Prion diseases are uniformly fatal neurodegenerative disorders caused by misfolding of the cellular prion protein (PrP^C) into a self-propagating pathogenic isoform (PrP^Sc). They reach psychiatry because the prodrome is often psychiatric — depression, anxiety, personality change, insomnia, frank psychosis — and because the tempo is wrong for the dementias residents see most. Sporadic Creutzfeldt-Jakob disease (sCJD) is the prototype, accounting for roughly 85% of human cases, with genetic and acquired forms (including variant CJD, iatrogenic CJD, kuru, and fatal familial insomnia) making up the remainder. DSM-5-TR classifies symptomatic cases under Major neurocognitive disorder due to prion disease, but the practical task at the bedside is recognizing a rapidly progressive dementia with myoclonus, ataxia, or visual disturbance and triggering the right workup before the window for diagnostic CSF and MRI closes. The bottom line: when a patient declines cognitively over weeks to months with neurologic signs, think prion early — the workup is specific, the prognosis is grim, and the public health implications are real.

Prion disease is rare but globally distributed, and its incidence has held steady for decades despite the dramatic decline in iatrogenic and variant forms.

Incidence and case mix

• Worldwide incidence of sCJD is approximately 1-2 cases per million population per year, with broadly similar rates across countries that maintain active surveillance.^[1-2]
• Sporadic CJD accounts for approximately 85% of human prion disease; genetic forms (familial CJD, Gerstmann-Sträussler-Scheinker disease, fatal familial insomnia) account for 10-15%; acquired forms (iatrogenic CJD, variant CJD, kuru) account for less than 1% in the current era.^[2-3]
• Variant CJD, linked to dietary exposure to bovine spongiform encephalopathy, peaked in the United Kingdom in the late 1990s and early 2000s; new cases are now exceedingly rare, with the cumulative global total of approximately 230 confirmed cases by the mid-2020s.^[3]

Demographics and onset

• Median age of onset for sCJD is approximately 67 years, with most cases between 55 and 75; variant CJD classically presents in younger adults with a median onset in the late 20s.^[2-3]
• Sex distribution in sCJD is approximately equal.^[2]
• Genetic prion diseases can present from the third decade onward depending on the PRNP mutation and codon 129 genotype.^[4]

Risk factors

• The codon 129 polymorphism in PRNP (methionine/valine) is the most important genetic modifier; methionine homozygosity predisposes to sCJD and historically was present in all definite variant CJD cases.^[4]
• Family history of early-onset dementia, ataxia, or unexplained progressive insomnia raises suspicion for genetic prion disease.^[4]
• Historical iatrogenic risk factors include dura mater grafts, cadaveric pituitary growth hormone, contaminated neurosurgical instruments, and corneal transplants; modern preparation and decontamination protocols have largely eliminated new cases.^[5]
• Dietary exposure to BSE-contaminated beef is the established risk factor for variant CJD; current bovine surveillance has substantially reduced this risk.^[3]

The unifying mechanism is templated misfolding: a misfolded prion protein recruits native protein into the same pathogenic conformation, producing self-propagating, transmissible neurodegeneration without nucleic acid.^[1]

Molecular mechanism

• The cellular prion protein PrP^C is a glycosylphosphatidylinositol-anchored membrane protein encoded by PRNP on chromosome 20.^[4]
• In disease, PrP^C undergoes conformational change to PrP^Sc, a beta-sheet-rich, protease-resistant isoform that aggregates and propagates by templating further misfolding.^[1,6]
• PrP^Sc accumulation produces the histopathologic triad of spongiform vacuolation, neuronal loss, and reactive astrogliosis, with variable amyloid plaque formation; florid plaques surrounded by spongiform halos are characteristic of variant CJD.^[3,6]

Genetics

• More than 50 pathogenic PRNP mutations are described; the most common is E200K (familial CJD), followed by D178N (which produces fatal familial insomnia or familial CJD depending on the codon 129 cis genotype) and P102L (Gerstmann-Sträussler-Scheinker disease).^[4]
• Inheritance is autosomal dominant with high but incomplete penetrance.^[4]
• Codon 129 modifies phenotype, age of onset, and disease duration in both sporadic and genetic forms.^[4]

