Introduction 

Creutzfeldt-Jakob Disease (CJD) is a human prion disease and a rare, progressive neurodegenerative brain disorder. It predominantly affects patients above the age of 60, with approximately 70% of patients passing away one year after diagnosis. It affects 1 in 1 million people worldwide per year.¹

CJD can manifest in various forms: sporadic, genetic, variant and iatrogenic. When the disease is transmitted through medical procedures, it is known as iatrogenic Creutzfeldt-Jakob Disease (iCJD).^1,2 Sporadic CJD is defined as the most common type of prion disease (about 85% of the cases).¹ It arises in two ways: spontaneous PRNP (prion protein gene) mutation or prion protein structural change. It is characteristically accompanied by progressive dementia.³ Genetic CJD is caused by mutations in the human PrP gene (PRNP). In other words, one can inherit CJD.^1,4

This article aims to unfold the particularities of iatrogenic Creutzfeldt-Jacob disease, also presenting the main types of CJD, the causes of iCJD, pathophysiology, clinical presentation, diagnosis, treatment and management, and some prevention and control strategies.

Epidemiology 

Analysing the trends of the different types of CJD, we can split them into four different categories: sporadic, genetic, iatrogenic and variant.¹

Sporadic (sCJD) 

This accounts for up to 85-90% of all CJD cases. It typically has an incidence rate of about 1 to 1.5 cases per million people per year, globally. It also occurs without any known risk factors or familial linkages and predominantly affects individuals aged 60 and older.^1,5

Genetic (gCJD) 

This type makes up to 10-15% of all CJD cases. It is linked to inherited mutations in the PRNP gene and is usually present earlier in life compared to sCJD, often in individuals in their 40s or 50s.^1,4

Iatrogenic (iCJD) 

As the rarest form of CJD, iCJD accounts for less than 1% of all cases. It is usually associated with contaminated surgical instruments, dura mater grafts, or human-derived growth hormone therapies. It is mostly found in countries where contaminated procedures occur more often.^1,2,6,7

Variant (vCJD) 

This form is linked to the consumption of beef infected with Bovine Spongiform Encephalopathy (BSE). Its possibility of occurring is very low, with currently fewer than 250 cases reported worldwide. It usually affects younger individuals, typically in their late teens and early twenties, and has a distinct pathology compared to sCJD. The majority of cases were identified in the UK, with a smaller number of cases in other countries like France. While cases of CJD have remained stable throughout the years due to increased regulations, vCJD experienced a notable peak in the late 1990s and the early 2000s.^1,5,8 

Pathophysiology 

CJD occurs due to the presence of proteinaceous infectious particles known as prions. They lack nucleic acid and are composed of proteinase K-resistant β-pleated sheet aggregates.^1,8 

The normal cellular prion protein undergoes a conformational change, transforming to become the pathogenic, misfolded form, which is rich in β-sheets and forms amyloid aggregates. This misfolded pathogenic form PrPSc is resistant to proteases, leading to its accumulation in the brain and resulting in subsequent neurodegeneration. The accumulation of pathogenic PrPSc forms insoluble amyloid plaques, which disrupt cellular function and contribute to neurodegenerative processes. Intermediate structures of pathogenic PrP may be particularly toxic, interacting with cellular membranes and causing cellular dysfunction.^1,8,9 

Causes of iatrogenic CJD

Iatrogenic CJD occurs when prions are transmitted through surgical procedures. This often is a result of contaminated instruments that become in contact with the central nervous system.^1,7 Prions are resistant to sterilisation, meaning that once the instruments have been in contact with infected areas, if used again, they can transmit iatrogenic CJD. Moreover, since the first introduction of dura mater grafts in 1987, over 200 cases of CJD transmission have been reported through this route worldwide.^1,5,6 

Additionally, cadaveric pituitary hormone therapy is another means of CJD transmission. These hormones were used to treat growth deficiencies in children, but if the pituitary glands were sourced from cadavers with undiagnosed CJD, the extracted hormones could transmit the disease to recipients. Although it is extremely rare, research shows that iatrogenic CJD developed in a 39-year-old Austrian man approximately 22 years after he received commercial cadaveric hormone therapy in Sweden during 1984–1985.^1,5,7 

Moreover, corneal transplants have also been implicated in the transmission of CJD. This particular procedure involves replacing damaged cornea with healthy donor tissue. However, if the donor has CJD, the disease could be easily transmitted. As a result, such historical incidents prompted significant changes in medical practices. This varies from the implementation of stricter sterilisation protocols to improve donor screening and the shift to synthetic growth hormones.^1,5,8

