Characterization of Laboratory-Confirmed Creutzfeldt-Jakob Disease From 3 Ontario Tertiary Care Centers Between 2012 and 2022: A Retrospective Cohort Study
Kayla Gaete, Soma Dalai, Ana Cabrera, Xena Li, Prameet M Sheth, Robert A Kozak, Mia J Biondi
Infectious Diseases, Volume 11, Issue 10, October 2024, ofae551, https://doi.org/10.1093/ofid/ofae551 Published: 28 October 2024
Abstract
Background
Globally, Creutzfeldt-Jakob disease (CJD) affects one in one million people annually, but there is a paucity of recent Canadian data. This study summarizes epidemiology trends and diagnostic timelines of laboratory-confirmed CJD cases in three tertiary Ontario hospitals.
Method
Using laboratory information systems, we identified 30 patients with a laboratory-confirmed CJD diagnosis between 2012 and 2022 at three major tertiary hospitals in Ontario. Retrospective chart reviews were then completed.
Results
Patients had a mean of 2.2 hospital visits (SD, 1.2) prior to being admitted for testing. The most common symptom presentations included loss of coordination (63.3%), behavioral changes (60%), progressive mobility loss (53.4%), memory loss (50.0%), and involuntary movements (50.0%). Magnetic resonance imaging findings showed potential CJD in 76.7% of cases, and 56.7% exhibited periodic sharp wave complexes characteristic of CJD on electroencephalogram. The mean duration from symptom onset to microbiologic testing was 91 days (SD, 90.7). End-point quaking-induced conversion (EP-QuIC) testing of cerebrospinal fluid was positive in 90.0% of patients, while 83.3% tested positive for 14-3-3 on enzyme-linked immunosorbent assay. Elevated cerebrospinal fluid 14-3-3 levels significantly correlated with shorter duration from symptom onset to death (R2 = 0.71, F = 19.55, P = .0022). Post-diagnosis, 46.7% of patients were discharged home, 16.6% were transferred to external palliative care or hospice facilities, and 36.7% died during admission. The mean time from symptom onset to death was 121 days (SD, 120.7), and from diagnosis to death 35 days (SD, 83.9).
Conclusions
This study highlights the importance of early CJD consideration and laboratory testing when appropriate neurologic symptoms are present.
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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.
FRIDAY, MAY 03, 2024
“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].”
February 14, 2001
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Terry S. Singeltary, Sr
Author Affiliations
JAMA. 2001;285(6):733-734. doi:10-1001/pubs.JAMA-ISSN-0098-7484-285-6-jlt0214
To the Editor: In their Research Letter, Dr Gibbons and colleagues1 reported that the annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable since 1985. These estimates, however, are based only on reported cases, and do not include misdiagnosed or preclinical cases. It seems to me that misdiagnosis alone would drastically change these figures. An unknown number of persons with a diagnosis of Alzheimer disease in fact may have CJD, although only a small number of these patients receive the postmortem examination necessary to make this diagnosis. Furthermore, only a few states have made CJD reportable. Human and animal transmissible spongiform encephalopathies should be reportable nationwide and internationally.
https://jamanetwork.com/journals/jama/article-abstract/1031186
https://creutzfeldt-jakob-disease.blogspot.com/2023/09/professor-john-collinge-on-tackling.html
26 MARCH 2003
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
Terry S. Singeltary, retired (medically)
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
https://www.neurology.org/doi/10.1212/01.WNL.0000036913.87823.D6
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