Creutzfeldt-Jakob disease

Background

• General term for human prion disease, including sporadic, genetic, and infectiously-acquired forms

Pathophysiology

• A prion protein gene PRNP encodes a protein, PrP^C, that is expressed in the brain and reticuloendethelial system
• Mutations of PRNP can create versions of PrP that folds abnormally, called PrP^Sc
• Misfolded PrP^Sc catalyzes other PrP^C molecules to misfold, thereby converting them into more PrP^Sc

Clinical Manifestations

• Clinical manifestations are heterogeneous, though are always characterized by rapid neuropsychiatric decline followed by death within one year of symptom onset
• Neuropsychiatric symptoms: can include dementia, abnormal or unusual behaviour, aphasia, apraxia, frontal lobe dysfunction
  • Early symptoms include impaired concentration and memory, poor judgment
  • Also mood disorders, emotional lability, anxiety, insomnia, hypersomnia, and psychosis (particularly visual hallucinations)
    • Any of the above could be the presenting symptom
  • Over time, the dementia becomes the overwhelming symptom
• Neurological signs or symptoms
  • Myclonus: including provoked by startle; may be absent at presentation but eventually develops in 90% of sCJD
  • Cerebellar dysfunction: nystagmus and ataxia, develops in 65% on sCJD, and may be the presenting symptom
  • Corticospinal tract involvement: hyperreflexia, upgoing plantar reflex, spasticity develop in about 60%
  • Extrapyramidal signs: hypokinesia/bradykinesia, rigidity
  • Eventually progresses to akinetic mutism
• Signs that suggest an alternative diagnosis include focal neurological defects, particularly cranial nerve findings or focal peripheral neurological dysfunction; vCJD can have sensory signs or symptoms, though it is uncommon in sCJD

Feature	sCJD	vCJD	f/gCJD	GSS	FFI
Mean age at onset	60-70 years	28 years	60 years	60 years	50 years
Duration of illness	5 months	14 months	6 months	5 years	14 months
Clinical features	rapid cognitive decline with myoclonus	early psychiatric symptoms, the cognitive decline	rapid cognitive decline with myoclonus	cerebellar signs	insomnia
MRI findings	hyperintensity in basal ganglia or cortex	pulvinar sign in 90%	hyperintensity in basal ganglia or cortex	usually normal	nonspecific atrophy
EEG findings	PSWCs in 60-70%	no PSWCs	PSWCs in 75%	rarely positive	rarely positive
14-3-3	positive in 90%	positive in 50%	positive in 90%	negative	rarely positive

Sporadic CJD (sCJD)

• Age 45-75
• Myoclonus, cerebellar signs and symptoms, and visual disturbance (includes cortical blindness)
• May have prodromal symptoms including fatigue, insomnia, depression, weight loss, headaches, general malaise and ill-defined pain sensation
• Pyramidal and extrapyramidal signs may also develop, with upper motor neuron signs on exam
• Akinetic mutism commonly develops 2–3 months after the onset of symptoms
• Rapid or subacute decline, with a median survival 7-9 months from symptom onset
• Can usually detect 14-3-3 protein in CSF
• Can have a variety of subtypes, including visual, cerebellar, thalamic, or striatal-predominant symptoms
• Subtypes are determined by presence of methionine (M) or valine (V) at codon 129, and may be homozygous or heterozygous for the mutation

Feature	Subtype
	MM1/MV1	VV2	MV2	MM2	VV1
Proportion of sCJD	60-70%	15%	10%	5%	1%
Mean age at onset	70 years	65 years	60 years	67 years	44 years
Duration of illness	4 months	6 months	18 months	14 months	21 months
Clinical features	rapid cognitive decline with myoclonus	progressive ataxia without myoclonus	prominent ataxia and cognitive decline	rapid cognitive decline with myoclonus	psychiatric changes, slowly-progressing dementia
MRI findings	hyperintensity in basal ganglia or cortex	hyperintensity in basal ganglia or thalamus	hyperintensity in basal ganglia with pulvinar sign	cortical changes, rare basal ganglia involvement	cortical hyperintensity, rare basal ganglia involvement
EEG findings	PSWCs in 80%	PSWCs in 10%	PSWCs in 10%	PSWCs in 40%	no PWSCs

