Incidence of Sporadic Creutzfeldt-Jakob Disease in the Emergency Department

Abstract

Introduction

Creutzfeldt-Jakob disease (CJD) is a fatal prion disorder marked by rapidly progressive dementia and neuropsychiatric features. Epidemiological data in Latin America are limited, and no incidence studies exist in Mexico. This study sought to quantify CJD incidence in a neurological reference center.

Methods

A cross-sectional study was conducted at the National Institute of Neurology and Neurosurgery, Mexico City, during 2023-2024. Clinical and paraclinical findings were reviewed. Incidence was calculated per 1000 emergency visits, with relative risk (RR) and 95% confidence intervals.

Results

Among 19 003 patients, 15 fulfilled probable CJD criteria. Incidence was 0.55/1000 in 2023 and 1.01/1000 in 2024 (RR 1.83; 95% CI 0.63-5.35; P = .309). Cognitive and behavioral symptoms predominated (psychosis in 68%). MRI revealed abnormalities in all cases, most often cortical ribboning (93%).

Conclusion

This first incidence study highlights the presence of CJD in specialized Mexican centers, underscoring the need for systematic surveillance and improved diagnostic access.

Introduction

Creutzfeldt-Jakob disease (CJD) is a progressive, fatal neurodegenerative disorder caused by misfolded, transmissible infectious protein particles, known as prions. ¹ The first cases were described in 1920 and 1921 by Hans Gerhard Creutzfeldt and Alfons M. Jakob.^2,3

Currently, three main forms of Creutzfeldt-Jakob disease are recognized: sporadic, genetic, and acquired forms, each with differing global incidence rates. ¹

The sporadic form accounts for 85% of CJD cases and is mainly described in middle-aged patients.^4,5 No specific risk factors for sporadic CJD (sCJD) have been identified, except for aging and certain polymorphisms in the PRNP gene at codons 129 and 219. Sporadic CJD typically occurs in individuals over 60 years old; cases in individuals under 50 are rare.^1,6 Genetic forms represent about 10% of all CJD cases. These are always associated with PRNP mutations and are inherited in an autosomal dominant pattern with variable penetrance. ⁷ Acquired forms of CJD represent approximately 6% of all prion disease cases. ⁶ This includes iatrogenic CJD (iCJD), such as the use of pituitary hormones derived from cadavers.

The classic phenotype of sporadic CJD is rapidly progressive dementia, defined as cognitive decline that compromises the individual’s functionality and independence within 1-2 years, accompanied by behavioural abnormalities (ranging from irritability, depression, and apathy to neuropsychiatric symptoms such as psychosis), ataxia (usually gait ataxia), extrapyramidal signs (tremor is common), and eventually, myoclonus.^7-9

Current diagnostic criteria for sporadic Creutzfeldt-Jakob disease classify cases as definite, probable, or possible. A definitive diagnosis requires the identification of a progressive neurological syndrome and neuropathological, immunocytochemical, or biochemical confirmation. Probable sCJD is defined by rapidly progressive cognitive decline plus two of the following: myoclonus, visual or cerebellar disturbances, pyramidal or extrapyramidal signs, or akinetic mutism, along with an abnormal EEG—or, in the absence of EEG, typical findings on brain MRI. Alternatively, a diagnosis can be made with a progressive neurological syndrome and a positive RT-QuIC test in CSF or other tissues. ¹⁰ Possible sCJD requires rapidly progressive cognitive decline plus two of the previously described clinical features, with disease duration under 2 years.

CJD has a global prevalence of one case per million people and is considered a rare disease according to WHO criteria and the National Organization for Rare Disorders (NORD). ¹¹ A study by Utley et al (2020) described the global incidence and prevalence of Creutzfeldt-Jakob disease, analyzing cases from 1993 to 2018. They reported a prevalence of 1.5 cases per million people and 5000 new cases annually worldwide. ¹

In Latin America, large case series on CJD are limited. In the early 2000s, Argentina reported a series of 517 patients, of whom 40% met the diagnostic criteria for probable CJD. ¹²

In Mexico, few studies have been published with enough cases to characterize the epidemiology of prion diseases. In 2007, a series of 15 cases with clinical and histopathological descriptions was reported. Later, in 2022, a retrospective analysis (2014-2019) that include 24 patients was published with the objective of identifying the main clinical and paraclinical features of patients who met the criteria for probable CJD. The main inclusion criterion was rapidly progressive cognitive decline. The rest of the clinical manifestations did not significantly differ from previous reports, with gait disturbances, movement disorders, and visual hallucinations being the most common. ¹³ In 2023 a database of 74 patients with the disease was compiled—the highest case series reported to date in Mexico. ¹⁴

