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Diagnostic Evaluation for Creutzfeldt-Jakob Disease in Massachusetts, 1991–2001

  1. Michele Jaraa,
  2. Betsey John,
  3. Silvia Kreindela,
  4. Elizabeth Wilk-Rivarda, and
  5. Alfred DeMaria Jr.
  1. Bureau of Communicable Disease Control, Massachusetts Department of Public Health, State Laboratory Institute, Jamaica Plain, Massachusetts
  1. Reprints or correspondence: Dr. Alfred DeMaria, Jr., Bureau of Communicable Disease Control, Massachusetts Department of Public Health, State Laboratory Institute, 305 South St., Jamaica Plain, MA 02130 (Alfred.DeMaria{at}state.ma.us).

  • ↵a Present affiliations: Epidemiology Consulting, Danbury, Connecticut (M.J.); US Department of Agriculture, Animal Plant Inspection Services, National Center for Import Export, Riverdale, Maryland (S.K.); and Department of Community Medicine, Mount Sinai Medical Center New York, New York (E.W.-R.).

 
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Abstract

Background. Surveillance for Creutzfeldt-Jakob disease (CJD) in the United States has become a focus of public health attention due to concerns about disease acquired through exposure to transmissible spongiform encephalopathy in other species. A definitive diagnosis requires neuropathologic examination, yet concerns about the invasiveness of procedures and infection control may be barriers to brain biopsy or autopsy in patients with suspected CJD.

Methods. We reviewed medical records of 50 of the 97 patients identified through the Massachusetts Department of Public Health CJD surveillance system for 1991–2001 and of an additional 21 patients in whom CJD was suspected but later ruled out.

Results. Of the 50 patients, brain biopsy was performed on 14 (28%), brain biopsy or autopsy was performed on 27 (54%), and brain biopsy and autopsy were performed on 4 (8%). Brain biopsy or autopsy was declined for an additional 7 patients (14%) by family or health care proxy. The proportion of patients on whom brain biopsy was performed was inversely correlated with age, with only 9 (21%) of the 43 patients >60 years old having brain tissue diagnosis. Brain biopsy was performed on patients in whom CJD was suspected but ruled out somewhat less often than it was for patients with confirmed CJD (4 [19%] of 21 patients vs. 7 [23%] of 30 patients, respectively; P = .71).

Conclusion. The majority of patients with CJD-related death whose medical records were available had a brain biopsy or autopsy performed or requested (34 [68%] of 50 patients).

Human transmissible spongiform encephalopathies occur as several clinical syndromes, including sporadic Creutzfeldt-Jakob disease (CJD), inheritable forms of disease (e.g., familial CJD, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia), and acquired forms of disease (e.g., kuru and iatrogenic CJD) [1]. Variant CJD was first described in the United Kingdom in 1996 [2], and the weight of epidemiologic, biochemical, and biologic evidence suggests that this disease is also acquired and derives from exposure to beef or other by-products from cattle affected by bovine spongiform encephalopathy [3]. Clinically and epidemiologically, variant CJD is relatively distinct from sporadic CJD. Bovine spongiform encephalopathy had emerged in the United Kingdom 10 years earlier.

Public health agencies have tracked human transmissible spongiform encephalopathies that arise from iatrogenic sources (e.g., pituitary derived human growth hormone, cadaveric dura mater grafts, and corneal transplants), but widespread surveillance of CJD in human populations was uncommon until spurred by the situation with bovine spongiform encephalopathy and variant CJD in the United Kingdom [4–7]. Surveillance for CJD began in Massachusetts in 1992, and CJD was made a reportable condition in the state in 2003.