Genetic CJD (gCJD)

• Autosomal dominant mutations in PRNP with high penetrance, of which E200K is the most common worldwide
• Median age of onset is 58 years
• There are some specific forms

Gerstmann-Straüssler-Scheinker Syndrome (GSS)

• Prominent early ataxia and corticospinal tract degeneration
• Dementia is a late feature
• Lasts for 3 months to 13 years

Fatal Familial Insomnia (FFI)

• First described in Italian families
• Starts with insomnia, autonomic hyperactivity (increased sweating, tearing, salivation, mild nocturnal hyperthermia, tachycardia, and hypertension)
• Later, motor disturbances including ataxia, myoclonus, spasticity, hyperreflexia, and dysarthria
• Dementia would be a late finding
• Median age of onset is 50 to 56 years, but can occur from 19 to 83 years

Variant CJD (vCJD)

• Younger age (mean 26 years and range 12 to 74 years)
• May be from bovine spongiform encephalopathy in people homozygous 129M polymorphism of PrP
  • Large outbreak in UK starting in 1995 related to an outbreak of BSE in 1985
• Can be transmitted via blood transfusion
• Prominent neuropsychiatric features: depression, anxiety, emotional lability, irritability, aggressive behavior, social withdrawal, delusions and hallucination
• Later, cerebellar syndrome with limb and gait ataxia, chorea, myoclonus, and dementia
• Median survival 14 months
• Can be diagnosed with PrP^Sc on tonsil biopsy

Iatrogenic CJD (iCJD)

• Transmitted by corneal and dura mater grafts, liver transplantation, growth hormone, neurosurgical procedures, and stereotactic EEG
• Incubation period ranges from 16 months to 25 years
• Presentation usually sCJD, but have also been cases of GSS and, rarely, vCJD

Differential Diagnosis

• Other causes of neuropsychiatric disease
• Degenerative
  • Dementia with Lewy bodies (most common misdiagnosis)
  • Alzheimer dementia
  • Frontotemporal dementia
  • Parkinson disease
  • Huntington disease
• Vascular
  • Vascular dementia
• Neoplastic
  • Cerebral lymphoma
  • Paraneoplastic syndrome
• Psychiatric disorders
• Inflammatory
  • Hashimoto encephalitis
  • CNS vasculitis
• Infectious
  • Neurosyphilis
  • Tuberculosis
  • Progressive multifocal leukoencephalopathy, if immunocompromised
  • HIV
  • Possibly also: Lyme disease, Trypanosoma brucei, Toxoplasma gondii, neurocysticercosis, Whipple disease

Diagnosis

• Before sending samples, contact the Canadian CJD Surveillance Coordination Office (phone: 1-888-489-2999)
• Review IPAC guidelines under Prevention, below

CSF

• CJD test panel in Canada includes 14-3-3 protein, Tau protein, and quaking-induced conversion (QuIC)
• QuiC directly detects misfolding of normal PrP protein
  • Current best test, with highest sensitivity and specificity

Marker	Sn	Sp	LR+	LR–
14-3-3	88% (82-93)	72% (69-75)	3.1 (2.8-3.6)	0.16 (0.1-0.26)
Tau >976*	91% (84-95)	88% (85-90)	7.4 (6.9-7.8)	0.1 (0.06-0.2)
Tau >1300**	84% (76-90)	92% (90-94)	10.9 (8.5-13.9)	0.17 (0.11-0.26)
S100B >2.5*	87% (80-92)	87% (84-91)	6.6 (6.1-7.1)	0.15 (0.09-0.2)
S100B >4.2**	52% (42-61)	97% (95-98)	15.3 (10.2-23.1)	0.5 (0.42-0.6)
Tau + S100B*			18 (12.9-25)	0.02 (0.01-0.09)
Tau + S100B + 14-3-3**			18.6 (13.1-26.3)	0.03 (0.01-0.1)

• * Optimal cutoffs based on a Canadian study
• ** Standard threshold
• CSF itself usually bland, non-inflammatory