Creutzfeldt-Jakob disease poses a diagnostic challenge due to its clinical heterogeneity and low prevalence. However, its true burden may be underestimated, particularly in countries lacking robust surveillance systems or specialized referral centers. In Mexico, there are no systematic data on annual incidence or multicenter studies to define regional patterns or effective diagnostic strategies. This knowledge gap hinders clinical care and public health planning. Our objective was to provide data to support the creation of a national CJD registry and to promote prion disease research in Latin America.

Methods

Study Design

This transversal study aimed to investigate the incidence of CJD in the emergency department of the National Institute of Neurology in Mexico City (INNN), a tertiary-level national neurological referral centre, during 2023 and 2024.

Patients and Statistical Analysis

A descriptive analysis was performed for sociodemographic, clinical, neurophysiological, and biochemical variables. Quantitative variables were summarized using measures of central tendency (mean or median) and dispersion (standard deviation or interquartile range), depending on their distribution. Qualitative variables were presented as absolute frequencies and percentages.

To estimate the cumulative incidence of probable Creutzfeldt-Jakob Disease (CJD), the numerator was the number of cases diagnosed in the Emergency Department (ED) of the National Institute of Neurology and Neurosurgery (INNN), and the denominator was the total number of patients evaluated in the ED during the corresponding year (2023 or 2024). Incidence was expressed per 1000 ED patients. The INNN is a national, third-level referral center located in Mexico City that exclusively attends neurological and neurosurgical emergencies. Patients are typically referred from second-level hospitals when a specialized neurological evaluation is required, when diagnostic work-up cannot be completed in the referring center, or when a second opinion is sought. Although most patients come from Mexico City and the metropolitan area, the INNN also receives referrals from across the country.

Annual incidences were compared as well as patients’ state of origin. Additionally, the incidence ratio (relative risk) with its corresponding 95% confidence interval (95% CI) was calculated to assess the magnitude of change between the two years.

A significance level of P < .05 was considered statistically significant. Statistical analyses were performed using SPSS 22v.

Results

During 2023, a total of 9069 patients were evaluated in the emergency department, of which 5 met diagnostic criteria for probable CJD. In 2024, 9934 patients were seen, and 10 were diagnosed with probable CJD. An additional case was detected in 2025 through the outpatient department but was excluded from incidence analysis.

The incidence of probable CJD in the emergency department of the National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez” was 0.55 cases per 1000 patients in 2023 and 1.01 cases per 1000 patients in 2024. The relative risk (RR) of receiving a diagnosis of probable CJD in 2024 was 1.83 compared to 2023. However, this difference was not statistically significant (P = .309; Fisher’s exact test, CI 0.63-5.35).

The mean age of patients was 58 years, with an average symptom duration of six months prior to hospital presentation. Patients originated from multiple regions across Mexico (Figure 1). A total of 25% of cases were from the state of Hidalgo, although this distribution was not statistically different compared to other states (P = .689). Individual, demographic and clinical characteristics are detailed in Table 1.

Figure 1.

Geographic Distribution of Patients With Probable Creutzfeldt-Jakob Disease (CJD) Diagnosed at the National Institute of Neurology and Neurosurgery, Mexico City, During 2023-2024. Red Markers Indicate the State of Origin of Each Patient

Table 1.

Patient’s Demographics

Case no	Sex (F 31% M 69%)	Age (mean 58)	State of origin	Education (mean 12 y)	RPD	Months of evolution (mean 6)	CSF protein (mean 35)	CSF glucose (mean 58)	CSF cells (mean 3)
1	Female	61	Oaxaca	7	Yes	1	37	92	38
2	Male	64	Mexico City	16	No	6	67	54	1
3	Male	60	Hidalgo	6	No	1.5	63	72	1
4	Male	61	State of Mexico	16	No	1	53	61	1
5	Male	58	Hidalgo	12	No	4
6	Male	66	Guerrero	17	Yes	12	55	42	9
7	Female	34	Mexico City	16	No	4	30	52	4
8	Male	74	Coahuila	16	Yes	9	39	67	0
9	Male	55	Guanajuato	9	Yes	14	44	62	1
10	Female	45	Michoacán	6	Yes	8	25	57	1
11	Female	55	Puebla	16	Yes	2	35	95	2
12	Female	74	Guerrero	12	Yes	24
13	Male	52	Zacatecas	9	No	9	36	61	0
14	Male	54	Hidalgo	9	Yes	5	24	76	0
15	Male	69	Mexico City	20	Yes	5	33	64	0
16	Male	48	Hidalgo	6	Yes	2	30	83	1

RPD, rapidly progressive dementia; CSF, cerebrospinal fluid.

