Overview
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of this fatal neurodegenerative disease.1 The disease is rare, with only 2 cases per million worldwide, and typically affects individuals over the age of 60.1 It is classified as a human prion disease and is caused by the abnormal folding of the human prion protein (PrP).2 These misfolded proteins aggregate in the brain, causing rapidly progressive dementia and motor deficits, such as loss of coordination and visual disturbances. However, age, symptoms, and progression rate can vary significantly.1 This article will discuss the causes, symptoms, diagnosis, treatment, and prognosis, and address some frequently asked questions. It is not designed to replace medical advice; if you are concerned about any symptoms, it is important to consult your doctor.
Pathophysiology
The role of prion proteins
Proteins are biomolecules, made from long chains of amino acids, which specialise to perform specific roles throughout the body. Each protein is encoded by a gene, which is a section of DNA, folded into chromosomes and contained within the nucleus (contains all the genetic material of a cell) of nearly every cell in the body.3 During protein production, DNA is replicated inside the nucleus, producing a copy called RNA, which is then translated into a chain of amino acids at the ribosome, inside the cell.3 Normally, proteins undergo folding and quality control in the endoplasmic reticulum of the cell to prevent abnormal protein accumulation.4
Prions (PrP’s) are one type of cellular protein, which are encoded by the gene PRNP, and are highly concentrated in the nervous system, where they have multiple roles.5 The central nervous system (CNS) consists of the brain and spinal cord, where electrical signals are generated and transmitted across networks of neurons (nerve cells).1,6 In sCJD, these glycoproteins become abnormally folded into the infectious prion PrPSc. The misfolded proteins aggregate, meaning they clump together, forming deposits across the brain.1,7 This disturbs the normal functioning of the CNS, leading to fatal neurodegeneration.7
What causes prion misfolding?
Research in this area is ongoing, however, a number of factors have been found to trigger prion misfolding, including:
- Stress
- Age
- Somatic mutation
- Stochastic protein alteration
- Overexpression of the protein
- SARS-CoV-2 (Covid-19)8
How prion misfolding affects the brain
This accumulation of misfolded prion proteins leads to several changes in the brain:2
- Spongiform change: when viewed under a microscope, the neutrophil (space surrounding the neuron’s cell body, such as dendrites, axons and synapses) appears to have round, empty spaces,9,10 leading to areas of hyperintensity, as seen on an MRI.11
- Microglial activation (CNS immune cells become inflamed)12
- Synaptic damage (the synapse is where neurons transmit a signal to another neuron, gland or muscle: damage impairs this signalling)13
- Neuronal loss1
- Reduced cortical thickness, particularly in the left hemisphere14
Signs and symptoms of sCJD
Although symptoms and rate of progression can vary significantly,15 the most common can be categorised into:
Motor symptoms
- Ataxia: coordination and balance difficulties2,7
- Dysarthria: slurred speech7
- Myoclonus: involuntary and uncontrollable muscle jerking
- Bradykinesia: slow movement14
- Spasticity: abnormal muscle tightness and muscle tone1,14
- Visual disturbances: cortical blindness, agnosia, visual field cuts, double vision, nystagmus7,15
- Dizziness7
- Sensory changes: numbness, pins and needles7
Cognitive symptoms
- Memory impairment: delayed verbal recall, naming and learning16
- Mood changes: severe depression, anxiety and withdrawal7
- Executive functioning difficulties: ability to plan, focus, multi-task, emotional and behavioural regulation16, 17
- Loss of intellect7
- Personality changes such as agitation or confusion18
- Hallucinations7
Advanced symptoms
- Dysphagia: swallowing difficulties
- Loss of speech
- Loss of voluntary movement
- Urinary and bowel incontinence
- Loss of appetite
- Loss of insight and awareness
- Pneumonia or respiratory failure7
Diagnosis of sCJD
There are a range of diagnostic tests that individuals may require to receive the correct diagnosis:
Magnetic resonance imaging (MRI)