Acquired forms

• Variant CJD is caused by transmission of the BSE prion strain to humans, most often through dietary exposure; rare secondary transmission has been reported through blood transfusion in the United Kingdom.^[3]
• Iatrogenic CJD followed dura mater grafts, cadaveric pituitary hormones, and contaminated neurosurgical equipment; standard prion-decontamination protocols and synthetic hormone preparations have largely eliminated new cases.^[5]
• Kuru, transmitted by ritual endocannibalism among the Fore people of Papua New Guinea, is now of historical interest only, though late cases with incubation periods over 50 years have been reported.^[2]

DSM-5-TR classifies symptomatic prion disease under Major or Mild Neurocognitive Disorder Due to Prion Disease; the substantive diagnostic work, however, is anchored in the updated CDC/EU clinical criteria for probable and definite CJD.^[8-9]

DSM-5-TR placement

• The diagnosis requires criteria for major or mild neurocognitive disorder plus insidious onset and rapid progression of impairment.^[8]
• Supportive features include motor signs (myoclonus, ataxia, chorea) or biomarker evidence (characteristic MRI, EEG, or CSF findings).^[8]
• The disturbance is not attributable to another medical condition or substance and is not better explained by another mental disorder.^[8]

Probable sCJD (updated clinical criteria)

• Rapidly progressive dementia plus at least two of: myoclonus, visual or cerebellar signs, pyramidal or extrapyramidal signs, akinetic mutism.^[9]
• Plus at least one of: typical periodic sharp-wave complexes on EEG, positive CSF 14-3-3 protein (when clinical duration is under two years), or characteristic high-signal abnormalities in caudate/putamen or at least two cortical regions (temporal, parietal, occipital) on diffusion-weighted imaging or fluid-attenuated inversion recovery MRI.^[9-10]
• Plus absence of an alternative diagnosis on routine investigation.^[9]
• Updated criteria additionally accept a positive CSF RT-QuIC assay as sufficient supportive evidence for probable sCJD.^[10]
• Definite diagnosis requires neuropathologic confirmation or detection of protease-resistant PrP by immunoassay on brain tissue.^[9]

Variant CJD criteria (abridged)

• Progressive neuropsychiatric disorder of at least six months' duration with routine investigations excluding alternative diagnoses, no history of iatrogenic exposure, and no evidence of genetic prion disease.^[11]
• Plus at least four of: early psychiatric symptoms (depression, anxiety, apathy, withdrawal, delusions), persistent painful sensory symptoms, ataxia, myoclonus or chorea or dystonia, dementia.^[11]
• Bilateral pulvinar high signal on FLAIR MRI (the "pulvinar sign") is highly supportive of variant CJD.^[11]

ICD-11 differences

• ICD-11 places prion disease under chapter 06 (Mental, behavioural or neurodevelopmental disorders) as a dementia due to a disease classified elsewhere, cross-referenced to chapter 08 neurology codes for the underlying prion disease.^[12]
• ICD-11 does not require the DSM major/mild distinction; functional decline is graded separately.^[12]

The hallmark is a rapidly progressive dementia with multifocal neurologic signs; the dominant early presentation varies enough by subtype that pattern recognition matters.

Sporadic CJD core picture

• Median illness duration from symptom onset to death is approximately 5 months, with roughly 90% of patients dying within one year.^[2,9]
• Cognitive decline is the presenting feature in most cases — executive dysfunction, memory impairment, and language disturbance progressing over weeks rather than years.^[2]
• Myoclonus develops in more than 80% of patients, often startle-induced, and is a diagnostic clue when paired with rapid dementia.^[2,9]
• Cerebellar signs (ataxia, dysarthria, nystagmus) occur in approximately 40% at presentation.^[2]
• Visual disturbances — cortical blindness, visual agnosia, hallucinations — define the Heidenhain variant, which can present to ophthalmology before neurology.^[2]
• Pyramidal and extrapyramidal signs typically follow, with akinetic mutism in the late stages.^[2]

Variant CJD presentation

• A prominent and prolonged psychiatric prodrome — depression, anxiety, apathy, social withdrawal, or psychosis — typically precedes neurologic signs by months.^[3,11]
• Persistent painful dysesthesias in limbs or face are a distinctive early feature.^[3]
• Ataxia, involuntary movements (chorea, dystonia, myoclonus), and dementia follow.^[3]
• Median illness duration is longer than sCJD, approximately 14 months.^[3]

