Introduction

Prion diseases are neurodegenerative disorders that worsen over time.¹ Prion diseases are fatal and can affect both animals and humans. The main prion disease affecting humans is Creutzfeldt-Jakob disease (CJD), for which there is currently no cure.

CJD is classified into different types based on the way it occurs.² Sporadic CJD (sCJD) is the most common type and happens due to random misfolding of prion proteins (PrPs). Genetic CJD results from an inherited genetic mutation and includes the subtype familial CJD. Infectious CJD, which accounts for a small percentage of cases, is caused by external transmission of the prion and includes subtypes iatrogenic and variant CJD (vCJD).

CJD typically presents early on with behavioural and psychiatric symptoms, including psychotic features like hallucinations and delusions, agitated features like aggression, and mood disorder symptoms such as low mood and withdrawal.³ While these psychiatric symptoms are typically associated with vCJD, they can also be seen in sCJD.

Due to the fact that these psychiatric symptoms are prominent in other conditions, such as OCD, they can lead to misdiagnosis and the initiation of different treatments.⁴ Therefore, recognising these symptoms as signs of CJD would help in early diagnosis and immediate treatment.

Overview of creutzfeldt-jakob disease

The pathophysiology of CJD is characterised by the misfolding of PrPs, leading to brain degeneration.² PrP is a neuronal protein with an alpha-helical and random coil structure. Normal prions can transform into the disease-causing state, known as PrP^Sc, either randomly or due to infection. These prions replicate using normal PrPs and convert the alpha helices into beta-pleated sheets, causing issues with protein folding and trafficking. This process can lead to further changes such as the degradation of astrocytes.

CJD can affect various brain regions, including the cerebral cortex, caudate nucleus, thalamus, putamen, and cerebellum.² Neurodegeneration in CJD can be rapid, presenting with rapidly progressive dementia (RPD). Cognitive decline is a significant feature seen in both sporadic and inherited forms of CJD. Other neurological symptoms can include myoclonus, characterised by involuntary muscle twitching or jerking.⁴

The average duration of CJD can vary depending on the specific form.² Sporadic CJD has a median duration of 4 to 5 months, with death usually within 1 year. Although it presents similarly to dementia, sCJD has a much faster rate of progression. In contrast, inherited CJD can have varying durations; for example, Gerstmann-Sträussler-Scheinker disease progresses slowly, while vCJD has a median duration of 13-14 months.

Psychiatric symptoms associated with CJD

Early-stage psychiatric manifestations

Depression is one of the most prominent symptoms in the early stages of sCJD, and it tends to worsen over time.⁵ Anxiety is also frequently reported, with patients experiencing anxiety without an apparent cause. Additionally, personality changes are often the first observed sign of CJD due to RPD.⁶ Sleep disturbances are widespread and were seen in 89% of the cohort.⁷ This includes insomnia and hypersomnia.

Progression of psychiatric symptoms

Other psychiatric symptoms that patients may experience include psychotic symptoms which are very common and have been reported within the first 100 days in 77% of cases.⁵ These include delusions and visual or hearing hallucinations.

Agitation and aggression similar to that seen in various types of dementia are also frequently observed.⁵

Apathy is a common symptom in sCJD, and patients tend to permanently dissociate from friends and family.²

Late-stage psychiatric and neurological overlap

Severe cognitive impairment and dementia are significant aspects of late-stage CJD.² Sporadic CJD can present similarly to dementia but with a significantly faster progression, leading to a substantial decline in cognitive abilities over time. On the other hand, dementia is observed as a late symptom in vCJD. CJD can also manifest as severe depression with catatonia, and in rare cases, lead to akinetic mutism.⁸

Differential diagnosis and challenges

Difficulty in distinguishing CJD from other psychiatric disorders

Depression is a top 10 misdiagnosis of sCJD.⁹ In addition, there are genetic similarities between prion disease and bipolar disorder.

Other potential misdiagnoses include schizophrenia or other psychoses.^{4, 10} For example, the VV1 subtype of sCJD has been misdiagnosed as schizophrenia,¹⁰ and CJD has also been mistaken for OCD.⁴ Therefore, it is crucial to conduct additional tests such as imaging to rule out these diseases.⁴

It is important to consider the progressive nature of CJD and other neurological signs such as myoclonus.^2,11

Diagnostic tools and biomarkers

The periodic sharp wave complexes in EEGs are a common diagnostic feature of CJD.²

Brain MRI is a useful diagnostic tool for identifying differences in the cortical grey matter and deep nuclei in sCJD.² It also shows hyperintensities in the basal ganglia, thalamus, and cortex.

There are several CSF protein biomarkers for rapid neurodegeneration, including the 14-3-3 protein, total tau (T-tau), and neuron-specific enolase (NSE).² Diffusion-weighted imaging (DWI) brain MRI was found to be more accurate in diagnosis compared to these tests.