PHAC/NML Interpretation

• From the Prion Diseases Section of the National Medical Laboratory

Marker	Sensitivity	Specificity	PPV	NPV
14-3-3 >20,000	84%	90%	68%	96%
Tau >976 pg/mL	92%	88%	66%	98%
EP-QuIC >4-fold increase	97.5%	99.4%	97.5%	99.4%

Imaging

• MRI is the most useful neuroimaging modality, especially with DWI
  • Increased T2 FLAIR signals in striatum
  • One sign is the "pulvinar sign", mostly for vCJD, which refers to bilateral FLAIR hyperintensities involving the pulvinar thalamic nuclei
• CT only useful for exclusion of other causes

EEG

• EEG can have characteristic abnormalities and should be routinely done
• Bilaterally periodic synchronic periodic sharp wave complexes (PSWCs)
  • Can be transient, and can also be absent at the start and towards the end
  • Most common in sCJD, but absent in vCJD

Histopathology

• Histopathology of brain tissue biopsy or autopsy is still the gold standard
• Biopsy should show neuronal loss, vacuolation of the neuropil, spongiform changes

Case Definitions

Sporadic CJD

Confirmed

• Neuropathologically confirmed, with confirmation of protease-resistant prion protein (immunohistochemistry, PET blot, or Western Blot)

Probable Case

• Rapidly progressive dementia, and
• At least two additional neurological manifestations, and
  • Myoclonus
  • Visual or cerebellar disturbances such as ataxia
  • Pyramidal or extrapyramidal symptoms
  • Akinetic mutism
• One of three clinical tests:
  • Typical electroencephalography (EEG): generalized bilateral or unilateral triphasic periodic complexes at approximately one per second, lasting continuously for at least 10 seconds
  • MRI with caudate nucleus and/or (anterior) putamen attenuation (preferred sequence DWI or FLAIR)
  • Positive assay for 14-3-3 protein in cerebrospinal fluid (CSF) and total disease duration less than 24 months

Suspect Case

• Rapidly progressive dementia, and
• At least two additional neurological manifestations, and
  • Myoclonus
  • Visual or cerebellar disturbances such as ataxia
  • Pyramidal or extrapyramidal symptoms
  • Akinetic mutism
• Duration of illness less than 2 years in the absence of a conclusive MRI and 14-3-3 protein assay

Variant CJD

Confirmed Case

• Progressive neuropsychiatric disorder, and
• Neuropathological confirmation of vCJD: spongiform change and extensive PrP deposition with florid plaques, throughout the cerebrum and cerebellum

Probable Case

• Either:
  • Progressive neuropsychiatric disorder of duration >6 months, where routine investigations do not suggest an alternative diagnosis and there is no evidence of iatrogenic exposure or a genetic form of CJD, with
    • Four out of five clinical criteria (below), and
      • Early psychiatric symptoms (e.g., depression, anxiety, apathy, withdrawal, delusions)
      • Persistent painful sensory symptoms, which includes frank pain and/or dysaesthesia
      • Ataxia
      • Myoclonus or chorea or dystonia
      • Dementia
    • Electroencephalography (EEG) does not show typical appearance of sporadic CJD: generalized triphasic periodic complexes at approximately one per second;or no EEG performed, and
    • MRI brain scan shows bilateral symmetrical pulvinar high signal, relative to the signal intensity of other deep gray-matter nuclei and cortical gray matter
  • Progressive neuropsychiatric disorder of duration >6 months, where routine investigations do not suggest an alternative diagnosis and there is no evidence of iatrogenic exposure or evidence of a genetic form of CJD, with
    • Tonsil biopsy positive for prion protein immunoreactivity

Suspect Case

• Progressive neuropsychiatric disorder of duration >6 months, in the absence of a conclusive MRI or tonsil biopsy, where routine investigations do not suggest an alternative diagnosis and there is no evidence of iatrogenic exposure or evidence of a genetic form of CJD, and
• Four out of five clinical criteria (below), and
  • Early psychiatric symptoms (e.g., depression, anxiety, apathy, withdrawal, delusions)
  • Persistent painful sensory symptoms, which includes frank pain and/or dysaesthesia
  • Ataxia
  • Myoclonus or chorea or dystonia
  • Dementia
• Electroencephalography (EEG) does not show typical appearance of sporadic CJD: generalized triphasic periodic complexes at approximately one per second; or no EEG performed