Fatal familial insomnia

• Progressive untreatable insomnia, autonomic dysregulation (hyperhidrosis, tachycardia, hypertension), and motor signs dominate the early course.^[4]
• Cognitive impairment and frank dementia appear later than in sCJD.^[4]
• Caused by the D178N mutation in cis with methionine at codon 129.^[4]

Gerstmann-Sträussler-Scheinker disease

• Slowly progressive cerebellar ataxia with later dementia, with illness duration of years rather than months.^[4]
• Most often associated with the P102L PRNP mutation.^[4]

The clinical task is separating prion disease from the long list of treatable mimics that present as rapidly progressive dementia, because several of those mimics are reversible if caught.^[13]

Other neurodegenerative dementias

• Alzheimer disease progresses over years and lacks early myoclonus or ataxia; rapidly progressive variants exist but are uncommon.^[13]
• Dementia with Lewy bodies features fluctuating cognition, visual hallucinations, and parkinsonism but lacks the diagnostic MRI and CSF signature of CJD.^[13]
• Corticobasal degeneration and progressive supranuclear palsy progress over years and feature distinctive movement abnormalities; rapid course argues against them.^[13]

Autoimmune encephalitis (the highest-yield mimic)

• Anti-NMDA receptor, anti-LGI1, anti-CASPR2, and other autoimmune encephalitides can present with subacute cognitive decline, psychiatric symptoms, seizures, and movement disorder.^[14]
• CSF pleocytosis, characteristic antibody panels, and response to immunotherapy distinguish them from prion disease.^[14]
• These are the most important do-not-miss mimics because they are often treatable.^[14]

Other treatable rapidly progressive dementias

• Hashimoto encephalopathy (steroid-responsive encephalopathy associated with autoimmune thyroiditis) presents with cognitive decline, myoclonus, and tremor, with elevated anti-thyroid antibodies.^[13]
• CNS infections — HIV, neurosyphilis, viral encephalitis, Whipple disease, cryptococcal meningoencephalitis — must be excluded with appropriate serology, CSF studies, and imaging.^[13]
• Metabolic and nutritional causes — B12 deficiency, thiamine deficiency, hepatic encephalopathy, uremia, severe hypothyroidism — are reversible if identified.^[13]
• Paraneoplastic syndromes (anti-Hu, anti-Yo, anti-Ma2) overlap clinically with autoimmune encephalitis and warrant malignancy workup.^[13-14]

Toxic and pharmacologic

• Heavy-metal exposure (mercury, bismuth, lithium toxicity) and chronic anticholinergic burden can mimic rapid cognitive decline.^[13]
• Serotonin syndrome and neuroleptic malignant syndrome can produce myoclonus and confusion but evolve over hours to days, not weeks.^[15]

Primary psychiatric mimics

• Severe depression with cognitive features improves with antidepressant treatment and lacks neurologic signs.^[13]
• Functional cognitive disorder may present with rapid subjective decline but lacks biomarker abnormalities.^[13]

A focused workup confirms or excludes prion disease quickly and rules out the treatable mimics in parallel; do not wait for one result before ordering the next.

History and bedside examination

• Establish tempo: time from first symptom to current state, with collateral history from a family member, is the single most useful piece of information.^[2]
• Document myoclonus (including startle-induced), cerebellar signs, visual symptoms, extrapyramidal signs, and behavioral or psychiatric features.^[2,9]
• Ask about family history of early-onset dementia, ataxia, or unexplained insomnia; iatrogenic exposures (dura graft, growth hormone, prior neurosurgery); and dietary history in regions with historical BSE exposure.^[3-5]
• Cognitive screening with the MoCA is reasonable but the test is insensitive to the fastest declines; serial bedside testing over days documents the trajectory.^[2]

Imaging

• Brain MRI with diffusion-weighted imaging (DWI) and FLAIR is the highest-yield single test: cortical ribboning and high signal in caudate, putamen, and thalamus support sCJD.^[10]
• The bilateral pulvinar sign on FLAIR is highly supportive of variant CJD.^[11]
• MRI also helps exclude structural mimics (tumor, stroke, abscess, autoimmune encephalitis with mesial temporal involvement).^[14]

