Characterization of Laboratory-Confirmed Creutzfeldt-Jakob Disease From 3 Ontario Tertiary Care Centers Between 2012 and 2022: A Retrospective Cohort Study

Abstract

Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disorder with a global incidence of approximately 1 to 2 people per million annually [1–3]. The pathophysiology of the disease occurs as a result of the accumulation of misfolded prion protein (PrP^Sc) in the brain, causing characteristic spongiform changes in cerebral tissue, which ultimately impairs neurologic function and leads to disease [1–4]. CJD manifests in several forms, with sporadic CJD (sCJD) representing the majority of cases. While it primarily affects older adults, other identifiable risks remain poorly understood [1, 2, 4–6]. In contrast, genetic CJD arises in individuals with mutations in the PRNP gene, which codes for normal prion protein (PrP), or patients may have a family history of CJD, fatal familial insomnia, or Gerstmann-Sträussler-Scheinker syndrome, which accounts for 10% to 15% of cases [4, 5]. Acquired CJD encompasses 2 subtypes: variant CJD, which is spread zoonotically by consuming bovine spongiform encephalopathy–infected cattle meat, and iatrogenic CJD. Less than 1% of cases are represented by both subtypes [2]. The disease course of CJD, regardless of form, is tragically, relatively short. It is characterized by a rapid decline in cognitive function, myoclonus, ataxia, memory loss, and visual changes [1–8]. As the disease progresses, mental deterioration intensifies, potentially leading to severe spasticity, loss of movement and speech, and ultimately coma, with a median survival time of 4 to 5 months [1–8].

Current diagnostic challenges impede timely and accurate identification of CJD. The disease's diverse clinical presentation can mimic symptoms of stroke, dementia subtypes (Lewy body and Alzheimer), encephalitis, psychiatric disorders, and movement disorders [5]. This resemblance to other neurologic or psychiatric conditions necessitates multidisciplinary consultation and extensive investigations to rule out alternative etiologies, especially considering the often-advanced age and comorbidities among those presenting with symptoms. Definitive diagnosis hinges on pathologic or microbiological confirmation. Given the complexities of achieving a conclusive diagnosis, clinicians must be equipped to recognize the early warning signs of CJD.

The epidemiology of CJD remains poorly understood, with disease trends varying across geographic regions. The Canadian Creutzfeldt-Jakob Disease Surveillance System, established in 1998 by the Public Health Agency of Canada, aims to systematically document all human prion diseases in the country [9, 10]. CJD is a reportable disease in Canada, and since 1998, 1378 cases have been reported nationwide, including 484 confirmed cases in Ontario over the past 25 years [1–4, 10]. However, there is currently a lack of up-to-date Canadian data on disease recognition, symptom presentation, linkage to care, and morbidity related to CJD. Regional data are crucial to understand disease patterns and identify potential risk factors associated with the disease. As such, this study examines CJD cases from three major academic centers recently in Ontario, Canada, over a 10-year period. The primary objective was to analyze trends and timelines related to CJD diagnosis through comprehensive retrospective chart review analysis.

METHODS

Study Design and Setting

This retrospective descriptive cohort study comprised a convenience sample of patients from three tertiary care centers in Ontario, Canada, with a laboratory-confirmed CJD diagnosis between 1 January 2012 and 31 December 2022. This cohort study followed the STROBE reporting guideline (Strengthening the Reporting of Observational Studies in Epidemiology). Data from patients’ electronic medical records were collected, deidentified, and entered into an encrypted REDCap platform through designated instruments to ensure uniformity in data collection from chart review and to minimize bias. Each field was prescriptive, limiting the amount of free text that could be entered.

Patient Consent Statement

This retrospective chart review was approved by the Western University research ethics board, and this multicenter study (project 4172) was approved through Clinical Trials Ontario. A waiver of consent was applied in accordance with Tri-Council Policy Statement 2, article 5.5A/B.

