patient who underwent surgery for a detached retina. According to the reports on the surgical outcome by the ophthalmologists of 7 patients, visual disturbance was unchanged in 2 patients, deteriorated in 1, and improved to some extent in 4 after surgery. All ophthalmologists reused some surgical instruments and cleaned instruments by either autoclaving or the ethylene oxide gas method, which have been reported to incompletely sterilize [PrP.sup.Sc] (9,12).

Clinical features were compared between sCJD patients who did and did not have ophthalmic surgery (Table 2). The patients who had ophthalmic surgery had a significantly longer disease duration than those without (p=0.0004). Regarding early clinical symptoms within 2 months after onset, the subgroup with visual symptoms without dementia was significantly overrepresented among the patients who had ophthalmic surgery compared with those who did not have surgery (p=0.0004).

Conclusions

Our study showed that, in 1.8% of the patients with prion diseases, eye tissues were operated on within 1 month before the obvious onset of prion disease or after the onset. In addition, the sCJD patients who underwent surgery had a significantly longer duration of the disease course as well as significant overrepresentation of visual symptoms without dementia in the early phase, compared with patients who did not have ophthalmic surgery.

The prevalence of ophthalmic surgery around the time of clinical onset of prion diseases in our study is similar to that (2.0%) in a report from the United Kingdom (13). In the UK study (13), patients with Heidenhain variant cases constituted 40% of sCJD patients who had ophthalmic surgery. Early visual impairment (due to prion diseases) would prompt ophthalmologists to perform surgery.

Currently, cataract surgery is recommended to improve physical or cognitive function in elderly patients (14,15). It should be noted that, after performing eye surgery on patients with prion disease, all ophthalmologists reused surgical instruments that were sterilized with procedures that are incomplete for the sterilization of [PrP.sup.Sc], although the WHO infection control guidelines for prion diseases (9) strongly recommend single-use surgical instruments for procedures involving highly infective tissues. The fact that no secondary iatrogenic cases that could be attributed to surgical procedures were found during our investigation does not diminish the need for ophthalmologists to be aware of CJD as a cause of visual symptoms (including symptoms mimicking those of cataracts) and highlight the importance of using disposable instruments whenever possible to avoid cross-contamination.

Acknowledgments

We thank Fumio Moriwaka, Yoshiyuki Kuroiwa, Masatoyo Nishizawa, Nobuyuki Sodeyama, Masatoshi Takeda, Yusei Shiga, Shigetoshi Kuroda, Shigeki Kuzuhara, Jun Tateishi, Hiroyuki Murai, and Shigeo Murayama for the CJD surveillance.

The CJD Surveillance Committee belongs to the Research Group on Prion Disease and Slow Virus Infection, funded by the Ministry of Health, Labour and Welfare, Japan; the funding source had no involvement in the publication of this article.

Dr Hamaguchi is a clinical research fellow in the Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. His primary research interest is prion diseases.

(1) Current affiliation: Ishikawa Prefecture Central Hospital, Kanazawa, Japan

(2) Member, Creutzfeldt-Jakob Disease Surveillance Committee, Japan

References

(1.) Kropp S, Schulz-Schaeffer WJ, Finkenstaedt M, Riedemann C, Windl O, Steinhoff BJ, et al. The Heidenhain variant of Creutzfeldt-Jakob disease. Arch Neurol. 1999;56:55-61.

(2.) Lueck CJ, McIlwain GG, Zeidler M. Creutzfeldt-Jakob disease and the eye. II. Ophthalmic and neuro-ophthalmic features. Eye. 2000; 14:291-300.

(3.) Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG. Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the "Heidenhain variant." Br J Ophthalmol. 2005;89:1341-2.

(4.) Tullo A. Creutzfeldt-Jakob disease and eye surgery--new disease, old disease. J Cataract Refract Surg. 2003;29:629-31.

(5.) Head MW, Northcott V, Rennison K, Ritchie D, McCardle L, Bunn TJ, et al. Prion protein accumulation in eyes of patients with sporadic and variant Creutzfeldt-Jakob disease. Invest Ophthalmol Vis Sci. 2003;44:342-6.

(6.) Head MW, Peden AH, Yull HM, Ritchie DL, Bonshek RE, Tullo AB, et al. Abnormal prion protein in the retina of the most commonly occurring subtype of sporadic Creutzfeldt-Jakob disease. Br J Ophthalmol. 2005;89:1131-3.

(7.) Duffy P, Wolf J, Collins G, DeVoe AG, Sreeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med. 1974;290:692-3.

(8.) Heckmann JG, Lang CJG, Petruch F, Druschky A, Erb C, Brown P, et al. Transmission of Creutzfeldt-Jakob disease via a corneal transplant. J Neurol Neurosurg Psychiatry. 1997;63:388-90.

(9.) World Health Organization (WHO). WHO infection control guidelines for transmissible spongiform eneephalopathies. Report of a WHO consultation, Geneva, Switzerland, 1999 March 23-26. Geneva: WHO; 1999. Available from http://www.who.int/csr/resources/ publications/bse/WHO_CDS_CSR_APH_2000_3/en/

(10.) Masters CL, Harris JO, Gajdusek DC, Gibbs CJ Jr, Bernoulli C, Asher DM. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol. 1979;5:177-88.