Impact on patient care and management

Psychiatric management in CJD patients

The interventions that have been attempted include antidepressants and antipsychotics.^12,13 However, sCJD patients did not experience relief from their depressive symptoms when taking antidepressants. Moreover, their use was also linked to a reduction in survival time, especially with SNRIs.¹² On the other hand, atypical antipsychotics were seen to be effective in managing agitation.¹³

In addition to medications, non-pharmacological approaches play a crucial role in treating CJD.² Psychosocial support can enhance the quality of life for patients, while emotional support has been utilised to help them manage mental health challenges.

Ethical considerations and end-of-life care

Palliative care is important for symptom management, and the needs include many symptoms such as mobility, mood, personal care, eating, and others.¹⁴ These needs have been drawn from assessing the burden on caregivers.

Palliative care is important for both patients and families.¹⁵ Although professionals may have limited knowledge of CJD due to its rarity, the service may be enhanced with the help of interdisciplinary teams of specialists. They can provide huge support, such as providing much-needed guidance when symptoms worsen.

Case studies and clinical observations

Case reports illustrating psychiatric symptoms in CJD

A case report documented a 63-year-old woman who was initially misdiagnosed with OCD and after undergoing treatment, there was no improvement in her symptoms.⁴ Instead, she developed additional symptoms such as upper limb tremors and mutism. She was eventually correctly diagnosed using a brain MRI and a positive CSF 14-3-3 protein test.

A different case report demonstrated the progression from psychiatric to neurological symptoms.¹⁶ Patients may initially present with psychiatric symptoms such as anxiety, mood disorder, and insomnia. Later, the signs to diagnose sCJD emerge and are investigated using various tests including EEG, different imaging, and 14-3-3 protein CSF testing. It is important to consider CJD as a potential diagnosis when early psychiatric symptoms occur.

Comparative analysis of psychiatric symptoms across CJD subtypes

Sporadic CJD is mainly characterised by neurological signs, while psychiatric symptoms are prominent early on in patients with vCJD.⁵ It has been observed that among sCJD cases, approximately 26% demonstrate psychiatric symptoms at presentation. On the other hand, psychiatric symptoms such as hallucinations and delusions are occasionally seen in familial CJD.¹⁷

Current research and future directions

Advances in understanding psychiatric symptoms in prion diseases

The use of neuroimaging has greatly improved our understanding and ability to detect prion diseases.^18,19 In the vCJD diagnosis, the pulvinar sign observed in brain MRI has become a distinctive feature.¹⁸ Furthermore, imaging studies have shown signal variances in the caudate nucleus and putamen or at least two cortical areas, in cases of sCJD. FDG-PET scans have indicated cortical-subcortical hypometabolism as a common feature of sCJD and thalamic hypometabolism for the familial form. Crucially, the introduction of DWI has vastly enhanced the detection of CJD.¹⁹

Genetic studies have also contributed valuable insights into PrP mutations.²⁰ All three types of prion diseases are linked to the PRNP gene, as the production of PrP^Sc is necessary for the disease to occur. Different variants of PRNP impact the level of penetrance, the clinical phenotype, and the age at which patients develop the condition. In genetic diseases, three types of PRNP mutations have been identified: missense mutations, nonsense mutations and insertions or deletions of specific regions. Additionally, PRNP polymorphisms can have varying effects, with codon 129 showing the greatest impact.

Potential for early detection and intervention

The advancement in diagnostic biomarkers has significantly enhanced the accuracy of diagnoses.²¹ These biomarkers, such as the concentrations of the 14-3-3 and T-tau proteins in CSF, have shown strong diagnostic performance. When combined, they further improve disease detection.

Ongoing research is focused on developing disease-modifying therapies, which are crucial for preventing neuronal death.²² A clinical trial has indicated the potential of flupirtine in reducing cognitive decline as measured by dementia tests.²³ Furthermore, flupirtine has demonstrated neuroprotective effects by counteracting the toxic effects of PrP^Sc.

Effective patient care requires a multidisciplinary approach due to the wide-ranging impact of CJD on a person's health.² The care team may involve specialists from various fields including mental health practitioners, neurosurgeons, palliative care specialists, and genetic counsellors, among others.

Conclusion

CJD, a condition with many different subtypes, can have a significant impact on an individual’s life. The recognition of early psychiatric symptoms as potential signs of CJD is crucial for diagnosis as misdiagnosis can affect the provision of the best care, including palliative care. Crucially, the identification of novel biomarkers and the use of various imaging techniques have allowed for faster and more accurate detection of the disease. Additionally, there have been advances in understanding the genetic causes and variations underlying CJD, and research on disease-modifying therapies has shown neuroprotective promise. Although these are steps in the right direction, further understanding of the psychiatric symptoms would guide treatment to ease the course of the disease for patients.