CJD may be mistaken for a variety of neurological disorders, including Alzheimer disease, dementia with Lewy bodies, Huntington disease, Pick disease, intracerebral hematoma, and vascular dementia [8]. Although diagnostic tests are available that can strongly suggest CJD when it is associated with the characteristic clinical presentation [9, 10], a definitive diagnosis requires brain biopsy or autopsy to identify the hallmark spongiform changes and other abnormalities in the brain [11–13]. The criteria of the World Health Organization (WHO) for possible, probable, and definite CJD is dependent on neuropathologic confirmation [14]. The US Centers for Disease Control and Prevention have called on physicians to arrange for brain biopsies in all cases of suspected or probable CJD [15].

Enhanced CJD mortality surveillance has been performed by the Massachusetts Department of Public Health to monitor trends in the baseline incidence of sporadic CJD, to detect occurrences of variant CJD (should it become evident on clinical or neuropathologic grounds) and to determine the intensity of diagnostic evaluation. We describe the results of a medical record review done as part of enhanced surveillance for CJD in Massachusetts.

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Methods

We attempted to review medical records for all cases of definite, probable, and possible CJD in the Massachusetts Department of Public Health CJD surveillance database. Finding cases of CJD in Massachusetts depends largely on review of death certificates and is supplemented by the Massachusetts' Uniform Hospital Discharge Data Set and occasional reports from hospital infection control practitioners and others. The surveillance system includes Massachusetts residents with the following characteristics: an International Classification of Diseases, Ninth Revision (ICD-9), code of 046.1 (1991–1998), or International Classification of Diseases, Tenth Revision, code of A81.0 (1999–2001), on their death certificate as an underlying or contributing cause of death; or an ICD-9, code 046.1, in the Uniform Hospital Discharge Data Set, with a diagnosis of CJD confirmed by medical record review. During medical record review, we abstracted information on clinical signs and symptoms and the use of electroencephalography (EEG), MRI, CSF analysis, brain biopsy, autopsy, and immunoassays for prion protein associated with spongiform encephalopathy. Whether an autopsy was performed was also determined for all deaths potentially caused by CJD that were identified by death certificates. χ2 Tests were used to examine statistical associations for diagnostic evaluation by demographic and other characteristics.

With use of a list of cases derived from the Uniform Hospital Discharge Data Set for hospital discharges from 1997 to 2000 with codes for a diagnosis of CJD, we compared cases of CJD confirmed during medical record review with those that were not confirmed. Comparisons were made on the basis of EEG, MRI, CT scanning, CSF analysis, immunoassay, brain biopsy, and autopsy. χ2 Tests were used to assess differences between CJD and non-CJD cases with respect to diagnostic tests.

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Results

From 1991 through 2001, a total of 90 deaths due to CJD were detected in Massachusetts from mortality data, and an additional 7 cases not detected by mortality data were found through the supplemental sources noted above, for a total of 97 cases statewide. Massachusetts had a mean of 8.8 deaths due to CJD per year (range, 5–10 deaths) and a mean annual age-adjusted death rate of 1.34 deaths due to CJD per million persons (95% CI, 0.45–2.34). The mean age at death caused by CJD was 70.5 years (range, 44–87 years). Thirty-two (33%) of 97 patients with CJD died in a hospital, 38 (39%) patients died in a long-term care facility, and 27 (28%) died while at home or in hospice care.

We reviewed medical records for 50 (52%) of the 97 patients with CJD. Patients with reviewed records were similar to patients with unreviewed records with respect to age and sex, but they differed by place of death. We were able to locate and review medical records for 27 (84%) of 32 patients who died in a hospital and 23 (35%) of 65 patients who died either at home, in hospice care, or at a long-term care facility.

Of the 50 patients for whom medical records were available, brain biopsy was performed on 14 patients (28%), only autopsy was performed on 13 patients (26%), brain biopsy or autopsy was performed on 27 patients (54%), and both brain biopsy and autopsy was performed on 4 patients (8%) (table 1). For 7 patients (14%), brain biopsy or autopsy was suggested but declined by the patient's family or health care proxy. Autopsy was performed on 13 (36%) of the 36 patients on whom brain biopsy was not performed; autopsy was also performed on 4 (29%) of the 14 patients on whom brain biopsy was performed. The proportion of patients on whom brain biopsy was performed was inversely correlated with age, with 5 (71%) of the 7 patients with ages <60 years, 9 (24%) of the 37 with ages of 60–79 years, and no patient with an age ⩾80 years (n = 6) having undergone the procedure (figure 1). There was no association between sex and the likelihood of having undergone either brain biopsy or autopsy.