CSF studies

• RT-QuIC (real-time quaking-induced conversion) detects PrP^Sc seeding activity in CSF with sensitivity above 90% and specificity approaching 100% for sCJD; it has largely replaced 14-3-3 as the preferred prion-specific CSF test where available.^[10]
• CSF 14-3-3 protein remains widely used but is nonspecific; elevations occur in any acute neuronal injury.^[9]
• CSF total tau is supportive when markedly elevated (commonly above approximately 1,150 pg/mL in sCJD), though cutoffs vary by laboratory.^[10]
• Routine CSF studies should include cell count, protein, glucose, and an autoimmune/infectious panel to exclude mimics.^[14]

EEG:

• Periodic sharp-wave complexes at 1-2 Hz are classic for sCJD but appear in only about 60-70% of cases and usually mid-to-late in disease.^[2,9]
• Variant CJD does not produce the classic EEG pattern.^[3,11]

Genetic testing

• PRNP sequencing identifies pathogenic mutations (familial CJD, fatal familial insomnia, Gerstmann-Sträussler-Scheinker disease) and the codon 129 genotype.^[4]
• Offer pre- and post-test genetic counseling; the implications for at-risk relatives are substantial.^[4]

Other labs

• Comprehensive metabolic panel, TSH, B12, HIV, syphilis serology, ANA, anti-thyroid antibodies, and paraneoplastic and autoimmune encephalitis antibody panels.^[13-14]
• Tonsillar biopsy is no longer routinely recommended for variant CJD diagnosis; blood-based assays under development may eventually replace tissue sampling.^[3]

Brain biopsy and autopsy

• Brain biopsy is rarely indicated; it carries procedural risk and infection-control burden, and noninvasive testing (MRI plus RT-QuIC) now establishes a probable diagnosis in most cases.^[10]
• Neuropathologic examination at autopsy remains the gold standard for definite diagnosis and is strongly encouraged in suspected cases for surveillance and family-counseling purposes.^[2,9]

No disease-modifying therapy exists; care is supportive, multidisciplinary, and palliative from diagnosis onward. The goals are symptom control, family preparation, and infection-control hygiene where applicable.^[15]

Pharmacotherapy

• It is uncertain whether any agent slows prion disease progression; randomized and open-label trials of quinacrine, pentosan polysulfate, doxycycline, and flupirtine have not demonstrated meaningful clinical benefit.^[15-16]
• A first-in-human treatment programme of the anti-prion monoclonal antibody PRN100 in a small cohort did not demonstrate clear clinical benefit and underscored the difficulty of disease-modifying intervention.^[17]
• Some experts recommend an early goals-of-care conversation rather than disease-directed pharmacotherapy, given the absence of effective therapy and the rapidity of decline.^[15]
• For myoclonus, limited evidence suggests clonazepam, levetiracetam, or valproate may reduce symptom burden; clonazepam is most commonly used first.^[18]
  • clonazepam 0.5 mg PO QHS titrated to effect, with attention to sedation in patients with bulbar involvement.^[18]
  • levetiracetam 500 mg PO BID is an alternative when sedation must be minimized.^[18]
• For agitation and psychotic symptoms, low-dose antipsychotics are commonly recommended, though high-quality evidence is lacking; choose agents with low anticholinergic and extrapyramidal burden.^[18]
  • quetiapine 12.5-50 mg PO QHS is frequently used for nocturnal agitation.^[18]
  • Avoid high-potency typical antipsychotics where parkinsonism or dystonia is already present.^[18]
• For depression and anxiety in the prodrome or early symptomatic phase, evidence suggests SSRIs are reasonable; sertraline 25-50 mg PO QD is a common starting choice.^[18]
• For pain (notable in variant CJD), gabapentin or low-dose opioids may be required; titrate against sedation and constipation.^[15,18]

Psychotherapy

• Limited evidence suggests supportive psychotherapy for patient and family, focused on grief, anticipatory loss, and practical planning, improves caregiver outcomes.^[15]
• Cognitive-behavioral techniques have a limited role given the pace of cognitive decline; therapy is reframed toward caregiver coping and advance care planning.^[15]

