We investigated 1,339 patients with suspected prion diseases who had been registered by the CJD Surveillance Committee in Japan from April 1999 through February 2008. The surveillance system was initiated in April 1999, and each patient was prospectively assessed with a surveillance protocol that assembled information about life history; previous medical history, including the history of surgical treatment and blood transfusion; clinical history; laboratory data; and results of molecular genetic and pathologic examinations. Information on patients with suspected prion diseases were obtained through 1) the application for registration with the Japanese Intractable Diseases Information Center (www.nanbyou.or.jp/english/nan_kenkyu_45.htm) by each patient’s family, 2) the law on infectious diseases, or 3) request for genetic or cerebrospinal fluid analyses sent to members of the CJD Surveillance Committee by the physicians. In Japan, 123 diseases have been defined as intractable disease, and for 45 of them, including prion diseases, patients receive additional economic support for medical costs. Furthermore, medical doctors must report patients suspected of having prion disease to the local public health department within 7 days after the diagnosis, according to the law on infectious diseases (which has been enforced since April 1999 in Japan to monitor some specific infectious diseases). After written consent approved by the Institutional Ethics Committee was obtained from each patient’s family, members of the CJD Surveillance Committee directly examined the patient and collected data from the clinical records. For each patient with a history of surgery, we collected information about the underlying disease from the patient’s family, including the date and hospital in which the operation was performed. For each patient with a history of blood transfusion, we collected information about the date of blood transfusion. Most information was collected by interviewing the patient’s family members.

On the basis of discussions by the CJD Surveillance Committee, we confirmed or denied the diagnosis of prion disease in each case. In patients with a confirmed diagnosis of prion disease, we classified prion diseases into 4 categories: sCJD, acquired prion disease, genetic prion disease, and unclassified prion disease. sCJD was diagnosed according to the revised classical criteria established by Masters et al. (13): definite CJD (neuropathologically confirmed spongiform encephalopathy or abnormal prion protein deposition in the brain); and probable CJD (neuropathologically unconfirmed cases showing progressive dementia, periodic sharp-wave complexes on electroencephalogram, and at least 2 of the following features: myoclonus, pyramidal signs/extrapyramidal signs, cerebellar signs or visual symptoms, and akinetic mutism). Acquired prion diseases included iatrogenic CJD, in which the criteria for sCJD were applied for a diagnosis with a history of iatrogenic exposure, and variant CJD, in which the diagnosis was based on the World Health Organization (WHO) 2001 criteria (14). Regarding the accuracy of the diagnosis of genetic prion diseases, pathologically verified cases were defined as “definite,” and cases demonstrating mutations in the PrP gene and neuropsychiatric manifestations compatible with prion diseases were defined as “probable.” We selected patients with definite or probable sCJD for analysis.

Patients who did not receive a diagnosis of prion diseases were classified into 3 categories: prion diseases definitely denied; prion diseases probably denied; and diagnosis unclear. “Prion diseases definitely denied” indicated patients whose conditions were definitively diagnosed as diseases other than prion diseases, and “prion diseases probably denied” indicated patients for whom the diagnosis of prion diseases was clearly unlikely due to the improving or nonprogressive disease course or for other reasons, although a definitive diagnosis of another disease was not established. Because patients with “prion diseases definitely denied” or “prion disease probably denied” had no or little possibility of prion disease, we selected these cases as the controls in our case–control study.