Figure 1
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Figure 1

Proportions of patients with Creutzfeldt-Jakob disease (CJD) whose medical records were reviewed and who underwent brain biopsy (14 of 50 patients) and patients with CJD on whom autopsy was performed (34 of 97 patients, ascertained by death certificate), by age at death.

Table 1
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Table 1

Performance of brain biopsy and autopsy on 50 patients with suspected Creutzfeldt-Jakob disease whose medical records were reviewed.

Table 2 presents information on selected diagnostic studies in patients with suspected CJD whose medical records were reviewed. All patients had at least 1 EEG. Forty-two (84%) of the 50 patients whose records were reviewed had at least 2 EEGs with ⩾1 that were suggestive of CJD (i.e., an EEG with diffuse background slowing and generalized periodic sharp wave complexes). Either brain biopsy or autopsy was performed on 21 (50%) of the 42 patients with an EEG suggestive of CJD, whereas either brain biopsy or autopsy was performed on 6 (75%) of the 8 patients whose EEG results did not suggest CJD (χ2 = 1.69; P = .19).

Table 2
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Table 2

Diagnostic evaluations performed on 50 patients with suspected Creutzfeldt-Jakob disease whose medical records were reviewed.

Applying WHO surveillance criteria [14] to these 50 patients, all of whom had a clinical presentation and/or a course consistent with CJD (clinical criteria), cases in 27 patients (54%) were classifiable as “definite” on the basis of neuropathology, cases in 21 patients (42%) were classifiable as “probable” on the basis of typical EEG findings and no alternative diagnosis, and cases in 2 patients (4%) were classifiable as “possible.” Medical record review failed to reveal any evidence suggesting iatrogenic or familial CJD.

Among all patients in the CJD surveillance system, death certificates demonstrated that autopsies were performed on 34 (35%) of 97 patients. For all of these cases of CJD captured by the surveillance system, the proportions of patients on whom autopsy was performed were as follows: 8 (24%) of 32 patients who died in hospitals, 16 (42%) of 38 patients who died in long-term care facilities, and 10 (37%) of 27 patients who died at home or in hospice care. Autopsy was not associated with age (figure 1) or with sex.

Medical records were reviewed for an additional 21 patients in whom CJD was suspected, according to hospital discharge coding, but CJD was later ruled out by determination of an alternative diagnosis, a lack of progression, or a survival of >2 years. Brain biopsy was performed on these patients less often than it was for the comparison group of patients diagnosed with CJD (definite, probable, or possible) in the same time period (4 [19%] of 21 patients vs. 7 [23%] of 30 patients, respectively; P = .71). There were statistically significant differences in the use of all other procedures related to the diagnosis of CJD (table 3). The rate of autopsy was 5% (1 of 21 patients) for patients in whom CJD was later ruled out, compared with 30% (9 of 30 patients) for patients with a diagnosis of CJD (χ2 = 4.99; P = .03). This is to be expected, because many of the patients in whom CJD was not a valid diagnosis survived, whereas there were no survivors among patients with CJD.

Table 3
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Table 3

Comparison of diagnostic evaluations of patients with confirmed cases of Creutzfeldt-Jakob disease (CJD) and patients determined not to have CJD, 1998–2000.

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Discussion

In Massachusetts, the diagnostic work-up for suspected CJD cases is substantial. This review of medical records reveals that patients with signs and symptoms consistent with CJD are evaluated extensively and intensively with clinical evaluation, multiple EEGs, imaging studies (both CT scanning and MRI), and brain biopsy and/or postmortem examination of the brain. Although multinational studies have demonstrated reasonable sensitivity and specificity for diagnostic criteria that include EEG, CSF analysis, and brain imaging studies in cases of CJD considered to be probable or possible on the basis of clinical evaluation, histologic and immunopathologic examination of brain tissue is still considered to be the only basis for definitive diagnosis [8, 9, 13, 14].

