Creutzfeldt-Jakob Disease (CJD) is an uncommon and rapidly progressing neurological condition capable of causing memory loss, behavioral changes, coordination difficulties, and motor impairment, potentially leading to death within a few months.
Global estimates indicate that between one and two cases occur per million inhabitants annually. However, neurologists in Brazil suggest that the number registered nationally may be lower than reality, which contributes to the discrepancy observed compared to other countries.
A major challenge in managing CJD is early recognition, as its initial symptoms can mimic other neurological pathologies, such as encephalitis or other forms of rapidly progressive dementia. Due to its accelerated nature, early investigations are crucial to rule out other treatable diseases.
The diagnostic process involves a combination of clinical evaluation with tests such as magnetic resonance imaging, electroencephalogram, and cerebrospinal fluid analysis, the fluid surrounding the brain and spinal cord. An important factor, however, is access to the RT-QuIC test, considered one of the most specific for identifying the disease, although this test is not yet widely available in Brazil.
Why is Creutzfeldt-Jakob Disease so rare?
CJD ranks among the rarest neurological conditions worldwide. Organizations like the NHS, the UK's public health system, estimate the incidence at 1 to 2 cases per million inhabitants annually, demonstrating its low frequency even in areas with robust surveillance systems.
In the Brazilian context, specialists assess that the known number may be underestimated. Jerusa Smid, a neurologist at the Hospital das Clínicas of USP, the Emílio Ribas Institute of Infectology, and the Albert Einstein Israeli Hospital, states that the disease is not as rare as the data available in the country suggests.
Between 2005 and 2021, the Ministry of Health received 1,576 suspected CJD notifications, of which 547 were confirmed, 457 ruled out, and 572 (or 36.3%) had no final classification defined.
To understand the rarity, it is necessary to analyze the biological basis of the disease: it is caused by prions, proteins that acquire an abnormal configuration. These proteins can, in turn, force healthy brain proteins to change shape. Jerusa explains that upon contact with another normal protein, the transformed form induces the latter to become a prion.
This cycle repeats, leading to the accumulation of these abnormal proteins and causing progressive damage to brain cells. In its most common manifestation, the sporadic form, scientists still do not know the initial trigger of this transformation, with no identified cause explaining why it affects certain individuals and not others. It is important to note that CJD is not the only prion disease; there are other rarer conditions in this group, such as Gerstmann-Sträussler-Scheinker syndrome and fatal insomnia.
Why does the disease progress so quickly?
The acceleration of CJD progression is directly related to how prions act in the brain. By adopting an anomalous conformation, these proteins are able to induce shape changes in healthy proteins, spreading the process through brain tissue via successive transformations.
As more proteins adopt the abnormal form, they accumulate, resulting in continuous deterioration of brain cells and impairment of various neurological functions. For this reason, symptoms can worsen in a much shorter period than in other neurodegenerative diseases.
Significant changes in memory, behavior, coordination, and movement can appear and intensify within a matter of months. This speed is an indicator that helps doctors suspect the illness, although it is not sufficient to confirm the diagnosis, as other causes of rapidly progressive dementia must be investigated and excluded.
Why can the diagnosis be so difficult?
A primary obstacle lies in the absence of an exclusive initial symptom of CJD. The clinical picture can present in varied ways, causing confusion with other neurological diseases.
Signs that may manifest include memory loss, behavioral modifications, difficulty moving, imbalance, lack of coordination, and involuntary movements. All these signs are common in much more prevalent pathologies.
Marcio Luiz Figueredo Balthazar, a professor in the Department of Neurology at the Faculty of Medical Sciences of Unicamp, clarifies that, generally speaking, Alzheimer's disease tends to evolve over years or decades, while Creutzfeldt establishes itself more rapidly and has a significantly shorter survival time. He adds that CJD falls into the differential diagnosis of what is called rapidly progressive dementia, which encompasses multiple etiologies.
Among the possibilities requiring investigation are encephalitis, autoimmune diseases, other neurodegenerative conditions, and metabolic alterations. This process is vital because some of these conditions are treatable, requiring that the investigation rules out other causes of rapid deterioration of memory, reasoning, and movement before reaching a definitive CJD diagnosis.
Although rapid progression serves as a clue, Balthazar emphasizes that speed alone does not confirm the diagnosis, as other causes of rapidly progressive dementia must also be considered.
What tests are used in the investigation?
There is no single standard test that resolves the investigation in all patients. Generally, the neurologist integrates the clinical history and physical examination with various complementary tests.
Among the most relevant procedures are brain magnetic resonance imaging, which can reveal characteristic patterns of the condition; lumbar puncture, used to analyze cerebrospinal fluid; RT-QuIC, a test that looks for evidence of abnormal prion protein in the cerebrospinal fluid; electroencephalogram (EEG), which monitors electrical brain activity; and other blood and cerebrospinal fluid tests to rule out infections, autoimmune diseases, and metabolic disorders.
Magnetic resonance imaging is particularly relevant because certain brain patterns can considerably reinforce the diagnostic suspicion. RT-QuIC, or Real-Time Quaking-Induced Conversion, represents a recent advance as it indirectly detects the characteristic activity of prions. Jerusa points out that despite being useful in most cases, its availability in Brazil is still limited.
When performed, RT-QuIC uses a cerebrospinal fluid sample, exposing it to normal proteins. If prions are present, they induce these proteins to undergo a shape change, allowing the reaction to be detected. The test was incorporated into clinical practice in the mid-last decade and gained importance in CJD investigation due to its high accuracy, showing near 100% specificity in studies with patient groups. However, sensitivity, which measures the test's ability to correctly identify the sick, can vary, implying that some cases may not be detected.
Why might there be underreporting in Brazil?
The rarity of the disease itself imposes an initial barrier: the disease must be remembered for the investigation to begin. A neurologist may see numerous patients with memory complaints but find few cases of CJD throughout their career.
Additionally, the necessary tests often require centers with greater infrastructure. Balthazar stresses that the disease is inherently rare and often difficult to suspect.
Jerusa also highlights the disparity between the internationally estimated occurrence and the volume of registered diagnoses in the country, indicating that there are likely unidentified cases. Official Brazilian records themselves show flaws; in the survey from 2005 to 2021, more than a third of notifications lacked a final classification. Furthermore, the Ministry of Health bulletin recorded a lack of information on clinical evolution in more than half of the analyzed notifications, limiting conclusions on how many cases are lost in diagnosis in Brazil, but highlighting restrictions in disease surveillance.