Management

• Supportive care
• No proven pharmaceutical treatments

Experimental Treatments

• Based on case reports, pentosan polysulfate may slow progression, though the observed slower progression may have been chance alone
  • In mouse models, it was only helpful if given intraventricularly before (not after) the development of symptoms
• Other failed drugs include quinacrine (failed in RCT), chlorpromazine, and flupirtine

Prevention

Infection Prevention and Control

• Standard precautions when caring for patients; no need for additional PPE
• No special precautions required for burial
• Use disposable instruments whenever possible, especially when it will contact high-infectivity tissue

Risk Assessment

• High-risk patients: confirmed, probable, or possible CJD, familial CJD, GSS, or FFI, undiagnosed rapidly-progressive dementia, or asymptomatic carrier of a genetic transmissible spongiform encephalopathy
• At-risk patients: recipients of human-derived pituitary hormones, dura mater grafts (until 1992 for Lyodura or 1997 for Tutoplast Dura grafts), or corneal graft from jurisdiction that does not screen for neurological diseases; or patients who have been exposed to high-infectivity tissue/instruments of a confirmed case of CJD
• Tissue risk of transmission
  • High (>50%): brain, CSF, dura mater, pituitary gland, posterior eye (optic nerve and retina), spinal cord, spinal ganglia, trigeminal ganglia
  • Low (10-20%, though no reported human cases): cornea, kidney, liver, lung, lymph nodes, placenta, spleen
  • None (0%): adipose tissue, adrenal gland, appendix, blood, cord blood, blood vessels, bone marrow, breast milk, dental pulp, epididymis, esophagus, feces, gingival tissue, heart, ileum, jejunum, large intestine, nasal mucosa, nasal mucous, ovaries, pancreas, pericardium, peripheral nerves, placental fluid, prostate, saliva, semen, seminal vesicle, skeletal muscle, skin, sweat, tears, testis, thymus, thyroid gland, tongue, tonsil, trachea, urine, uterus

CJD Reprocessing

• Instruments should be kept moist until they are processed
• Stainless steel instruments can tolerate this procedure, while plastics, electronics, and steel alloys cannot
  • Items, including endoscopes, that cannot undergo this procedure should be discarded
• The recommended process is:
  1. Clean thoroughly
  2. Soak in 1N sodium hydroxide for 1 hour
  3. Rinse thoroughly
  4. Sterilize in a prevacuum autoclave at 134ºC for 60 minutes
• Alternatively, can use 2% NaOCl rather than the NaOH, and autoclave for 18 minutes rather than 60 minutes

High-Risk Patients Managed Prospectively

	High-infectivity tissue	Low-infectivity tissue	No infectivity tissue
Confirmed CJD	Discard	CJD decontamination if possible, or discard	Routine reprocessing
Suspected CJD	Quarantine and discard if CJD confirmed	CJD decontamination if possible, or quarantine and discard if CJD confirmed	Routine reprocessing
Asymptomatic carrier	Discard	Routine reprocessing	Routine reprocessing

High-Risk Patients Managed Retrospectively

	High-infectivity tissue	Low-infectivity tissue	No infectivity tissue
High-risk patient	Follow above algorithm, if instruments are identifiable or have been reprocessed 9 or fewer times; otherwise, there is the option of continuing to reuse without specific reprocessing		Continue to reuse

At-Risk Patients

• Following routine reprocessing

Lumbar Puncture

• CSF specimen handling MUST be performed with increased safety precautions, wearing single use gloves, mask and gown within a BSC
• CSF to be collected in leak-proof, puncture resistant primary container, placed in a biohazard bag
• Package using the triple packaging system for transport to the appropriate laboratory section
• Label as “CJD” for laboratory processing, decontamination and disposal

Further Reading

• Classic Creutzfeldt-Jakob Disease in Canada: Quick Reference Guide 2007. Public Health Agency of Canada. 2007.
• Creutzfeldt-Jakob disease: updated diagnostic criteria, treatment algorithm, and the utility of brain biopsy. J Neurosurg. 2015;39(5). doi: 10.3171/2015.8.FOCUS15328
• UK Guidance to minimise transmission risk of CJD and vCJD in healthcare settings.