Creutzfeldt-Jakob Disease (CJD)

Queensland Health Guidelines for Public Health Units

Revision History

 Version  Date  Changes
 1.0 December 2008  Full revision of guideline. 

Description

Transmissible Spongiform Encephalopathies (TSEs) are rare, fatal neurodegenerative disorders that occur in a wide variety of animals including humans.  These include kuru and Creutzfeldt-Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals.

TSEs are incompletely understood; they may be both inheritable and transmissible.  The term "prion" was coined to denote the proteinaceous infectious units that appear to cause transmissible spongiform encephalopathies.  Prions are unusually resistant to physical or chemical treatments that inactivate other known infectious agents.

Creutzfeldt-Jakob disease (CJD)

Classical CJD (sometimes denoted cCJD) is a rapidly progressive and fatal neurodegenerative human prion disease.  There are three forms of classical CJD:

  1. Sporadic CJD is the most common form of CJD, with an incidence of about 1 per million per year.  It usually occurs in people over the age of 40 years.
  2. Iatrogenic CJD occurs when CJD is accidentally transmitted during the course of medical or surgical procedures.  Cases of CJD have been associated with human growth hormone extracted from cadaveric human pituitary tissue (last used in Australia in the early 1980s); corneal transplant; use of contaminated EEG depth electrodes; neurosurgical instruments and dura mater grafts.
  3. Familial (genetic) CJD accounts for 5 to 15% of classical CJD patients.  As there is an autosomal dominant inheritance pattern, there is usually a family history of CJD.  In genetic CJD, genetic analysis can identify specific mutations of the prion protein gene.

Variant CJD (vCJD) was identified in the UK in 1996 with the reporting of 10 cases of CJD in unusually young patients with neuropathological changes and clinical course atypical of sporadic CJD.  These cases occurred a decade after the first reports of a new neurodegenerative disease of cattle (BSE) in the UK in 1986.  Initially, UK public health officials were of the view that BSE did not pose a risk to human health.

There is now convincing evidence that vCJD is due to infection of humans with the BSE agent, most probably via contaminated food.  vCJD tends to occur in younger individuals who present with behavioural or psychiatric symptoms and have a relatively slower progression, although it is also invariably fatal.  Of the 209 cases of vCJD diagnosed throughout the world between 1996 and September 2008, 167 occurred in the UK and 23 in France.  As of September 2008, only 5 of these were still alive.

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Infectious Agent

Prions, see above and below.

Notification Criteria

CDNA case definitions are still under development at November 2008.  All potential CJD cases are followed up by the Australian National CJD Registry (ANCJDR) and classified using internationally recognised case definitions.  While awaiting definitive classification ANCJDR classifies all cases as 'suspect'.  ANCJDR classifies CJD cases as 'definite' (equivalent to 'confirmed') if they have been neuropathologically confirmed either by brain biopsy or post-mortem examination.  Classical CJD cases are classified as 'probable' on the basis of clinical profile and a characteristic electroencephalogram (EEG) or a positive 14-3-3 cerebrospinal fluid (CSF) test. In addition to progressive dementia of less than two years duration, probable cCJD cases must display at least two of the following: myoclonus; visual or cerebellar signs; pyramidal or extrapyramidal features; or akinetic mutism. Cases are classified as 'possible' cCJD if they fulfil the same clinical profile in the absence of a typical EEG and either no 14-3-3 CSF test or a negative result.  International systems for classification of 'probable' and 'possible' vCJD cases rely on typical clinical profile (see clinical features below), and for 'probable' cases the presence of bilateral pulvinar high signals on magnetic resonance imaging (MRI) scans.

Notification Procedure

Pathology Laboratories:
To notify on diagnosis, ideally by telephone on same day of diagnosis for variant CJD, and by usual means for classical CJD.

Attending Medical Practitioners/Medical Superintendents (or Delegates):
To notify on provisional clinical diagnosis, by telephone or facsimile.

Australian National CJD Registry
To notify on clinical or pathology diagnosis, any subsequent change in classification status, or identification of issues of public health concern, by facsimile direct to NOCS.

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Reporting to NOCS

Report all suspect cases of CJD.

All suspect cases reported to NOCS will alert to relevant PHU.  Once PHU confirms that ANCJDR is aware of the case, PHU should request that NOCS force closed as 'unsure'.

Objectives of Surveillance

  1. To identify issues of public health concern so that appropriate public health action can be taken.
  2. To ensure that information on CJD incidence collected and then reported at state and national level is as accurate as possible.

