Diagnostic Challenges in Sporadic Creutzfeldt--Jakob Disease: A Case Study of Typical Clinical Presentation with Negative Findings

Introduction

Creutzfeldt-Jakob disease (CJD) is a rare and fatal neurodegenerative disorder caused by misfolded isoform (PrPSc), known for its rapid progression and potentially contagious nature. No effective treatment currently exists, and the mortality rate is exceptionally high, at 100%. Among its subtypes, sporadic CJD (sCJD) is the most common in humans, with an estimated annual incidence of 1.5 to 2.0 cases per million [1].

Key diagnostic tools for CJD include EEG, revealing the distinctive periodic spike-wave complexes (PSWC), with 64% sensitivity and 91% specificity. Brain MRI, with characteristic changes observed in 83% of cases, is valuable for diagnosis. Real-time vibration-induced conversion inoculation tests (RT-QuIC) of cerebrospinal fluid or olfactory mucosa samples offer excellent sensitivity (96%) and almost 100% specificity, emerging as crucial diagnostic methods [2,3]. Adjunctive testing in CJD has limited usefulness; clinical symptoms remain pivotal in diagnosis. Characterized by severe dementia, cerebellar ataxia, and myoclonus, these distinctive and severe symptoms differentiate CJD from other neurodegenerative diseases. Widely used diagnostic criteria for sporadic CJD encompass cognitive impairment, nervous system abnormalities, and positive test results.

Although sCJD should ideally be managed by neurologists, its rarity and the broad range of early symptoms often lead patients to seek treatment in other departments at the onset. These departments typically lack experience with sCJD, resulting in missed or incorrect diagnoses. The case presented in this article exemplifies this issue: the patient initially consulted multiple departments and was even admitted to a psychiatric hospital. Regrettably, it took 2 months from the onset of symptoms before Neurology finally considered the possibility of sCJD. This significant delay in diagnosis not only postponed appropriate care, but also greatly increased the emotional and financial burden on the patient and her family.

This case underscores the need for greater awareness of sCJD and other rare diseases among non-neurology departments. It also highlights the importance of early multidisciplinary collaboration in diagnosing complex conditions, to avoid unnecessary delays and improve patient outcomes. By sharing this case, we hope to prompt reflection on clinical pathways and diagnostic practices, aiming to prevent similar problems in the future.

Case Report

This report complies with the Declaration of Helsinki and received approval from the Human Research Ethics Committee of Beijing Huilongguan Hospital [Protocol No. 2023-103]. The patient’s husband signed a written informed consent.

A 58-year-old woman, retired and previously in good health with no significant medical history or family history of hereditary diseases, presented with 2 episodes of sudden dizziness occurring within a few days. Each episode lasted for a few minutes and occurred without any apparent precipitating factors. EEG and blood tests showed no abnormalities. Days later, she had difficulty falling asleep and woke up easily.

Approximately 14 days after the onset of dizziness, her condition deteriorated, manifesting as speech disorders, gait instability, and emotional dysregulation. Her speech and demeanor occasionally exhibited a childish naivety and tone. Consequently, she was admitted to a general hospital. In an effort to stabilize her emotional state and mitigate her immature behavior, she was prescribed clonazepam and citalopram. However, due to the lack of therapeutic efficacy, these medications were subsequently discontinued, yet her symptoms persisted. Comprehensive evaluations, including EEG, brain MRI, and assessments of immune factors, complement C3, and complement C4, revealed no abnormalities. Following multidisciplinary consultations, no physical illness was identified that could account for her symptoms. Therefore, the general internist hypothesized that this might be a psychiatric disorder and subsequently referred the patient to the Psychiatry Department.

The patient was admitted to our psychiatric hospital 32 days after the initial episode of dizziness. Based on the internist’s exclusion of somatic diseases, combined with the patient’s peculiar clinical symptoms, the admission diagnosis was established as hysteria.

