Diagnostic challenge of sporadic Creutzfeldt‐Jakob disease revealed by a psychiatric presentation

Creutzfeldt-Jakob disease (CJD) is a rare and incurable neurodegenerative disorder caused by prions. Prion disease is characterised by the accumulation of misfolded proteins in the central nervous system. These proteins result from the conversion of the normal cellular prion (PrPc), formed by an alpha-helical structure, to a misfolded aggregated and pathogenic β-sheet form called prion protein scrapie (PrPSc).1 CJD is classified into three groups: sporadic, inherited and acquired (including iatrogenic CJD, variant CJD and Kuru). All subtypes of CJD are transmissible, illustrating the public health issue raised by this entity. Sporadic CJD is the most common and accounts for 85% of all CJD cases.1 Its annual incidence is estimated at 1–2 cases per million people.1 The age at onset of sporadic CJD is usually between 60 and 70 years,1 and the outcome is fatal within a median time of 5 months.2 Inherited CJD is observed in 10–15% of cases, and results from mutations in the prion protein gene (PRNP).1 Inherited CJD usually appears earlier and is associated with a longer survival than sporadic CJD.1 Among acquired subtypes, variant CJD is related to epizootic bovine spongiform encephalopathy, first identified in 1995 in the United Kingdom.1 Variant CJD has been in decline since a peak in 2000. From a clinical point of view, the accumulation of the pathological prion proteins induces a brain matter degeneration resulting in diverse symptoms such as rapidly progressive dementia, myoclonus, tremors, cerebellar ataxia, extrapyramidal and pyramidal involvement.1 Other presenting symptoms at the onset of the disease may be psychiatric and behavioural disturbances, illustrating the diagnostic challenge raised by this rare neurodegenerative disease. Diagnosis of sporadic CJD is based on typical clinical features, coupled with additional investigations comprising: characteristic magnetic resonance imaging (MRI) changes in the basal ganglia and/or cortex; electroencephalogram showing characteristic periodic sharp wave complexes; elevated levels of 14-3-3 protein in cerebrospinal fluid (CSF) and the detection of PrPsc in CSF using real-time quaking-induced conversion (RT-QuIC), which provides a high specificity of almost 100% for the diagnosis of sporadic CJD.2, 3 Herein we report the case of a woman aged of 73 years, known for a bipolar disorder, who presented with a depressive episode. She rapidly developed a cognitive impairment associated with motor and gait abnormalities. Based on additional investigations, the diagnosis of probable sporadic CJD was made according to the current CJD criteria. A woman, aged 73 years old, was referred to our department for behavioural changes and decline of autonomy. The patient's medical history was a bipolar disorder stabilised on valpromide and risperidone. There was no family history of neurological or psychiatric disorders. In the preceding months, she developed a depressive mood, with appetite loss and bradyphrenia. She was treated by the psychiatrist at the local mental health hospital with paroxetine (20 mg per day) 2 months before admission. No signs of motor or gait dysfunction were noted. However, forgetfulness and word-finding difficulties were noticed by her peers. Due to a deterioration of her general condition characterised by a severe apathy and difficulties in performing basic activities of daily living despite the recent treatment, she was referred to the internal medicine department for additional explorations and to have a neuropsychiatric evaluation. At admission, she exhibited an extrapyramidal syndrome including bradykinesia and rigidity. She appeared unsteady on standing with a wide-based gait, and examination of her upper limbs revealed a dysdiadochokinesia and dysmetria, consistent with a cerebellar picture. There was no abnormalities in power or sensation, and Babinski reflexes were absent. The rest of the clinical examination was unremarkable. There was no impairment of single-word comprehension, but short and long-term memory were impaired. She scored 14 points on the Mini-Mental State Examination (MMSE). Routine laboratory tests were unremarkable, serologic screening for human immunodeficiency virus and syphilis was negative, as well as thyroid autoimmunity and antinuclear antibodies. CSF analysis demonstrated both normal protein and glucose levels and a normal cell count. The computed tomography scan of chest, abdomen and pelvis was unremarkable. CSF and serum autoimmune encephalitis panels were negative. Brain MRI revealed hyperintensity of the caudate nuclei on T2-weighted, fluid-attenuated inversion recovery (FLAIR) and diffusion weighted imaging (DWI) sequences, and hyperintensity of the bilateral frontal cortex on