Creutzfeldt-Jakob disease mimicking limbic encephalitis as a cause of rapid neurological deterioration
•,,,,,.
...
Abstract
Background A broad range of inflammatory and neurodegenerative conditions manifest with progressive cognitive and behavioural changes. A diagnostic challenge is the differentiation of limbic encephalitis (LE) from Creutzfeldt-Jakob disease (CJD). LE and CJD are distinct neurological conditions with distinct variations in their clinical course, with overlapping clinical presentations. LE can be subdivided into autoimmune paraneoplastic and non-paraneoplastic subtypes, under the umbrella of autoimmune LE. CJD is the most prevalent form of human prion disease and the subtype sporadic CJD (sCJD) the most common.
Case presentation This case study presents a 68-year-old man with a 6-week history of progressive cognitive decline and behavioural changes, ultimately leading to a dire clinical state. The initial symptoms included confusion, intermittent headaches and episodes of aggression towards his wife, preceded by 2 weeks of visual hallucinations. On examination, the patient displayed an ataxic gait, with signs of cerebellar dysfunction. The clinical course evolved, marked by myoclonic jerks, culminating in a decline in both his Glasgow Coma Scale (GCS) score and overall clinical status.
Conclusion The patient’s rapidly deteriorating condition over 6 weeks was thought to be too rapid for sCJD, and the patient was treated initially as an LS. However, post-mortem biopsy findings confirmed CJD. Asymmetric periodic discharges on EEG, asymmetric neuroimaging changes and the manifestation of psychiatric symptoms should not preclude the diagnosis of sCJD. This case highlights the importance of recognising the potential rapid deterioration of sCJD, which would alert clinicians to earlier diagnosis and management.
Background
Severe progressive dementia represents a broad range of conditions, including inflammatory and neurodegenerative. A diagnostic challenge is the differentiation of limbic encephalitis and Creutzfeldt-Jakob disease (CJD).
Limbic encephalitis refers to the subacute onset of episodic memory impairment, disorientation and agitation, commonly associated with seizures, hallucination, sleep disturbance and histological evidence of medial temporal lobe inflammation. MRI signal changes in the medial temporal lobes or hippocampi are frequently found.1 Limbic encephalitis, particularly in its autoimmune non-paraneoplastic form linked to VGKC antibodies, may present with cognitive decline, memory loss, psychiatric disturbances and seizure symptoms that can resemble those seen in sporadic CJD (sCJD).2 The relative rarity of limbic encephalitis, coupled with the uncommon autoimmune subtype, may lead to a lack of awareness among healthcare professionals. This can contribute to the misdiagnosis of limbic encephalitis as sCJD due to shared neurological symptoms and rapid disease progression.
CJD is the most prevalent among human prion diseases, also known as transmissible spongiform encephalopathies. It is characterised by a rapidly progressing constellation of symptoms that include dementia, myoclonus, extrapyramidal and pyramidal signs and ataxia. The pathophysiology of CJD is related to protease-resistant prion protein (PRP) infiltration of the central nervous system tissues. Prion forms insoluble aggregates and results in the established histopathological changes of neuronal loss, astrocytic proliferation and spongiform changes. sCJD is the most common form of CJD, accounting for 85–90% of reported cases. The average duration of symptoms ranges between 4 and 24 months to years, according to its subtypes. CJD clinically manifests non-specifically, and a definitive diagnosis is made on the basis of identifying the pathological form of PRP in a brain biopsy.3 A more rapid clinical decline should prompt consideration for alternative and potentially treatable diagnoses.
Case presentation
We report a 68-year-old man with a 6-week history of progressive confusion, uncharacteristic episodes of aggression towards his wife and intermittent headaches. He was on a fishing trip with his family, and he drove there and back, without any issues, only days prior to the onset of symptoms. His admission to the hospital was triggered by his erratic behaviour with a gun. The 68-year-old man pulled out his gun because he had visual hallucinations of intruders in his backyard. These visual hallucinations began 2 weeks before his progressive confusion and other symptoms. His house backed on to a school, and the patient’s son was very concerned that his father might shoot a school child.
On initial hospital examination, he was afebrile and oriented. His gait was ataxic, with past pointing of the left arm and intention tremor. The cardiopulmonary examination was unremarkable, and his blood pressure was normal despite his background of hypertension. There was a distant surgical history of tongue squamous cell carcinoma resection.