On the day of admission, the patient was conscious and briefly able to communicate, but her orientation was incomplete. She was able to correctly give the year, her name, and city, but made mistakes in giving the season and her age at the time. Unable to take care of herself, she relied on passive participation in feeding. Her speech lacked coherence, and communication was hesitant and interrupted when answering questions. She required repeated reminders and showed a lack of focus and poor memory, and performed poorly on intelligence tests, giving approximate answers, such as calculating 3+7 as 21. Emotionally, the patient showed uncoordinated reactions with sluggish and limited facial expressions. Her emotional stability was also poor. When she mentioned the death of her mother-in-law 3 years ago, tears suddenly broke out that lasted a few minutes before she calmed down. While conversing, she remained in bed and made erratic and aimless movements similar to those of a baby. Occasionally she would twist her body, open the window with her feet, and try to remove her clothes. The patient was unable to walk unaided and exhibited tension when holding the supporter’s arms. Sometimes she screamed for no reason.

According to the patient’s family members, prior to the onset of the disease, she had not experienced any major life events, psychological setbacks, trauma, or animal bites. Apart from the occasional salmon sashimi, she had never eaten raw meat.

On the day of admission, the patient received 10 mg diazepam and slept well. Decreased language skills, infrequent responses to questions, dull facial expression, and passive negativism were reported on the second day. By the third day, she became silent and unresponsive. Her limbs were tense and lacked voluntary movement, maintaining fixed positions. On the fifth day, her muscle tone was high, symmetrical tendon reflexes were present, and there were no pathological signs in the extremities. Cooperation issues hindered a complete physical examination, but staff assisted with basic needs. The electrocardiogram showed a sinus rhythm of 112 beats per minute with complete right bundle branch block. During the hospital stay, she received 5 mg/day haloperidol for 3 days and 2 sessions of electroconvulsive therapy, but with no improvement. Her family members were informed that the likelihood of the patient suffering from a mental illness was very low and recommended referral her to the Neurology Department. The patient was discharged on the sixth day of hospitalization.

After discharge, the patient was readmitted to the Neurology Department of another hospital, where she underwent a series of evaluations. We were only able to gather subsequent information through follow-up phone consultations with her family. Follow-up EEG showed diffuse moderate to severe abnormalities, mainly scattered low and medium amplitude theta waves in the 4 to 7 Hz range and some very sharp waves. No characteristic periodic 1 Hz PSWC was observed. The RTQuIC assay yielded a negative result. Brain MRI showed increased bilateral caudate and lenticular diffusion-weighted imaging signal, slightly decreased apparent diffusion coefficient signal, and slightly increased T2Flair and T2WI signals, and the contrast-enhanced MRI did not demonstrate any significant enhancement (Figure 1A, 1B). Given the insufficient supportive findings for CJD, the neurologist undertook a comprehensive array of additional investigations to exclude other neurological disorders. Investigations of blood and cerebrospinal fluid, including autoimmune brain antibodies, tumor antibodies, Epstein-Barr virus, Cryptococcus, Toxoplasma gondii, rubella virus, herpes virus, myelin basic protein, and other parameters, did not reveal any abnormalities. Based on these findings, the patient was diagnosed with sCJD and recommended symptomatic and supportive treatment and holistic care.

Another head MRI was performed 6 months after onset, and the characteristic changes were still present (Figure 2). Twenty-one months after the onset of the disease, the patient remains at home, unconscious and in a vegetative state. Her muscle tone remained higher but was somewhat improved compared to the initial stage of the disease. The patient died of pneumonia infection 23 months after the onset. No autopsy was performed.

Discussion

CJD is generally characterized by rapid progression and a typical survival time of 4 to 6 months from diagnosis to death. A study conducted in China with 152 sCJD patients revealed a mean age at diagnosis of 61.44 years, a mean survival time of 7.34 months, and a mortality rate of 82.10% within 1 year after onset of the disease. This patient was ill for 21 months, which is longer than the average survival time for CJD. Research has indicated that factors such as female sex, later age at onset, and the absence of periodic sharp wave complexes (PSWC) on EEG are associated with longer survival in sCJD [4]. While this patient exhibited some of these characteristics, the lack of comprehensive assessments leaves other relevant factors unclear. Additionally, a critical consideration is the post-illness care provided to the patient. Following the loss of her self-care abilities, her family offered meticulous support in daily activities, which may also have contributed to prolonging her survival. In fact, it is clinically observed that some individuals survive the disease longer. The cases with the longest survival are typically associated with familial CJD, with a maximum survival of 16 years [5]. The longest reported sCJD case survived up to 14 years [6]. However, it is important to note that these cases generally present with marked and severe progressive dementia and neurological symptoms within the first year of illness and require continued care during the longer survival period.

