Using Catchment Population to Estimate Sporadic Creutzfeldt–Jakob Disease Incidence

ABSTRACT

Introduction

Catchment populations have several uses. A method using catchment population to estimate the incidence of sporadic Creutzfeldt–Jakob disease (sCJD) is described.

Materials and Methods

A cohort of nine consecutive patients diagnosed with sCJD, symptom onset spanning 26 months, were observed at a rural tertiary university medical center that has approximately 40,000 hospital discharges annually. An effective catchment population was determined using surrounding county utilization frequency that captured all nine sCJD patients and accounted for over 87% of discharges.

Results

The effective sCJD hospital catchment population was 1.266 million, implying an annual sCJD incidence rate of 3.39 per million (95% CIs, 1.55-6.43), assuming a Poisson distribution for sCJD occurrence.

Conclusions

This annual incidence rate suggests that many sCJD patients are unrecognized and unreported. An advantage of this catchment population method is independence from death certificate accuracy, important in rare diseases that are both rapidly and invariably fatal. The relative absence of significant healthcare systems competition in this rural population enhances the reliability of this finding. The most likely explanation for the high sCJD incidence rate suggested by this study is enhanced clinical suspicion and improved diagnostic accuracy.

INTRODUCTION

Hospital catchment populations have long captured interest and were originally focused on planning for medical needs.^1,2 However, catchment populations can also have relevance for specific diseases.³ For example, if the occurrence of a specific disease (numerator) in a hospital catchment population (denominator) over a specified period of time can be determined, then the necessary elements to calculate an incidence rate exist. Rare diseases, if accurately recognized and diagnosed, might be particularly well-suited to a study aimed at estimating an incidence rate from a catchment population.

The global annual incidence of sporadic Creutzfeldt–Jakob disease (sCJD) is estimated at 1-2 cases per million and is slowly increasing.⁴ Sporadic Creutzfeldt–Jakob disease (sCJD) is a rare, rapidly progressive, and uniformly fatal disorder⁵ that accounts for 85% of human prion diseases⁶ and is characterized by accumulation of abnormal prion protein (PrP).⁷ In sCJD, the normal cellular PrP, rich in α-helical content, assumes a disease-causing isoform PrP^CJD, rich in β-sheet structure. Resistant to protease digestion, PrP^CJD accumulates producing a characteristic spongiform encephalopathy.^5,7 Sporadic Creutzfeldt–Jakob disease (sCJD) is characterized by rapidly progressive dementia with associated ataxia, myoclonus, and dystonia progressing to obtundation and death within months.⁸

Evaluation for sCJD includes electroencephalography (EEG), detection of cerebrospinal fluid (CSF) 14-3-3 protein, and brain magnetic resonance imaging (MRI).

The characteristic EEG finding is positive sharp wave complexes (PSWCs), having a sensitivity and specificity of about 65% and 85%, respectively.^9–11 The CSF 14-3-3 protein detection has a sensitivity and specificity of about 90% and 85%, respectively.^12–14 Characteristic abnormalities on brain MRI (especially basal ganglia hyperintensity) have a sensitivity and specificity of about 60% and 85%, respectively.^15,16 The development of an ultrasensitive human PrP detection CSF assay facilitated the antemortem diagnosis of sCJD.¹⁷ This real-time quaking-induced conversion (RT-QuIC) assay has a sensitivity of about 96% and specificity of 100%, respectively.¹⁸

The observation of a cohort of nine consecutive patients with sCJD at a rural tertiary university medical center prompted a study aimed at estimation of the incidence rate of sCJD using this hospital’s catchment population for this disease.

METHODS

A Not Human Subjects Research waiver was obtained from the West Virginia University Institutional Review Board.

West Virginia University Hospital (WVUH) is a large rural tertiary university medical center primarily serving northern West Virginia (WV), eastern Maryland (MD), southwestern Pennsylvania (PA), and southeastern Ohio (OH). In 2020, there were 39,564 discharges, coming from 452 U.S. counties. A single discharge came from 206 counties, and 318 counties contributed three or less discharges. Thus, the vast majority of counties were not part of WVUH’s usual catchment population. Six counties (four in WV and two in PA) with a population of 427,605 accounted for 20,253 (51.19%) discharges. Ranking counties by utilization (dividing county discharges by county population) revealed 11 counties (9 in WV, 1 in PA, and 1 in MD having a combined population of 343,263) accounted for 20,024 (50.16%) discharges. Doubling either of those population counts to estimate a catchment population would not be appropriate for the sCJD catchment population since those discharges represented more frequent and less complicated conditions.

A descending ranking of counties by utilization rate was used until all nine sCJD cases were captured. Using this method, 35 counties (30 in WV, 2 in PA, 2 in MD, and 1 in OH with a combined population of 1,105,313) were required to capture all nine sCJD cases and accounted for 34,537 (87.29%) hospital discharges. The 1,105,313 number was population-adjusted by multiplying by 39,564/34,537 to calculate a sCJD WVUH catchment population of 1,266,196. This adjustment provided a population-weighted utilization average for the 35 counties required to capture all sCJD cases.

The number (N) of events (sCJD cases) is the product of population (P), rate (R), and time (T),

Since R (sCJD incidence rate) is the unknown

where R is sCJD cases per million, N is number of sCJD cases, P is the population in millions, and T is the time in years.