Anecdotal reports suggest that physicians and pathologists may be hesitant to perform brain biopsy or autopsy on patients with suspected CJD. A recent review of CJD mortality data in California found that the autopsy rate was low, just 21% for 1990–2000. More than one-third of neurologists who responded to a questionnaire said that they had never considered pursuing autopsy in a case of CJD, and only 35% of pathologists were comfortable recognizing classic CJD neuropathology. The proportion of pathologists who were comfortable recognizing variant CJD neuropathology was 15% [16]. In addition to concern about the invasiveness of craniotomy for brain biopsy, there is concern about the risk posed to health care workers who handle the brain tissue, despite this risk being extraordinarily low [17]. Instruments must be subjected to more stringent decontamination procedures because of the resistance of prions to standard disinfection and sterilization measures [18]. Respondents to the California survey cited infection control (77%), lack of experience (62%), and institutional limitation (53%) as major obstacles to autopsy performance [16]. Additional factors that discourage the performance of brain biopsies include cost, the risk of a false-negative result if biopsy is performed on an unaffected region of the brain, and the lack of benefit to the patient from a definitive diagnosis of CJD, because the disease is invariably fatal.

The majority of patients with CJD-related deaths whose medical records we reviewed had or had been offered brain biopsy or autopsy. The rate of brain biopsy differed according to age. Brain biopsy was routinely performed on patients at the younger end of the age range; as age increased, brain biopsy was performed on proportionately fewer patients. The proportion of autopsies performed on patients who were suspected of having a CJD-related death was substantially higher than the proportion of autopsies for all deaths performed statewide (35% vs. 5%; Massachusetts Registry of Vital Statistics). These results suggest that physicians and pathologists were not very reluctant to perform brain biopsy or autopsy on patients with suspected CJD. The willingness to perform autopsies is important, because neuropathologic examination is not only crucial for confirming CJD, but also for distinguishing variant CJD from the sporadic form. Autopsy findings may also contribute to research efforts to develop premortem diagnostic tests and treatment modalities.

An important limitation of this study is that we only had data regarding diagnosed or suspected cases. Our data sources were limited to hospital discharges, death certificates, and occasionally, reports from practitioners. Case ascertainment for CJD using death certificates is considered efficient, particularly when supplemented with active surveillance to confirm the diagnosis [19, 20]. However, the proportion of cases in which the diagnosis of CJD was missed is unknown. This limitation may itself be caused, in part, from reluctance to perform the invasive procedures necessary for diagnosis. An intensive retrospective surveillance effort in Australia by the Australian National Creutzfeldt-Jakob Disease Registry reported a sensitivity for death certificate diagnosis of CJD of 83%, with a rate of false-positive results of 11.5% [21]. In a study of possible misclassification of CJD-related deaths in England, Majeed et al. [22] found that structured review of medical records of patients with a variety of neurological diseases failed to reveal new cases of CJD or variant CJD; like us, they were able to retrieve ∼50% of clinical records.

In conclusion, we did not observe evidence of a significant hesitance in Massachusetts to perform brain biopsy or autopsy for patients with suspected CJD, especially for patients of younger age. However, further work is needed to determine the extent to which CJD may be underdiagnosed.

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Acknowledgments

Financial support. Centers for Disease Control and Prevention, Epidemiology and Laboratory Capacity Program Cooperative Agreement (U50/CCU115217) (salary support to M.J.).

Potential conflicts of interest. All authors: no conflicts.

  • Received March 3, 2005.
  • Accepted May 10, 2005.
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  1. Clin Infect Dis. (2005) 41 (6): 829-833. doi: 10.1086/432723
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