DWI, suggestive of CJD (Fig. 1). CSF 14-3-3 and RT-QuIC assays were positive. The PRNP gene was sequenced and revealed homozygosity for methionine in codon 129. No pathogenic mutation was detected, excluding a familial CJD. The possibility of iatrogenic CJD was also ruled out because she had no history of neurosurgical treatment, surgery, or other invasive procedures at risk of transmission of prion proteins. The electroencephalogram showed diffuse slowing activity, without triphasic wave complexes or epileptic activity. Thus, the diagnosis of probable sporadic CJD was made according to the current CJD criteria.3 On the 19th day of hospitalisation, myoclonus appeared in the lower extremities and her cognition deteriorated. Two months after diagnosis, the patient had severe bulbar dysfunction and died of sepsis in a palliative care setting. A brain autopsy for diagnostic confirmation was not authorised by the family of the deceased. We present a rare case of prion disease, revealed by psychiatric manifestations. Diagnosis of probable sporadic CJD was made on the subsequent occurrence of clinical manifestations compatible with this entity, the detection of protein 14-3-3 in the CSF and the positivity of the RT-QuIC test, MRI findings consistent with CJD, and the exclusion of alternative diagnoses.3 Electroencephalogram did not have the characteristic periodic sharp and wave complexes in our patient. These abnormalities are usually found in advanced stages of CJD.4 First symptoms may be nonspecific, including depression, memory loss, sleep disturbances, frequently encountered in the elderly. Specifically in this case, initial depressive symptoms could be attributed to a relapse of her bipolar disorder, leading to a diagnostic delay. However, the diversity of psychiatric manifestations potentially associated with sporadic CJD, the persistence and worsening of symptoms despite appropriate psychiatric treatment, and the rapid occurrence of neurological manifestations, could suggest a neurodegenerative disorder such as potential sporadic CJD. Since clinical manifestations of sporadic CJD can overlap with other underlying diseases, a multidisciplinary management including a systematic geriatric and neurological assessments is mandatory to achieve to the most appropriate diagnostic approach. Psychiatric prodrome followed by neurological manifestations were demonstrated in a retrospective review of 126 cases of sporadic CJD, showing 26% of patients had psychiatric symptoms at presentation.5 The most commonly recorded manifestations were sleep disturbances, psychotic symptoms, and depression.5 Thus, psychiatric manifestations as first symptoms of CJD may be carefully considered as a prominent feature of sporadic CJD. The differential diagnoses include other neurodegenerative disorders such as Alzheimer's disease, frontotemporal dementia, Parkinson disease, cerebrovascular disease, inflammatory disorders, paraneoplastic encephalitis. Definite diagnosis is made by neuropathological examination requiring brain biopsy or post-mortem analysis. The International CJD Surveillance Network diagnostic criteria were revised in 2017, and incorporated MRI findings and the RT-QuIC assay with high sensitivity and specificity, contributing to improved diagnostic accuracy and epidemiological surveillance.2, 3 Moreover, diagnostic criteria avoid unnecessary treatments and allow appropriate palliative care management. We describe a case of probable sporadic CJD revealed by psychiatric manifestations and more precisely depression, illustrating the diagnostic challenges raised by this entity. We draw clinician's attention to psychiatric symptoms in sporadic CJD, which may occur at the early stage of the disease. A clinical suspicion based on psychiatric prodromes followed by rapid development of neurological symptoms, could prompt additional investigations including brain MRI, electroencephalogram and lumbar puncture. To date, we do not have a curative treatment and the prognosis remains fatal within a few months. MP conceived the study and drafted the manuscript; LM helped in comprehensive clinical examination and editing; MEJ assisted in draft revision and editing; AMM revised the manuscript. All authors have read and approved the final manuscript. The authors would like to thank Adriana Vasseur for her assistance. This work did not receive funding from external or internal sources. The authors declare they have no conflicts of interest in this research. This case report was conducted in accordance with ethics guidelines, and has been approved by the ethics committee of Centre Hospitalier Victor Dupouy, France. Written informed consent was obtained from the legal guardian of the patient for publication of this report and any accompanying images. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.