The typical EEG findings for CJD have high specificity but low sensitivity, detecting PSWC in only 64% of cases. Although multiple EEGs were performed in this patient, no PSWC was observed. The RT-QuIC assay, which has a high sensitivity of 96% and a specificity of almost 100% [2,3], yielded negative results in this patient. Although there is limited evidence of testing for CJD, the patient’s clinical presentation is consistent with typical CJD symptoms. Extensive physical and mental examinations were conducted to exclude other potential disorders. Therefore, while the current diagnosis of sCJD includes a degree of speculation, it is regarded as the most probable based on the clinical symptoms and the characteristic changes observed on MRI. Studies have demonstrated that diffusion-weighted magnetic resonance imaging (DWMRI) exhibits superior sensitivity compared to conventional MRI in detecting early-stage abnormalities in CJD [7]. This may account for the initial lack of significant findings in this case, where the patient underwent conventional MRI during the early stage of the disease.

The time the patient spent in the Psychiatry Department and the treatment she received clearly did not facilitate any improvement in her condition, which is a source of considerable regret and self-reproach for us. Had the possibility of CJD been considered earlier, this situation might have been mitigated.

In the early stages of the patient’s illness, cranial MRI showed no significant abnormalities, and multiple EEGs conducted throughout her disease course did not reveal the characteristic changes associated with CJD. Additionally, most non-neurologists lack awareness of the signs of CJD. The patient initially consulted the general internal medicine department at a comprehensive hospital and was subsequently referred to psychiatry, without a timely evaluation by the Neurology Department. These factors contributed to the delayed consideration of CJD as a potential diagnosis. Notably, the patient’s early assessments for several common disorders yielded negative results, culminating in a misdiagnosis of a psychiatric disorder, which significantly complicated her overall diagnostic journey. This underscores a challenge frequently encountered by patients with rare diseases, highlighting the imperative for heightened vigilance regarding rare conditions and the necessity for improved interdisciplinary communication.

Regrettably, the patient did not undergo genetic testing for familial CJD, and while there was no significant family history, this factor should still have been considered. Furthermore, testing for 14-3-3 protein in the cerebrospinal fluid was not conducted. Due to the lack of facilities for these specific tests at our psychiatric hospital, subsequent evaluations were conducted at another institution. We are unclear about the reasons for not performing these tests and could only gather the available results. The incomplete nature of the assessments represents a significant limitation of this study.

Conclusions

Although the diagnosis of this patient is speculative and definitive confirmation may require brain biopsies, it is crucial to acknowledge that excessive dependence on supplementary examinations contributed to an initial misdiagnosis as a psychiatric disorder. This led the patient on a convoluted path during the course of medical consultations, significantly increasing her burden. Furthermore, insufficient communication between disciplines resulted in clinicians’ lack of awareness regarding rare diseases, compounding the diagnostic challenges.

This medical case report holds significance as it prompts reflection on the pitfalls of over-reliance on supplementary examinations and the disconnect between medical specialties in diagnosis and treatment. The patient’s tumultuous journey through consultations underscores how these issues can lead to misdiagnosis, treatment delays, and increased patient burden. This case highlights the importance of comprehensive clinical observation and assessment to gain a fuller understanding of the patient’s condition and to implement appropriate treatment measures. Additionally, it calls for improvements in interdisciplinary communication to enhance awareness of rare diseases and ensure timely, accurate diagnoses.

The patient suffered from a serious and rare disease of the central nervous system. Whether it was CJD or another unknown rare disease, she lost consciousness, had aphasia and limited mobility, and completely lost the ability to live independently. This placed a significant burden on both the patient and her family. Caregiver care plays a vital role in the survival and well-being of patients like her. Unfortunately, current medical treatments have had limited effectiveness. What healthcare providers can do is offer more attention, understanding, and comfort to patients and their caregivers. It is hoped that future advances will open up new avenues to improve the management and treatment of these rare diseases.