Neuromodulation

• There is no role for ECT, TMS, or DBS in prion disease management; these are not recommended.^[15]

Adjunctive

• Multidisciplinary palliative care involvement from diagnosis is recommended; early hospice referral aligns with the trajectory.^[15]
• Speech and swallowing assessment as bulbar function declines; address aspiration risk with diet modification and family education.^[15]
• Physical therapy for safety and contracture prevention; occupational therapy for equipment and home modification.^[15]
• Genetic counseling for first-degree relatives when a PRNP mutation is identified.^[4]
• Infection-control consultation for surgical or dental procedures in confirmed or probable cases; standard sterilization does not inactivate prions.^[5,7]

No disease-modifying therapy has shown benefit in any rigorously conducted trial, so the harms picture is dominated by symptomatic medication side effects, monitoring burden in a dying patient, and the limits of the diagnostic toolkit itself.

Adverse effects of symptomatic pharmacotherapy

• Benzodiazepines used for myoclonus and agitation cause sedation, respiratory depression, falls, and paradoxical disinhibition in cognitively impaired patients.^[18]
• Antipsychotics for agitation or psychosis increase mortality in patients with major neurocognitive disorder and carry FDA boxed warnings; extrapyramidal effects worsen pre-existing motor disease.^[18]
• Levetiracetam often causes neuropsychiatric adverse effects — irritability, depression, suicidal ideation — that can be misattributed to disease progression.^[18]
• Anticholinergic burden from any agent worsens delirium and is poorly tolerated in advanced prion disease.^[18]

Serious or rare adverse outcomes

• Failed disease-modifying trials (quinacrine, doxycycline, pentosan polysulfate) exposed patients to hepatotoxicity, QT prolongation, and intrathecal catheter complications without benefit.^[15-16]
• Aspiration pneumonia from dysphagia is the most common proximate cause of death and is incompletely prevented by feeding modifications.^[15]
• Iatrogenic transmission risk requires specific neurosurgical and ophthalmologic precautions; standard autoclaving is insufficient to inactivate prions.^[5,7]

Monitoring and end-of-life burden

• Repeated MRI, lumbar puncture, and EEG impose burden on a patient whose course is short; sequencing tests to answer a specific diagnostic question rather than running them serially reduces waste.^[15]
• Genetic testing requires pre- and post-test counseling because results affect asymptomatic relatives.^[4]
• Caregiver distress is severe given the speed of decline; bereavement risk is elevated and warrants proactive support.^[15]

Limitations of the evidence base

• Disease rarity precludes adequately powered RCTs; most trials are small, short, and underpowered to detect modest disease-modifying effects.^[15-16]
• Diagnostic test characteristics (RT-QuIC, MRI, EEG) were validated largely in sCJD cohorts and perform less well for variant CJD, genetic forms, and atypical sporadic subtypes.^[10-11]
• Surveillance data depend on autopsy confirmation, which is incomplete; true incidence is likely modestly underestimated.^[2]
• Most psychiatric symptom management is extrapolated from major neurocognitive disorder of other etiologies; prion-specific trials are absent.^[18]

The age and exposure profile of prion disease shapes who shows up in clinic, and a few populations deserve specific consideration.

Pediatric and adolescent presentations

• Sporadic CJD is exceedingly rare under age 30; a young patient with rapidly progressive dementia should prompt evaluation for variant CJD, genetic prion disease, autoimmune encephalitis, and inborn errors of metabolism.^[2-3,14]
• Variant CJD has affected adolescents and young adults, with a median age at onset in the late 20s and a prominent psychiatric prodrome.^[3,11]
• Kuru, now historical, primarily affected children and women in the Fore population of Papua New Guinea through ritual endocannibalism; the last cases reflected incubation periods exceeding 50 years.^[2]

Geriatric considerations

• Sporadic CJD peaks at ages 60-70; in this group the differential against Alzheimer disease, vascular dementia, and Lewy body disease is the practical challenge.^[2]
• Older patients tolerate symptomatic medications poorly, with heightened sensitivity to benzodiazepines, antipsychotics, and anticholinergics.^[18]
• Establishing goals of care early — given a median survival of months — is more humane than aggressive symptomatic escalation late.^[15]