An MRI scan of the brain is one of the main diagnostic tests. It is a painless scan lasting 15-90 minutes, and images are produced using a strong magnet and radio waves.19 Specifically, diffusion-weighted imaging (DW-MRI) is superior in detecting changes in the brain, such as hypersensitivity in at least two cortical areas or cerebral atrophy.11,20 Abnormalities are correctly detected in 96% of individuals with sCJD.21
Electroencephalogram (EEG)
An EEG is a painless procedure lasting 20-40 minutes. Approximately 20 small electrodes are attached to the scalp and connected to a machine to record electrical activity in the brain. This can detect abnormalities shown in sCJD, such as periodic sharp wave complexes.21 However, EEG is less sensitive than an MRI, with only 69% sensitivity, and may show normal results in the early stages of the disease, so it should be used in conjunction with other tests.21
Lumbar puncture
A lumbar puncture is a more invasive procedure, involving the insertion of a needle into the space between the lumbar (lower spinal) vertebrae. The procedure takes 45 minutes and can be uncomfortable, but is very safe.22 It is used to obtain a sample of cerebrospinal fluid (CSF). CSF is a clear fluid that surrounds the central nervous system and can be tested for biomarkers of sCJD.
One of the main biomarkers is the 14-3-3 protein. A positive test can help to confirm the diagnosis of sCJD. However, sensitivity is lower in the early stages of the disease, meaning the test may produce a false negative.20 Alternatively, the test may provide a false positive in individuals experiencing acute stroke, dementia, subarachnoid haemorrhage, or glioblastoma, so further tests may be necessary.23 In addition, the RT- QuIC test is positive in 95% of individuals with sCJD.24 Tau proteins are also significantly elevated in sCJD but are not currently part of the clinical criteria for diagnosis.20
Brain biopsy
A biopsy involves obtaining a sample of tissue from the brain for analysis, either using tissue obtained during surgery or via stereotactic biopsy. It is, however, a very invasive procedure, so is avoided where possible, as it is unlikely to change the course of treatment.25
Treatment and management
There is currently no cure for sCJD, so treatment is focused on providing symptom relief, specialist and supportive care.
Symptomatic treatment
- Myoclonus can be treated using sodium valproate and clonazepam7
- Dysphagia can be treated using a modified, soft diet, speech and language therapist support and/or inserting a feeding tube7,24
- Depression and anxiety can be treated using antidepressants such as SSRIs7
- Pain may be treated with opiate-based medication7
- Motor symptoms may be treated with the support of a physiotherapist or occupational therapist24
Specialist care
In the UK, individuals with suspected CJD are referred to the National Care Team for CJD in Edinburgh or the National Prion Clinic in London. Specialist doctors will liaise with the local care team, assisting with diagnosis and management.7
Supportive and palliative care
Rapid disease progression means that care preferences should be discussed soon after diagnosis. Individuals often need significant care and support, which may include:
- An advanced directive is a statement of treatment preferences written with the individual in advance of disease progression7
- Social services can provide financial advice and community care planning24
- Palliative hospice care
- Carer breaks and respite care7
This can be a distressing and emotional time for individuals and their families/carers. If you are concerned about yourself or a loved one, you can reach out for emotional and practical support here.
Research and advances
New research is focused on recruiting autoimmune cells to develop gene therapy, targeted immunomodulator therapy, stem cell technology and protein degradation therapy.26 For example, the development of monoclonal antibody (PRN100) therapy, which inhibits the misfolded prion protein proliferation, has proven safe and effective in individuals with CJD, although findings are still in the early stages.27
Research is also continually developing into identifying proteins as diagnostic biomarkers. For example; α-Synuclein, a synaptic protein, and plasma glial fibrillary acidic protein (pl-GFAP), a filament protein, have been found to be higher in the CSF of individuals with sCJD compared to dementia.28,29 This could lead to the development of additional biomarkers. However, large-scale randomised control trials are difficult to achieve in research due to the low incidence of CJD and the rapid progression of symptoms.26
FAQs
What is the prognosis/life expectancy of sCJD?