To estimate the risk for sCJD through past surgery or blood transfusion, we performed a case–control study. Operations were divided into the following categories: neurosurgery, ophthalmic surgery, and surgery other than neurosurgery or ophthalmic surgery (other surgery), because neurosurgery or ophthalmic surgery for those with prion diseases are categorized in the guidelines of the CJD Incident Panel in the United Kingdom as high- or medium-risk procedures for transmission of infective PrP (15). In these guidelines, procedures involving the olfactory epithelium are also categorized as medium risk (15). However, the number of persons who underwent the operation possibly involving the olfactory epithelium is too small to be estimated by statistical analysis (2 sCJD patients and 2 controls underwent surgery for sinusitis), and we categorized these operations as other surgery. Neurosurgery included operations on the brain, cerebral blood vessels, and spinal cord. Ophthalmic surgery included all operations involving the eyeball and optic nerve. Other surgery included all surgical procedures other than neurosurgery and ophthalmic surgery. Furthermore, the committee performed a detailed investigation of sCJD patients who underwent neurosurgery or ophthalmic surgery at a hospital where other patients with any type of prion disease had ever undergone neurosurgery or ophthalmic surgery.

We analyzed sCJD patients who underwent surgical procedures after the onset of sCJD because such procedures might cause secondary transmission of the disease through contaminated instruments. In particular, for neurosurgery and ophthalmic surgery, we investigated the reason for the operation, interval between the operation and onset of sCJD symptoms, age at onset of sCJD, and symptoms at onset of sCJD.

Between the sCJD and control groups, age at onset was compared by Student t test, and medical procedures before the onset of diseases were compared by Fisher exact test. The case–control study of surgical procedures and blood transfusions before the onset of diseases was estimated by logistic-regression analysis. Because age at onset was different among sCJD patients (mean ± SD, 67.7 ± 9.5 years) and controls (59.3 ± 16.6 years) (p<0.0001), we divided the sCJD patients and controls into 3 categories according to age at disease onset; 31–50 years, 51–70 years, and >71 years. We performed a single regression analysis for any operation, neurosurgical procedure, ophthalmic surgical procedure, other operation, and blood transfusion in each age group. The strength of association between sCJD and putative risk factors was assessed by the odds ratios and 95% confidence intervals. Significance was defined as p<0.05. Statistical analyses were performed by using StatView J-7.5 (Abacus Concepts, Berkeley, CA, USA).

Frequencies of medical procedures before the onset of sCJD in sCJD patients and in controls are compared in Table 3. For both the sCJD and control groups, ≈50% had a history of surgery, and ≈10% had received a blood transfusion. No significant differences were found between them in frequency of any surgery, neurosurgery, ophthalmic surgery, other surgery, or blood transfusion (Table 3). In the logistic-regression analysis, no significant risk was associated with any medical procedures investigated in this study (Table 4).

Five sCJD patients had a history of neurosurgery or ophthalmic surgery at hospitals where neurosurgery or ophthalmic surgery had been performed on patients in whom prion disease later developed (Table 5); intervals between operations at the same hospitals were >3 years (Table 5).

Except for 2 patients suspected of having prion disease, who had undergone brain biopsy with disposable instruments, 34 (4.5%) of 760 sCJD patients underwent some type of surgical procedure before the diagnosis of prion disease, including neurosurgery in 6 (0.8%), ophthalmic surgery in 14 (1.8%), and other surgery in 16 (2.1%). The 6 case-patients who underwent neurosurgery had these operations within 3 months after sCJD onset: procedures performed for subdural hematoma (n = 3), aneurysm (n = 2), and menigioma (n = 1) (Table 6). All 14 case-patients who underwent ophthalmic surgery underwent operations for cataracts, and 7 of these patients had had visual disturbance as an initial symptom of sCJD (Table 7). Among 5 patients for whom information on the effects of ophthalmic surgery could be obtained, 2 had some improvement of visual symptoms after surgery, but the other 3 patients had no improvement. Although both cataracts and sCJD could contribute to the visual symptoms, sCJD would contribute to visual symptoms in patients who had no effects of ophthalmic surgery. We have obtained information about instrument cleaning and sterilization procedures for 3 of 5 patients who underwent neurosurgery and for 5 of 14 patients who underwent ophthalmic surgery after the onset of sCJD. All surgeons reused some of the surgical instruments, but according to the WHO guidelines (16), the sterilization methods of the instruments were not appropriate for eliminating infectious PrP, including the use of ethylene oxide gas or incomplete autoclaving.