Clinical presentation 

If CJD is expected, individuals may showcase the following neurological effects and symptom progression:^1,3,10

Initial phases

Early symptoms of CJD are often non-specific and may include fatigue, sleep disturbances, and behavioural changes. As the disease progresses, one may notice that more distinct symptoms emerge, such as rapidly progressive dementia and personality changes. Furthermore, patients may develop muscle jerks, loss of coordination and visual disturbances.^1,3,10

Advanced stages

Patients typically become bedridden and unresponsive. Severe neurological impairment leads to loss of speech, as well as the inability to move. Additional symptoms can include muscle stiffness, tremors, and seizures. Pathologically, the brain tissue exhibits a spongiform appearance due to microscopic vacuoles within neurons, particularly affecting the cerebral cortex. Consequently, a glial cell-increase in response to neuronal damage alongside amyloid plaques composed of pathogenic PrPSc may be found. At terminal stages, CJD typically leads to death within a year of symptom onset.^1,3,10

Diagnosis

Diagnosing CJD can be challenging due to its overlapping symptoms with other diseases such as dementia. It can be diagnosed in the following ways:^1,2,3,11

• Magnetic Resonance Imaging (MRI) - Radiologists often use Diffusion-Weighted Imaging (DWI) and Fluid-Attenuated Inversion Recovery (FLAIR) sequences. MRI findings may show hyperintensities in specific brain regions, such as the basal ganglia and thalamus, which are indicative of spongiform changes. Another indication would be the hyperintensity of grey matter in the scan
• Cerebrospinal Fluid (CSF) Analysis involves measuring biomarkers in the cerebrospinal fluid. If there is an elevated presence of 14-3-3 proteins (specific pion disease test), it would strongly suggest the diagnosis of CJD
• Electroencephalogram (EEG) involves using electrodes to measure the brain’s electrical activity by utilising a non-invasive brain computer interface (BCI). To find evidence of CJD, one can notice diffusion slowing and frontal rhythmic delta activity (FIRDA) for early diagnosis. One may also notice periodic sharp wave complexes (PSWC) for more advanced stages. Ultimately, evidence would also involve unreactive coma traces in terminal stages of the disease 

Treatment and management 

There is currently no cure for any type of Creutzfeldt-Jakob disease. Once a neuron has been destroyed, it cannot be regenerated. However, scientists and engineers are working towards developing therapeutic measures to prolong and improve the quality of life of patients.^1,12,13

Anti-prion agents - Various compounds, such as pentosan polysulfate, quinacrine and doxycycline are being investigated for their ability to inhibit the conversion of normal prion protein PrPC to the pathogenic prion protein PrPSc form, and to destabilise prion aggregates.^1,13

Immunotherapy - Researchers at Medical Research Council Prion Unit at University College London (UCL) have created a humanised monoclonal antibody known as PRN100 which was administered to six patients with CJD. This treatment was well-tolerated and appeared to have a modest positive influence on the clinical presentation temporarily, although the neurological deterioration continued for all the patients.¹⁴ 

Given the rapid progression of this disease, multidisciplinary and palliative care are essential to preserve the patient’s quality of life. Managing symptoms, such as sleep disturbances, emotional and behavioural challenges, alleviating the pain and minimising the uncontrollable muscle movements via various therapies and medication improve the patient’s experience and reduce their suffering. However, the disease’s course seems to remain unaltered by such measures.^1,13 

Prevention and control

Regulatory agencies such as the World Health Organisation (WHO), the Centers for Disease Control and Prevention (CDC) have established guidelines for managing CJD to prevent iatrogenic CJD transmission. Such guidelines include the safe handling of tissues from suspected CJD patients, decontaminating surgical instruments, and managing potential exposure.¹⁵ Moreover, medical guidelines also encourage the usage of disposable instruments and equipment for procedures involving high-risk tissues.

Summary 

• iCJD is a rare and severe form of Creutzfeldt-Jakob Disease that occurs due to transmission of prions through medical procedures or treatments 
• Possible transmission routes include the use of contaminated surgical instruments, dura mater grafts, cadaveric pituitary hormone therapy and corneal transplants
• The core pathology of CJD involves the misfolding of normal prion proteins into pathogenic forms leading to deceased neurons
• Key diagnostic methods include MRI, cerebrospinal fluid analysis and EEG
• While there is currently no cure for iCJD, there are ongoing experimental trials which offer optimism for improved patient outcomes