Sadly, 90% of individuals with sCJD will die within a year of symptom onset, although this can range from a few months to a few years.24
What is the difference between familial CJD and sporadic CJD?
Familial CJD is inherited, meaning it is due to a germline mutation, whereas sporadic CJD occurs spontaneously, due to a somatic mutation. Although symptoms present similarly, they develop more rapidly in sporadic CJD (around 6 months), versus around 2 years in familial CJD.1,7
Which are the differential diagnoses to consider?
Alzheimer’s disease, dementia with Lewy bodies, Huntington’s disease, progressive supranuclear palsy, frontotemporal dementia, multiple sclerosis, and Pick disease may need to be ruled out by healthcare professionals.23 MRI can also rule out other conditions such as ischaemia.20
Is sCJD infectious?
sCJD can only be transmitted through the consumption or injection of infected tissue; it cannot be transmitted through physical contact or bodily fluids.7
Summary
Sporadic CJD is a rare, fatal neurodegenerative disease. It is caused by the spontaneous misfolding of the prion protein and affects the central nervous system. Symptoms such as dementia, myoclonus, ataxia and visual disturbances develop and progress rapidly. Individuals typically die within a year of symptom onset and require significant care and support. Treatment currently focuses on providing symptom relief, but there is no cure.
References
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- Bernardini A, Gigli GL, Janes F, Pellitteri G, Ciardi C, Fabris M, et al. Creutzfeldt-Jakob disease after COVID-19: infection-induced prion protein misfolding? A case report. Prion [Internet]. 2022 [cited 2024 Jun 18];16(1):78–83. Available from: https://www.tandfonline.com/doi/full/10.1080/19336896.2022.2095185
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- Spocter MA, Hopkins WD, Barks SK, Bianchi S, Hehmeyer AE, Anderson SM, et al. Neuropil distribution in the cerebral cortex differs between humans and chimpanzees. J of Comparative Neurology [Internet]. 2012 [cited 2024 Jun 17];520(13):2917–29. Available from: https://onlinelibrary.wiley.com/doi/10.1002/cne.23074
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- Thameem Dheen S, Kaur C, Ling E-A. Microglial Activation and its Implications in the Brain Diseases. Current Medicinal Chemistry [Internet]. 2007 [cited 2024 Jun 18]; 14(11):1189–97. Available from: https://pubmed.ncbi.nlm.nih.gov/17504139/.
- Budak M, Zochowski M. Synaptic failure differentially affects pattern formation in heterogenous networks. Front Neural Circuits [Internet]. 2019 [cited 2024 Jun 17];13:31. Available from: https://www.frontiersin.org/article/10.3389/fncir.2019.00031/full
- Navid J, Day GS, Strain J, Perrin RJ, Bucelli RC, Dincer A, et al. Structural signature of sporadic Creutzfeldt–Jakob disease. Euro J of Neurology [Internet]. 2019 [cited 2024 Jun 18];26(8):1037–43. Available from: https://onlinelibrary.wiley.com/doi/10.1111/ene.13930
- Bosque PJ, Tyler KL. Prions and prion diseases of the central nervous system(Transmissible neurodegenerative diseases). In: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases [Internet]. Elsevier; 2015 [cited 2024 Jun 18]. p. 2142-2153.e4. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9781455748013001818
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- NHS. Overview - MRI Scan. In: NHS [Internet]. 2017 [cited 2024 Jun 18]. MRI scan. Available from: https://www.nhs.uk/conditions/mri-scan/
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- Mead S, Khalili-Shirazi A, Potter C, Mok T, Nihat A, Hyare H, et al. Prion protein monoclonal antibody (Prn100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme. The Lancet Neurology [Internet]. 2022 [cited 2024 Jun 19];21(4):342–54. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1474442222000825
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