Perinatal and reproductive issues

• Vertical transmission of prion disease has not been documented; pregnancy and breastfeeding are not contraindicated in carriers of pathogenic PRNP variants.^[4]
• Reproductive decisions in families with genetic prion disease (E200K, D178N, octapeptide repeat insertions) benefit from genetic counseling and reproductive options including preimplantation genetic testing.^[4]

Comorbid medical illness

• Concurrent delirium from infection, metabolic derangement, or medication effects can mimic acute prion progression; a stepwise medical workup is required before attributing acute decline to the underlying disease.^[14]
• Patients with comorbid neurodegenerative disease (e.g., Parkinson disease) may have copathology that complicates the clinical picture; definitive diagnosis often awaits autopsy.^[2]

Cultural and occupational considerations

• Occupational exposure (neurosurgery, pathology, abattoir work, hunters of cervids in chronic wasting disease endemic areas) merits specific occupational history; iatrogenic CJD from contaminated instruments, dura mater grafts, and cadaveric growth hormone is historically important and informs sterilization practice.^[5,7]
• Family disclosure of genetic prion disease has cultural dimensions; the approach to predictive testing should follow Huntington-style protocols with multidisciplinary support.^[4]

Prion disease is uniformly fatal, and the prognostic conversation should be honest from the first visit at which the diagnosis is probable.

Natural history by variant

• Sporadic CJD has a median survival of approximately 5 months from symptom onset, with roughly 90% of patients dying within one year.^[2,19]
• Variant CJD has a longer median survival, on the order of 14 months, reflecting both younger age and a different clinical tempo.^[3,11]
• Fatal familial insomnia progresses over a median of approximately 12-18 months, with later-stage autonomic and motor features.^[4]
• Gerstmann-Sträussler-Scheinker disease has the longest course, often 5-10 years, dominated by progressive cerebellar ataxia.^[4]

Functional trajectory

• Akinetic mutism — wakeful but unresponsive — is the terminal state in most cases, typically reached within months of onset.^[2,9]
• Loss of independent ambulation, swallowing, and continence occur in rapid succession; goals-of-care discussions belong early in the course, not at the end.^[15]
• Caregiver burden tracks the speed of decline; bereavement support should be offered proactively.^[15]

Mortality drivers

• Aspiration pneumonia is the most common immediate cause of death.^[15,19]
• Other contributors include sepsis from pressure injuries and inanition; cardiac events are unusual unless co-existing.^[19]
• Autopsy with histopathology and Western blot remains the diagnostic gold standard and is encouraged for surveillance and family counseling, particularly in genetic and iatrogenic forms.^[2,9]

Acute presentations of prion disease intersect psychiatric emergency care in three predictable ways: agitation from rapidly progressive cognitive decline, suicidality during the period of preserved insight, and the diagnostic question of rapidly progressive dementia in a patient brought to the emergency department.

Hospitalization criteria

• New-onset rapidly progressive cognitive decline with neurologic signs (myoclonus, ataxia, visual disturbance) warrants admission for expedited workup, even when the differential includes treatable mimics.^[14]
• Safety concerns — agitation, falls, swallowing failure, suicidal ideation — meet inpatient psychiatry or medicine criteria depending on the dominant problem.^[13,18]

Suicide risk

• Preserved insight in early disease, particularly in genetic prion disease where the diagnosis may be made before severe cognitive impairment, creates a window of elevated suicide risk.^[4,13]
• Standard assessment for ideation, plan, intent, access to means, and protective factors applies; the catastrophic prognosis is a recognized risk factor and warrants explicit attention.^[13]

Agitation management

• Identify and treat reversible contributors — pain, constipation, urinary retention, infection, medication effect — before escalating psychotropics.^[18]
• Non-pharmacologic measures (familiar caregiver presence, structured environment, sleep-wake regulation) come first.^[18]
• When pharmacotherapy is needed, low-dose quetiapine 12.5-25 mg PO BID-TID PRN or lorazepam 0.5-1 mg PO/IM q4-6h PRN are pragmatic choices, recognizing the boxed warning for antipsychotics in major neurocognitive disorder.^[18]

Infection control

• Standard precautions are sufficient for routine care; prion-specific precautions apply only to high-infectivity tissues (brain, spinal cord, eye) during neurosurgery, ophthalmologic surgery, and autopsy.^[5,7]
• Notify infection prevention and surgical pathology when prion disease is suspected before any biopsy or procedure involving central nervous system tissue.^[5,7]
• Single-use instruments are preferred for any neurosurgical procedure on a patient with suspected or confirmed prion disease.^[5,7]

Prion disease sits at the intersection of unsettled mechanism, unstable epidemiology, and unproven therapeutics. The controversies below are worth knowing for boards and bedside.