(11.) World Health Organization (WHO). The revision of the variant Creutzfeldt-Jakob (vCJD) case definition. Report of a WHO consultation. Edinburgh, United Kingdom, 2001 17 May (WHO/CDS/CSR/EPH/2001.5). Geneva: WHO; 2001.

(12.) Taylor DM. Inactivation of transmissible degenerative encephalopathy agents: a review. Vet J. 2000; 159:10-7.

(13.) S-Juan P. Ward HJ, De Silva R, Knight RS, Will RG. Ophthalmic surgery and Creutzfeldt-Jakob disease. Br J Ophthalmol. 2004;88:446-9.

(14.) Brenner MH, Curbow B, Javitt JC, Legro MW, Sommer A. Vision change and quality of life in the elderly. Response to cataract surgery and treatment of other chronic ocular conditions. Arch Ophthalmol. 1993; 111:680-5.

(15.) Tamura H, Tsukamoto H, Mukai S, Kato T, Minamoto A, Ohno Y, et al. Improvement in cognitive impairment after cataract surgery in elderly patients. J Cataract Refract Surg. 2004;30:598-602.

Tsuyoshi Hamaguchi, * (1) Moeko Noguchi-Shinohara, * Yosikazu Nakamura, [dagger] (2) Takeshi Sato, [double dagger] (2) Tetsuyuki Kitarnoto, [section] (2) Hidehiro Mizusawa, [paragraph] (2) and Masahito Yamada * (2)

* Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; [dagger] Jichi Medical University, Shimotsuke, Japan [double dagger] National Center for Neurology and Psychiatry, Ichikawa, Japan; [section] Tohoku University Graduate School of Medicine, Sendai, Japan; and [paragraph] Tokyo Medical and Dental University, Tokyo, Japan

Address for correspondence: Masahito Yamada, Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8640, Japan; email: [e-mail]

Table 1. Characteristics of sCJD patients and ophthalmic surgery *

                       Disease
                       duration,
Patient   Sex/age,y    mo ([double   Symptom at    Ophthalmic
no.       ([dagger])   dagger])      sCJD onset    disease

1            M/81           8        Visual        Cataract
2            M/61          15        Dementia      Cataract
3            F/64          20        Visual        Cataract
4            F/59           3        Dementia      Detached retina
5            F/57          10        Dementia      Cataract
6            F/79           5        Dementia      Cataract
7            M/74          16        Visual        Cataract
8            F/63           5        Visual        Cataract
9            M/79           6        Gait          Cataract
                                     disturbance
10           F/66           3        Dementia      Cataract

           Interval,       Visual
Patient       mo          symptoms        Reused
no.       ([section])   after surgery   instruments   Cleaning method

1              4        NA                  NA        NA
2              0        Improved            Yes       Autoclave
                                                      (135[degrees]C
                                                      for 9 min)
3             14        Not changed         Yes       EOG
4             -1        Improved            Yes       EOG
5             10        NA                  NA        NA
6             -1        Improved            Yes       EOG
7              3        Improved            Yes       Autoclave
                                                      (132[degrees]C
                                                      for 10 min), EOG
8              1        Deteriorated        Yes       Autoclave
                                                      (132[degrees]C
                                                      for 10 min)
9              2        Not changed         Yes       Autoclave
                                                      (121[degrees]C
                                                      for 60 min)
10             1        NA                  NA        NA

* sCJD, sporadic Creutzfeldt-Jakob disease; visual, visual impairment;
NA, not available; EOG, ethylene oxide gas.

([dagger]) At sCJD onset.

([double dagger]) Disease duration, the duration from onset to akinetic
mutism state or death if the patients never displayed akinetic mutism.

([section]) Between surgery and sCJD symptoms.

Table 2. Clinical symptoms of sCJD within 2 mo after disease onset *

                                Ophthalmic surgery

Characteristic         No, n = 458          Yes, n = 10

Female/male         263/195                6/4
Age at onset, y      66.8 [+ or -] 9.9    68.3 [+ or -] 9.1
 mean [+ or -] SD
Disease duration,     4.2 [+ or -] 4.8     9.1 [+ or -] 6.0
 ([dagger])
 mean [+ or -] SD
Clinical symptoms
 (%)
 Dementia (+)/      153 (34.2)             4 (40.0)
 visual
 impairment (+)
 Dementia (+)/      239 (53.3)             3 (30.0)
 visual
 impairment (-)
 Dementia (-)/       16 (3.6)              3 (30.0)
 visual
 impairment (+)
 Dementia (-)/       40 (8.9)              0
 visual
 impairment (-)

Characteristic              Total        p value

Female/male         269/199              0.57
Age at onset, y      66.8 [+ or -] 9.9   0.74
 mean [+ or -] SD
Disease duration,     4.3 [+ or -] 4.9   0.0004
 ([dagger])
 mean [+ or -] SD
Clinical symptoms
 (%)
 Dementia (+)/      157 (34.3)
 visual
 impairment (+)
 Dementia (+)/      242 (52.8)           0.0004
 visual
 impairment (-)
 Dementia (-)/       19 (4.1)
 visual
 impairment (+)
 Dementia (-)/       40 (8.7)
 visual
 impairment (-)

* sCJD, sporadic Creutzfeldt-Jakob disease; SD, standard deviation;
+, with; -, without.

([dagger]) Disease duration, the duration from onset to akinetic
mutism or death if patients never displayed akinetic mutism.