Cognitive symptoms were the initial manifestation in 62% of patients. The most frequently affected cognitive domains were language impairment and disorientation. Additionally, 10 patients exhibited movement disorders, including tremor (60%), myoclonus (40%), and stereotypies (30%). Psychotic symptoms were reported in 68% of cases, with delusions (63%) and visual hallucinations (36%) being the most common. Affective symptoms occurred in 37% of patients, most frequently depression (66%), followed by irritability (33%) and anxiety (33%). Most patients underwent a complete diagnostic evaluation in the emergency department, including lumbar puncture, brain MRI, and electroencephalography (EEG). Lumbar puncture was not performed in two cases due to family refusal. Clinical profiles and main paraclinical findings are summarized and explained in Table 2.

Table 2.

Clinical Manifestations, Electroencephalographic Changes and Magnetic Resonance Imaging Features

Category	Finding	Percentage
Cognitive symptoms	Executive	70% (7/10)
N = 10	Language	90% (9/10)
	Orientation	100% (10/10)
	Memory	80% (8/10)
	Visuospatial	40% (4/10)
Movement disorders	Dystonia	20% (2/10)
N = 10	Myoclonus	40% (4/10)
	Parkinsonism	20% (2/10)
	Ataxia	10% (1/10)
	Tremor	60% (6/10)
	Catatonia	20% (2/10)
	Stereotypies	30% (3/10)
Psychotic symptoms	Delusional ideas	36% (4/11)
N = 11	Visual hallucinations	63% (7/11)
	Auditory hallucinations	27% (3/11)
	Agitation	18% (2/11)
	Inappropriate laughter	18% (2/11)
Affective symptoms	Depression	66% (4/6)
N = 6	Anxiety	33% (2/6)
	Obsessive ideas	16% (1/6)
	Irritability	33% (2/6)
	Mania	16% (1/6)
Electroencephalogram	Generalized slowing	68% (11/16)
N = 16	Lateralized periodic discharges	37% (6/16)
	Epileptic discharges	6% (1/16)
	Normal	6% (1/16)
	Triphasic waves	68% (11/16)
Magnetic resonance imaging	Cortical ribboning	81% (13/16)
N = 16	Hyperintensities in basal ganglia	56% (9/16)
	Pulvinar sign	31% (5/16)

Mean CSF findings were: Proteins 40 mg/dL, Glucose 60 mg/dL, Cells 4 cells/mm³

On MRI, all patients had suggestive changes. The most frequent finding was generalized cortical ribboning (93%), followed by restricted diffusion in the basal ganglia (62%) (Figure 2) EEG was performed in 15 patients. EEG information was not available for 1 patient. Among those evaluated: 73% showed generalized dysfunction with triphasic waves, 6% had lateralized periodic discharges, 6% had a normal EEG (Figure 3).

Figure 2.

Magnetic Resonance Imaging Findings in CJD. Brain Magnetic Resonance Imaging (MRI) in the Diffusion-Weighted Imaging (DWI) Sequence Shows Hyperintensity in the Right Caudate and Diffuse, Asymmetrical Cortical Ribbon Hyperintensities With Right Predominance (A–C), Basal Ganglia Hyperintensities (D), and Generalized Cortical Ribbon Hyperintensities (E)

Figure 3.