Investigations

In this study, laboratory-confirmed CJD diagnosis was defined as a positive end-point quaking-induced conversion (EP-QuIC) assay, positive 14-3-3 protein and total tau (t-tau), or positive PrP^Sc. The term acute phase was defined as occurring 6 months before diagnosis, whereas chronic phase occurred >6 months before diagnosis. Retrospective data collected included patient demographics, admission history, risk factors, personal medical history, presenting illness history, disease progression, CJD subtype, laboratory findings at diagnosis, blood and cerebrospinal fluid (CSF) analyses, neurologic assessments (eg, Glasgow Coma Scale, Montreal Cognitive Assessment [MoCA], Mini-Mental Status Examination, electroencephalogram [EEG] tests, and magnetic resonance imaging [MRI] scans), and post–diagnostic care outcomes. Post–diagnostic care outcomes were recorded in patients’ charts and monitored until discharge, with additional data gathered from readmitted patients to supplement the results.

Statistical Analysis

Descriptive statistics were used to calculate means, medians, and standard deviations. Graphs were created with Prism (version 10.1.2; GraphPad).

RESULTS

Study Cohort

We identified 30 individuals from three institutions within the study period (n = 10, site 1; n = 4, site 2; n = 16, site 3). The mean age was 67.4 years (SD, 8.8) and 70.0% (n = 21) were male. Few patients had known risk factors, with 13.0% reporting a family history of dementia and 20.0% a family history of other neurologic conditions. Only 6.0% of patients reported an extended travel history to the United Kingdom (Table 1). None of the individuals had a family history of CJD, received human growth hormone treatment before 1985, underwent dura/corneal transplant, or reported potential consumption of infected beef. Most cases (n = 28, 93.3%) were determined to be sCJD, with 1 case of variant CJD and 1 case of genetic CJD. None of the patients were diagnosed with iatrogenically acquired CJD. Interestingly, a significant portion of CJD cases in our study emerged after 2020 (Figure 1).

Figure 1.

Number of Creutzfeldt-Jakob disease (CJD) cases at 3 tertiary care centers in Ontario, Canada, from 2012 to 2022.

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Time to Diagnosis

Patients in the study had a mean 2.2 hospital visits (range, 1–5; SD, 1.2) prior to their admission for further diagnostic evaluation of their condition. The intervals between neurologic presentation visits were as follows: 32.3 days (range, 1–310; SD, 67.5) between the first and second visits, 17.8 days (range, 2–89; SD, 22.3) between the second and third visits, and 18.2 days (range, 3–70; SD, 26.0) between the third and fourth visits (Table 1).

Symptom Presentation and Comorbidities

Symptom presentation was divided into 2 phases: acute (<6 months prior to diagnosis) and chronic (>6 months prior to diagnosis). During the acute phase, patients reported experiencing a mean 6.8 symptoms (range, 1–12; SD, 2.7). No single symptom was common to all patients, and the most prevalent symptoms included loss of coordination/balance (63.3%, n = 19), changes in behavior (60%, n = 18), and progressive mobility loss (53.4%, n = 16). Notably, memory loss and involuntary movement were both reported by 50% of patients (Figure 2). Among the cohort, 4 patients had chronic symptoms, with a mean 2.0 symptoms (range, 1–4). Within this phase, symptoms encompassed loss of intellect/memory in 2 patients, alongside manifestations such as changes in behavior/personality, increased irritability/agitation, lack of coordination/loss of balance, slurred speech, numbness/tingling, sleep disturbances, and involuntary movements. Patients had a mean 3.5 comorbidities (range, 0–12; SD, 2.6), with 16.6% diagnosed with depression, 13.3% diagnosed with anxiety, and 10% experiencing insomnia (Table 1). No patients had a history of myocardial infarction, cerebral amyloid angiopathy, hypertensive encephalopathy, or vasculitis.

Figure 2.

Distribution of symptoms reported by patients in the 6 months prior to diagnosis.

