Prion Diseases

Prion diseases are a group of rare, invariably fatal neurodegenerative conditions caused by the misfolding of a normal host protein (the prion protein, PrP) into an abnormal, disease-causing conformation (PrPSc).

PrPSc templates further misfolding of normal protein in a self-propagating manner, without involving nucleic acid. This is a fundamentally distinct disease mechanism from any conventional infectious agent.

Creutzfeldt-Jakob disease (CJD) is the most common human prion disease, occurring in four forms:

• sporadic: roughly 85% of cases, spontaneous misfolding with no identifiable external cause
• genetic/familial: inherited PRNP gene mutations, autosomal dominant
• iatrogenic: historically from contaminated human-derived pituitary growth hormone or dura mater grafts, and, rarely, from inadequately decontaminated neurosurgical instruments, given the notable resistance of prions to standard sterilization methods
• variant CJD (vCJD): acquired through dietary exposure to the bovine spongiform encephalopathy agent, "mad cow disease," now very rare following the control of BSE in the cattle food supply

• Sporadic CJD typically presents in patients over 60 with rapidly progressive dementia (over weeks to a few months). The pace of decline is dramatically faster than typical Alzheimer's disease or other common dementias, and this rapidity is itself a major diagnostic clue.
• It is accompanied by myoclonus, cerebellar signs (ataxia), visual disturbance, and, characteristically, startle myoclonus.
• Progression to akinetic mutism and death typically occurs within months of symptom onset, with a median survival of only a few months from diagnosis.
• Variant CJD typically affects a younger population, with a more prominent early psychiatric presentation (depression, anxiety, withdrawal) and painful sensory symptoms preceding the neurological decline, with a somewhat longer overall disease course than sporadic CJD but still uniformly fatal

• MRI brain, particularly diffusion-weighted imaging, shows characteristic cortical ribboning and basal ganglia hyperintensity in sporadic CJD, and the specific "pulvinar sign" (bilateral posterior thalamic hyperintensity) in variant CJD, both with good diagnostic sensitivity when present
• EEG may show characteristic periodic sharp wave complexes in sporadic CJD, though this finding is less consistently present in variant CJD
• CSF testing: real-time quaking-induced conversion (RT-QuIC) assay, where available, offers high sensitivity and specificity for detecting the abnormal prion protein. It has become the preferred CSF-based test.
• It supersedes the older and less specific 14-3-3 protein and total tau markers, which remain supportive but less definitive.
• Genetic testing for PRNP mutations is performed where familial disease is suspected, with appropriate genetic counseling given the implications for the patient and family
• Definitive diagnosis requires neuropathological confirmation (brain biopsy, rarely performed given the risks and lack of any curative treatment to justify it, or, more commonly, at post-mortem), showing the characteristic spongiform change.
• A confident clinical diagnosis using the criteria above is generally sufficient to guide management and counseling in life.

There is currently no curative or disease-modifying treatment for any human prion disease, and management is entirely supportive and palliative, focused on symptom control, dignity, and support for the patient and family through what is typically a rapid and devastating decline.

• Myoclonus may be partially managed symptomatically with clonazepam or sodium valproate, though with limited overall effect on disease progression

• Multidisciplinary palliative care input, addressing nutrition and swallowing difficulties (often requiring careful decision-making around feeding as the disease progresses), pressure area care, and psychological support for the family, is central to management

• Infection control precautions are important given the resistance of prions to standard decontamination methods.

  Instruments used in neurosurgical or other high-risk procedures on a confirmed or suspected case require specific enhanced decontamination or, in some cases, disposal per specialist infection control guidance. Blood, organ, and tissue donation is contraindicated.

• Given the invariably fatal, currently untreatable nature of these conditions, early and honest discussion of prognosis, advance care planning, and connection with specialist palliative and, where relevant, prion disease specific support services is a core part of management from the point of diagnosis

Referral: neurology and, where available, a specialist national prion disease surveillance and referral center for diagnostic confirmation and family counseling; palliative care from the point of diagnosis given the uniformly poor prognosis; genetic counseling for suspected familial disease.