Generalized Periodic Discharges, With Triphasic Waves. Electroencephalogram that Shows Background Activity Replaced by a Pattern of Generalized Periodic Discharges (GPD), Made up of Paroxysms of Biphasic and Triphasic Sharp Waves With an Interdischarge Interval of 0.5-1 s

Discussion

This study represents one of the first efforts to quantify the incidence of probable Creutzfeldt-Jakob disease (CJD) in a neurological emergency department in Latin America. The reported incidence rates—0.55 and 1.01 cases per 1000 patients in 2023 and 2024, respectively—cannot be directly compared to population-based rates (typically 1-1.5 cases per million annually), they emphasize that CJD may be more frequently encountered in specialized centers than previously appreciated. ¹ The difference in incidence did not reach statistical significance between the two years. This does not necessarily indicate the absence of cases in other regions, but rather highlights the possibility of limited access to specialized and comprehensive diagnostic evaluation in more remote areas. ¹⁵ A major case series from Mexico reported 24 cases over a 6-year period, whereas our study identified 16 cases within only two years. This does not necessarily reflect a true increase in incidence but may instead be explained by greater awareness, improved diagnostic recognition, or reduced misdiagnosis. Importantly, in our study we systematically reviewed potential mimics and included atypical “chameleons” to ensure diagnostic accuracy. ¹³

The predominance of cognitive and behavioral symptoms—particularly psychotic features observed in over two-thirds of cases—highlights the need for increased diagnostic vigilance in patients presenting with rapidly progressive new onset neuropsychiatric syndromes. Notably, mood symptoms frequently preceded classical neurological signs such as myoclonus or cerebellar ataxia, which may contribute to misdiagnosis and delayed referral. Careful assessment of demographics, medical history, and associated symptoms can help differentiate neurodegenerative causes from primary psychiatric disorders. Importantly, the presence of behavioral changes, psychosis, or sleep disturbances does not exclude CJD and should prompt further neurological evaluation when seen in the context of rapid progression.^16,17

Language disturbances in our series were among the most frequent cognitive symptoms; however, whereas the literature reports that they usually occur in only 2% of patients. This discrepancy may be due to the lack of formal neuropsychological evaluation in our emergency department, which could lead to overestimation. Nevertheless, in patients presenting with new-onset language disturbances—even those meeting criteria for another neurodegenerative syndrome (eg, primary progressive aphasia)—Creutzfeldt-Jakob disease should not be ruled out.^18,19

All of our patients showed MRI abnormalities and met validated neuroimaging criteria for suspected CJD, as illustrated in Figure 2. Our center has the advantage of having neuroradiologists available 24 h a day, which allows for early detection of these changes, something that does not necessarily occur in other hospitals. As reported in other series, cortical ribboning was the most frequently observed sign. ²⁰

The typical EEG finding in prion disease is generalized periodic triphasic waves, which are considered part of the traditional diagnostic criteria. However, it is important to note that this is not always the most frequent abnormality; as reported in other series, the most common abnormality in our series was diffuse slowing. Periodic discharges are present heterogeneously, ranging from 64% to 97% of cases, making them a frequent but late finding. ²¹ This is relevant because the diagnosis should not be excluded in the presence of an EEG without the classical findings, or even with a normal EEG.

This study has several limitations. As a single-center referral study, there is a risk of referral bias that may overestimate disease frequency and limit generalizability. Due to the specialized nature of our institution, the emergency department volume is substantially lower than that of general hospitals, with fewer than 10 000 annual consultations. This reflects its referral-based role rather than the true population prevalence of neurological emergencies, therefore, the incidence rates per 1000 emergency consultations cannot be compared with population-based data. In addition, the small sample size reduces statistical power. Only emergency department cases were included, excluding outpatients and possibly underestimating incidence. Clinical characterization lacked systematic neuropsychological testing, which may have overestimated some symptoms. Diagnostic certainty was limited by the absence of neuropathological confirmation and the restricted availability of biomarkers such as RT-QuIC and 14-3-3. These tests are not covered by public institutions and, when available, must be paid for out-of-pocket by patients, which may lead to underdiagnosis in cases without characteristic MRI findings. ²² Despite these limitations, this is one of the first attempts to quantify probable CJD incidence in a Latin American emergency department, and future follow-up is needed as incidence may be increasing and requires surveillance. Latin American efforts have been conducted and confirm that regional prion disease surveillance, although limited, can yield a significant case series and supports the notion that specialized centers, as ours, play a crucial role in identifying otherwise underrecognized CJD cases. ¹²

Ongoing follow-up of these patients and future surveillance efforts will be essential to determine whether the observed incidence reflects a true increasing trend or is primarily the result of improved recognition and diagnostic capacity. We hope to clarify the epidemiological behavior of CJD in our region and provide a stronger basis for developing systematic monitoring strategies and public health policies.