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Diagnostic Investigations

CJD diagnosis involves cognitive/memory assessment, neuropsychology evaluation, physical examination, MRI, EEG, and microbiological testing of the CSF (eg, RT-QuIC, 14-3-3 protein levels) [5–8]. We assessed the various investigations performed on this cohort to gauge their utility (Table 2). It was noted that 83.3% underwent EEG testing upon presentation, with only 56.7% exhibiting periodic sharp wave complexes characteristic of CJD. MRI scans were conducted in 80.0% of cases, revealing potential CJD indicators, such as diffuse restriction/cortical banding in 76.7% of patients, asymmetrical hyperintensities in 50.0%, and pulvinar sign in 3.3%. The mean duration from symptom onset to EEG testing was 74.9 days (SD, 88.3), while MRI scans were conducted at 86.7 days (SD, 90.6). Furthermore, the mean duration from symptom onset to CJD laboratory testing of CSF was 91 days (SD, 90.7). Additionally, only a subset of patients received neurologic scoring tests, with the MoCA being the most common (36.7%). At first presentation, the mean MoCA score was 16.6 of 30 (SD, 4.9), indicative of cognitive dysfunction.

The blood biochemistry profile 7 days prior to the laboratory testing for CJD did not reveal any abnormalities (Table 3). CJD testing results indicated that 90.0% of patients were positive by the EP-QuIC and 83.3% of patients showed positivity for 14-3-3 and t-tau proteins. All test results for cryptococcal antigen, HSV-1, HSV-2, varicella-zoster virus, and CSF autoimmune encephalitis were negative. Importantly, all biochemical parameters for CSF, including protein, glucose, and white blood cells, remained within normal ranges at the time of diagnosis.

The levels of CSF 14-3-3 and t-tau were analyzed over the timeline from symptom onset to death to investigate if higher levels of these biomarkers correlated with shorter disease duration. CSF 14-3-3 levels showed a significant trend of being higher in patients who had a shorter duration from symptom onset to death (R² = 0.71, F = 19.55, P = .0022; Supplementary Figure 1). A similar, though less pronounced, trend was observed in the t-tau levels (R² = 0.40, F = 5.42, P = .0483; Supplementary Figure 2).

Admission and Care Outcomes

The mean length of admission was 17.5 days (range, 1-55; SD, 14.1; Table 1). Post–diagnosis care outcomes revealed that 46.7% of patients were discharged home, 16.6% were transferred to external palliative care or hospice facilities, and 36.7% died during their hospital stay, with 10 of 11 of these patients dying in hospital-based palliative care. For patients who died during admission, the mean duration from symptom onset to death was 121.0 days (SD, 120.7), while the mean duration from laboratory diagnosis of CJD to death was 35.1 days (SD, 83.9). Only 16.6% of patients underwent autopsy examinations. No patients were transferred to long-term care facilities or requested/underwent Medical Assistance in Dying (MAID).

DISCUSSION

CJD possesses a public health challenge due to its rarity, its similarity to other conditions requiring multiple visits and extensive investigations for a definitive diagnosis, and its significant impact on those affected. The goal of this study was to present the current state of CJD cases in specific areas of Ontario. This descriptive study, which examined recent CJD cases from three institutions over a 10-year period, provides valuable insights into the trends of this rare disease, allowing health care practitioners to identify warning signs that may indicate this diagnosis. In our study, the mean age of CJD onset was 67.4 years, with a male predominance (70.0% vs 30.0%). Although a small smaple, our findings are in contrast the literature, which shows a higher prevalence of CJD in older females [11–13]. Furthermore, comprehensive data on mean hospital visits or comorbidities among patients with CJD are lacking in existing literature, which our study addresses by demonstrating a mean 2.2 hospital visits before further testing and 3.5 comorbidities per patient, with prevalent conditions including depression, anxiety, and insomnia.