He subsequently clinically progressed to develop right-sided face and limb myoclonic jerks, followed by deterioration in both his Glasgow Coma Score (GCS) and clinical status. He was treated for limbic encephalitis and received a 5-day course of intravenous methylprednisolone. Despite treatment, he deteriorated rapidly, and an informed decision was made by his family to palliate him. He passed away in hospital within 24 hours of commencing palliative end-of-life care.
Investigations
Initial investigations revealed a white blood cell count (WBC)=11.9×109 /L, Na=131 mmol/L and a normal non-contrast brain CT. Cerebrospinal fluid (CSF) analysis revealed elevated red blood cell count (>1250×1012/L), WBC (>10x109/L) and raised total protein concentrations (>1 g/L). Autoimmune antibodies were not detected.
Day 1 MRI brain revealed predominantly right extensive cortical and basal ganglia diffusion-weighted signal abnormality (figure 1); an EEG demonstrated asymmetric periodic discharges (online supplemental figure 1).
Axial MRI DWI of the brain shows signal hyperintensity at the parieto-occipital cortex bilaterally.
Repeat EEG at D12 showed ongoing asymmetrical, large amplitude 1.2 Hz discharges (online supplemental figure 2), and MRI at D14 (online supplemental figure 3) demonstrated persistent bilateral corpus striatum and hippocampus diffusion-weighted restriction more prominent on the right. Protein 14-3-3 was present in the CSF to support the clinical diagnosis of probable sCJD. Additionally, post-mortem T-tau protein ELISA was positive (8830 pg/mL). RT-QuiC assay was sent for analysis; however, the results were uninterpretable due to a bloody tap. Autopsy and histopathological examination later demonstrated neuronal loss and microvacuolar degeneration in keeping with CJD (online supplemental figure 4).
Discussion
The clinical diagnosis of probable sCJD requires rapidly unexplained cognitive decline associated with cerebellar, pyramidal or extra-pyramidal signs. Periodic discharges on EEG and elevated titres of protein 14-3-3 in the CSF support the diagnosis.3
The positive predictive value under these circumstances is reported to be 98%.4
Elevated presence of protein in the CSF can hamper the CSF RT-QuiC assay, rendering it negative. Additionally, RT-QuiC is less sensitive in rarer CJD types, such as sCJD-MM2 associated with cortical changes and sCJD-VV1.5 Among different prion diseases, the sensitivity varies from 100% for gCJD to 80% for sCJD, according to recently published data.4 5
While ancillary tests increase the diagnostic probability, these are not always readily feasible or available, and ultimately the precise diagnosis of CJD is obtained by post-mortem histopathology study.
Finally, sCJD can also present as a symmetrical neuroimaging finding, mimicking strokes particularly when presenting with lateralised clinical findings.3 6 7
Learning point
Focal or lateralised EEG abnormalities associated with psychiatric manifestations in individuals with rapid cognitive decline should not preclude the diagnosis of sCJD, irrespective of the RT-QuiC assay status.8 9
Post-mortem biopsy and histopathology are ultimately the only tools to precisely determine a CJD case.
Contributors: This work was done as a collaborative effort involving neurologists and neuropathologist. This work received invaluable contribution from family of deceased patient. VR—manuscript writing and revision. DPPC—data collection and manuscript revision. YH—conception, data collection and interpretation and manuscript revision. LS—data collection and interpretation and manuscript revision. MB—data interpretation and manuscript revision. RTM—conception, data collection and interpretation, manuscript writing and revision. RTM is the guarantor of this article.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication:
Consent obtained from next of kin.
Ethics approval:
Not applicable.
Vincent A, Buckley C, Schott JM, et al. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain (Bacau)2004; 127:701–12.
Senesi M, Lewis V, Varghese S, et al. Diagnostic performance of CSF biomarkers in a well-characterized Australian cohort of sporadic Creutzfeldt-Jakob disease. Front Neurol2023; 14.
Yoon SS, Chan S, Chin S, et al. MRI of Creutzfeldt-Jakob disease: asymmetric high signal intensity of the basal ganglia. Neurology (ECronicon)1995; 45:1932–3.