RESULTS

Table I shows laboratory details of nine consecutive sCJD patients (symptom onset, June 2018 to August 2020). The RT-QuIC was positive in 7 of 8. In patient 6, RT-QuIC was not collected, but 14-3-3 was positive and EEG displayed PSWC discharges. In patient 9 (in whom RT-QuIC was negative), 14-3-3 was positive, EEG displayed PSWC discharges, and brain MRI displayed characteristic sCJD abnormalities. Patient 7 underwent brain biopsy (not performed for sCJD) which demonstrated spongiform encephalopathy. Of note, there was no family history of rapidly progressive dementia leading to death in any of these nine cases. Eight of these nine patients died within 4 months of symptom onset. One patient was lost to follow-up.

Using eqn (2) above, the incidence rate of sCJD is readily calculated

Therefore, the annual sCJD incidence rate in the WVUH catchment population is 3.39 cases per million. Rare events over time conform to a Poisson distribution if they occur randomly and independently, and the probability is constant over time. Given one observation of nine rare events, the 95% CIs of the Poisson rate parameter lambda (λ) is readily located.¹⁹ The lower 95% CI value for λ is 4.12. The upper 95% CI value for λ is 17.08. Using 4.12 and 17.08 in eqn (3) in place of 9 yields 95% CIs. Thus, the 95% CIs for the annual sCJD incidence rate is 1.55 to 6.43 cases per million.

DISCUSSION

The lower 95% CI rate of 1.55 cases per million population for sCJD found in this study is within the generally reported incidence rate of 1-2 cases per million population. The incidence rate⁴ of 3.39 cases per million population found in this study, however, might suggest that sCJD was over-diagnosed at this hospital. However, seven cases were RT-QuIC positive. Patient 6 had PSWC on EEG and 14-3-3 in the CSF, but there were no characteristic findings on brain MRI. The likelihood that patient 6 does not have sCJD, given these findings and assuming the tests are independent, is the product of false positive EEG times false positive 14-3-3 times true negative brain MRI (or 0.35 × 0.10 × 0.60) which is 0.021 (or 2.1%). Patient 9 had PSWC on EEG, 14-3-3 in the CSF, and characteristic abnormalities on brain MRI. The likelihood that patient 9 does not have sCJD is the product of false positive EEG times false positive 14-3-3 times false positive brain MRI (or 0.35 × 0.10 × 0.40) which is 0.014 (or 1.4%). Consequently, it is unlikely that sCJD cases were overdiagnosed. Rather, it is more likely that some sCJD cases could have occurred and not been admitted to WVUH.

As sCJD is both rapidly and invariably fatal, incidence and mortality rates of sCJD should be equivalent. The Centers for Disease Control and Prevention tracks deaths attributed to sCJD.²⁰ From 1979 through 2019, sCJD deaths increased from a low of 172 in 1980 to a high of 561 in 2019.²⁰ However, these mortality statistics are dependent upon diagnoses entered on death certificates. This increase in the number of sCJD deaths likely reflects increased disease awareness and improved diagnostic capability.

If the WVUH catchment population for sCJD is 1.266 million, the U.S. population is 328.2 million, and this rural population is representative of the U.S. population, which would imply an expected 1843 sCJD deaths in the USA per year. However, is the WVUH rural catchment population representative of the U.S. population with respect to sCJD? The older age demographics of this rural tertiary university medical center catchment population could increase the expected sCJD incidence rate. However, this demographic effect is insufficient²¹ to account for the magnitude of the implied higher-than-reported sCJD incidence. Additionally, rural populations have been noted to have dietary habits that include the consumption of wild animal brains.^22–24 However, no evidence of this practice has been substantiated in sCJD or was reported in this cohort of patients by their families. Consequently, our results suggest that sCJD deaths are likely underreported on death certificates. Indeed, an advantage of this study is that it infers a sCJD incidence rate from a catchment population and is independent of death certificates.

No family history of rapidly progressive and fatal dementia occurred in this cohort of nine sCJD cases. Accordingly, these nine patients were not tested to identify mutations in the prion protein gene (PRNP) gene. The PRNP mutations account for 10-15% of human prion diseases.^25–27 The ages and short duration of illness in this cohort are characteristic of sCJD, rather than familial or genetic prion disease.^25–27 While spongiform encephalopathy was pathologically confirmed in one patient in this cohort, brain biopsy in patients with suspected transmissible spongiform encephalopathy, such as sCJD, is not routinely performed or advocated.^28,29

This study involved new diagnoses of sCJD in a rural population with little healthcare systems competition, a situation difficult to replicate at most locations. However, this limitation can be alternatively viewed as an opportunity to capture a sense of the magnitude of the actual sCJD incidence rate and is supportive of the suspicion that many cases of sCJD go unrecognized. As no treatment is available for sCJD, referral bias treatment patterns³⁰ did not likely have an impact on this estimated sCJD incidence rate. Accordingly, the most likely explanation for the higher sCJD incidence rate suggested by this study is enhanced clinical suspicion and improved diagnostic accuracy.

ACKNOWLEDGMENT

None declared.

FUNDING

None declared.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES

Author notes