A notable increase in cases, particularly evident in 2022, prompts exploration of factors such as improved diagnostic techniques, delayed medical care seeking, the impacts of COVID-19 infection, or possible environmental influences [11]. Literature hints at a potential link between COVID-19 inflammation and accelerated prion disease progression [14–18], necessitating additional research for a possible correlation. This demonstrates the importance of further investigating the etiology of this disease, which appears to be steadily increasing over time. Our results are consistent with nationwide patterns observed in the Creutzfeldt-Jakob Disease Surveillance System, showing a steady increase in CJD cases across the country, particularly in Ontario and Quebec, with annual increases in certain years [9, 10]. Of all the cases of CJD reported in Ontario in 2022, this study includes 12 of 28 cases, constituting 42.9% of the annual cases. Among the 435 cases in Ontario between 2012 and 2022, our study accounted for 30, representing approximately 6.9% of the provincial total.

The primary diagnosis was sCJD, in 93.3% of cases, with variant CJD and genetic CJD each accounting for one case. Risk factors such as family history of dementia (13.3%), other neurologic conditions (20%), or extended travel to the United Kingdom (6.7%) were noted among some patients. However, given the predominance of sCJD, understanding its etiology remains challenging. sCJD typically arises from a random mutation in the PrP codon 129, which can be classified into 6 subgroups (MM1, MM2, MV1, MV2, VV1, VV2), each contributing to the pathologic features of the disease [19]. Unfortunately, the hospitals in our study did not report the specific subtypes of sCJD for the patients, which would have provided valuable clinical data. Therefore, reporting subtypes should be prioritized for this rare disease.

Neurologic scoring via the MoCA was conducted at presentation for 36.7% of patients, with a mean score of 16.6 of 30, indicating cognitive impairment. While the Glasgow Coma Scale and Mini-Mental State Examination were utilized, there is a lack of standardized tools for CJD-related cognition testing; therefore, a significant delay in CJD testing has been shown to occur if nonprion disease is first suspected [20]. The CJD Neurological Symptom scale developed by Cohen et al provides a specialized tool for assessing neurologic symptoms in patients with CJD. This scale demonstrated high diagnostic accuracy, with sensitivity and specificity rates of 97% and 100%, respectively [21]. It is recommended as a supplementary tool alongside other cognitive assessments for more accurate diagnosis and monitoring of patients with CJD, and its implementation in the diagnostic process of CJD should be considered.

At first presentation, most patients underwent EEG (83.3%) and MRI (80.0%), revealing significant findings, such as periodic sharp wave complexes on EEG (56.7%) and varied MRI abnormalities, including diffuse restriction or cortical banding (76.6%), asymmetrical hyperintensities (50.0%), and pulvinar sign (3.3%). Carswell et al noted characteristic MRI signals of CJD in 91.0% of cases at the National Prion Clinic, as compared with only 47.0% at referral clinics, suggesting potential missed diagnoses, especially in advanced stages of the disease [22]. The utility of MRI in diagnosis is notable; however imperfect, necessitating repeat scans. Our study underscores the low sensitivity of MRI in detecting CJD, as evidenced by the absence of indicators in all patients. Notably, patients with initially normal MRI results in our study underwent repeat testing due to red flags for CJD, highlighting the necessity of comprehensive evaluation and follow-up in suspected cases. On average, patients underwent EEG and MRI testing approximately 2.5 to 3 months after symptom onset, with EEG conducted at 74.9 days and MRI slightly later at 86.7 days. The duration from symptom onset to confirmed diagnosis through lumbar puncture averaged around 3 months (91 days). In previous research, Paterson et al found a mean 3.8 misdiagnoses and a median 7.9 months from symptom onset to correct diagnosis for patients with sCJD [23]. Additionally, Mastrangelo et al suggested prioritizing MRI scans, followed by lumbar puncture for RT-QuIC/EP-QuIC confirmation testing, to enhance diagnostic efficiency [24]. Our study highlights a consistent pattern of EEG and MRI testing within 3 months after symptom onset and a mean 16.2 days from lumbar puncture to diagnosis, further demonstrating that as time progresses, timely diagnoses occur, enabling faster intervention.

