Creutzfeldt-Jakob disease

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Background

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

Pathophysiology

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

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 PrPSc 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

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

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
  • 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
  • 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
      • 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
  • 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

  • Patient risk of transmission
    • 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, dura mater, pituitary gland, posterior eye (optic nerve and retina), spinal cord, spinal ganglia, trigeminal ganglia
    • Low (10-20%, though no reported human cases): CSF, 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

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