• The contribution of PrP^Sc seeding versus loss of normal PrP^C function to neurodegeneration remains debated, and the relative weights have implications for whether knockdown strategies will be neuroprotective or harmful.^[6]
• Whether asymptomatic carriers identified by appendix-tissue surveillance after the BSE epizootic represent a future wave of clinical variant CJD or a self-limited cohort is unresolved; UK appendix-tissue prevalence studies suggest subclinical infection may be more common than overt disease.^[7]
• The boundary between rapidly progressive Alzheimer disease, autoimmune encephalitis, and atypical sCJD remains clinically blurred, and early MRI plus RT-QuIC have shifted but not eliminated the rate of misdiagnosis.^[10,14]
• Optimism around antisense oligonucleotide and small-molecule PrP-lowering agents in early-phase development must be tempered by the failure of every prior disease-modifying candidate (quinacrine, doxycycline, pentosan polysulfate, flupirtine, PRN100) in adequately powered or carefully conducted studies.^[15-17]
• Chronic wasting disease in North American cervids has expanded geographically, and whether it will cross the species barrier to humans is an open public health question; surveillance is ongoing but no confirmed human case has been reported to date.^[20]
• Genetic testing for PRNP raises ethical complexities — penetrance varies by mutation, predictive testing in asymptomatic at-risk relatives requires structured counseling, and insurance and disclosure considerations differ by jurisdiction.^[4]

• Sporadic CJD accounts for approximately 85% of human prion disease and typically presents in the sixth or seventh decade with rapidly progressive dementia.^[2]
• The classic sCJD clinical triad is rapidly progressive dementia, myoclonus, and a characteristic EEG with periodic sharp-wave complexes, though myoclonus and the EEG findings often appear later in the course.^[2,9]
• RT-QuIC on CSF has sensitivity above 90% and specificity approaching 100% for sporadic CJD and is the single highest-yield antemortem test.^[10]
• Diffusion-weighted MRI showing cortical ribboning and/or basal ganglia hyperintensity is more sensitive than EEG in early sCJD and should be obtained with DWI sequences specifically.^[10]
• CSF 14-3-3 and total tau are supportive but not specific; they can be elevated in stroke, herpes encephalitis, and other rapid neurologic decline, so a positive result does not establish the diagnosis on its own.^[9-10]
• Variant CJD differs from sCJD by younger age of onset (median in the late 20s), psychiatric and sensory prodrome, the pulvinar sign on MRI, and a longer clinical course.^[3,11]
• Fatal familial insomnia is caused by the D178N PRNP mutation in cis with methionine at codon 129 and presents with progressive insomnia, autonomic dysfunction, and dementia.^[4]
• Gerstmann-Sträussler-Scheinker disease classically presents with prominent cerebellar ataxia and a slower course than sCJD, often caused by the P102L PRNP mutation.^[4]
• Codon 129 methionine homozygosity is a risk factor for sporadic CJD and was present in all early clinically diagnosed variant CJD cases.^[3-4]
• Kuru, transmitted historically through ritual endocannibalism among the Fore people of Papua New Guinea, is the prototype acquired prion disease and presented with progressive cerebellar ataxia.^[2]
• Standard hospital sterilization does not reliably inactivate prions; suspected cases require dedicated single-use or specialized reprocessing protocols for invasive instruments.^[5,7]
• No disease-modifying therapy has demonstrated efficacy in randomized trials for any human prion disease, and management is supportive and palliative.^[15-17]
• Median survival in sporadic CJD is approximately 5 months; over 90% of patients die within one year of symptom onset.^[2,19]
• Suspected or confirmed prion disease is a reportable condition in most jurisdictions; cases should be notified to public health authorities and registered with national CJD surveillance units.^[7]

No external funding. No conflicts of interest declared. Peer-review status: pending.