In our study, 90.0% of patients tested positive for prion protein via EP-QuIC, while 83.3% were positive for 14-3-3 and t-tau proteins. Although these established biomarkers showed significant positivity, their diagnostic limitations and specificity for CJD remain a concern, as highlighted by other studies. A 2019 Canadian study assessed EP-QuIC's negative and positive predictive values, revealing a negative predictive value of 100.0% and a positive predictive value of 83.0%, which increased to 100.0% after protocol optimization [25]. Similarly, a study comparing CJD with other mimic diseases found that the 14-3-3 protein was neither sensitive nor specific for CJD, raising concerns about the diagnostic utility of this biomarker in the modern era of more accurate detection assays [26]. Both studies, like ours, highlight the challenges in diagnosing CJD due to its resemblance to other diseases, conflicting biomarker data, and variations in diagnostic tools such as EEG and MRI.

Our findings align with recent reports suggesting prognostic potential for 14-3-3 and t-tau levels. Shir et al proposed that visual or cerebellar features, myoclonus, and elevated CSF protein 14-3-3 and t-tau levels could be associated with shorter disease duration, suggesting potential prognostic value [27]. Additionally, another study demonstrated that patients with lower levels of 14-3-3 and t-tau proteins took longer to exhibit symptoms and receive a diagnosis, suggesting that lower levels of these biomarkers may be indicative of slower disease progression [28]. In our study, patients with the highest levels of t-tau and 14-3-3 exhibited a shorter disease life span and died earlier during hospitalization, suggesting their potential as prognostic markers. Unfortunately, 14-3-3 and t-tau protein levels were not available for all patients, which could have strengthened these findings and provided more insight into disease progression. With increasing evidence suggesting the prognostic utility of these biomarkers, further research is needed to validate this connection.

Outcomes after diagnostic care revealed that 46.7% of patients were discharged home, 36.7% were directly transferred to palliative care, and 36.7% died during their hospital admission. The mean duration from symptom onset to death was 121 days (approximately 4 months), and that from diagnosis to death was 35 days. According to the National Institutes of Health, nearly 70.0% of patients with CJD die within one year of symptom onset, highlighting the disease's severity and rapid progression [2]. However, individual outcomes may vary due to factors such as disease subtype, comorbidities, and access to care. Given the small cohort size, the timelines and outcomes observed may not be representative of significant trends, including the lack of outcome data once discharge from the hospital occurred.

A limitation of our study was the relatively small cohort size, which resulted in only descriptive statistics performed. The rarity of the disease is a challenge to accumulating large numbers of cases. While we focused our study on tertiary academic care centers that are likely to encounter CJD cases, some patients may be misdiagnosed or may not seek additional care following diagnosis. Additionally, prion genotyping results were not available, preventing the linking of any mutations with clinical data.

CONCLUSION

This study sheds light on the current state of CJD in Ontario, Canada. Importantly, including the CJD Neurological Symptom assessment tool could improve identification of patients, which may have led to earlier microbiologic testing and imaging, both of which took up to 3 months from initiation presentation. While currently there are no interventions to stop disease progression, early diagnosis has the potential to improve symptom management and support earlier patient linkage to transitional or home care.

Supplementary Data

Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. We thank the clinical, laboratory, and administrative teams who assisted with this work.

Author contributions. Conceptualization and study design: R. A. K., M. J. B. Investigation: K. G., X. L., P. M. S., M. J. B., R. A. K., S. D., A. C. Analysis and summary of data: K. G., X. L., S. D., A. C., P. M. S. Funding acquisition: M. J. B., R. A. K. Supervision: R. A. K., M. J. B. Writing–original draft: K. G., R. A. K., M. J. B. Writing–editing: All authors reviewed the manuscript and approved the final version to be published and agreed to be accountable for all aspects of the work.

References

Author notes