Public Health Significance and Occurrence

Public health surveillance for CJD in Australia has been motivated by the need to detect cases that may reflect transmission either by iatrogenic means or by consumption of contaminated food products.

Iatrogenic CJD

Between 1976 and 1985, cadaver derived pituitary hormones were supplied to 2,163 Australians as treatment for infertility and short stature or metabolic growth problems, under The Australian Human Pituitary Hormones Program (AHPHP).  The AHPHP ceased in May 1985 after overseas reports of deaths from CJD in people who received treatment with human growth hormone.  Between 1988 and 1995, seven recipients of human growth hormone in Australia have been investigated as possible cases of CJD: three were confirmed as having died of CJD, one was classified as probable and one as a possible case.  To date, there have been no further cases among human growth hormone recipients in Australia.

There have also been five dura mater graft-related cases in Australia (2 definite, 3 probable), the most recent being in 2000.

Iatrogenic transmission of the CJD agent has been reported in over 250 patients worldwide.  The majority have been linked to the use of contaminated human growth hormone or to dura mater grafts.  Six cases have been linked to the use of contaminated equipment: four were associated with neurosurgical instruments and two with stereotactic EEG depth electrodes.

Australian National CJD Registry

The National CJD Case Registry, now known as the Australian National CJD Registry (ANCJDR) was established in 1993 in response to the risk of accidental transmission of CJD from treatment under the AHPHP.  It is located within the University of Melbourne.  ANCJDR is funded by the Australian Government to:

  • monitor new cases of CJD and other TSEs in Australia
  • retrospectively investigate TSE cases from 1970
  • examine risk factors
  • provide advice to health authorities and clinicians on request
  • undertake research into TSEs

Between 1 January 1970 and 31 March 2008, ANCJDR has reported 364 definite (equivalent to confirmed) and 209 probable cases of CJD in Australia; 90.6% sporadic CJD, 8% familial and 1.4% iatrogenic.

Variant CJD

Investigations since the first cases of vCJD were characterised in 1996 provides strong evidence for the link between BSE, the food-chain and vCJD.  Evidence also suggests that the risk of vCJD is low, even after consumption of contaminated product.  This new form of CJD heightened interest in surveillance for human TSEs globally.

Cases of vCJD worldwide as of September 2008 are listed below:

Country

 Total number (number alive)

 Secondary cases: blood transfusion (number alive)

 Resided in UK > 6 months 1980 - 1996
UK

 164 (3)

 3 (0)

 167
France

 23 (0)

 -

 1
Republic of Ireland

 4 (0)

 -

 2
Italy

 1 (0)

 -

 0
USA

 3 (0)

 -

 2
Canada

 1 (0)

 -

 1
Saudi Arabia

 1 (1)

 -

 0
Japan

 1 (0)

 -

 0
Netherlands

 2 (0)

 -

0
Portugal

2 (1)

-

0
Spain

4 (0)

-

 0

All UK cases resided in the UK for greater than 6 months during the period 1980 to 1996.

While there have been no cases of variant CJD in Australia to date, a case may present in Australia in an individual who either lived in or visited the UK or another BSE endemic country in the relevant years (1980 to 1996).

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Clinical Features

Affected patients usually present with behavioural changes, a rapidly progressive dementia, visual abnormalities, and muscle incoordination, which can evolve into ataxia. Speech abnormalities may develop during the course of the disease, with most patients developing abnormal reflexes, spasticity, tremors and rigidity. Some patients experience marked agitation and hallucinations may occur.  Akinetic mutism is common during the terminal phase.

The key differences between classical and variant CJD are summarised below.

Characteristic Classical CJD Variant CJD
Median age at death 68 years 28 years
Median duration of illness 4 - 5 months 13 - 14 months
Clinical signs and symptoms Dementia, early neurologic signs Prominent psychiatric/ behavioural symptoms, painful dysaesthesiae, delayed neurologic signs
EEG changes (periodic sharp waves) Often present Not seen
MRI changes ("pulvinar sign" in posterior thalami) Not reported Present in > 75% cases
Brain biopsy: neuropathological investigation) Plaque deposits uncommon Florid plaques present in large numbers
Brain biopsy: immunohistochemical analysis Variable accumulation of protease-resistant prion Marked accumulation of protease-resistant prion
Tonsillar biopsy Protease-resistant prion not readily detected Protease-resistant prion readily detected

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Mode of Transmission

Most cases of CJD are sporadic.  Sporadic CJD is believed to occur through the spontaneous transformation of normal prion proteins into abnormal prions.

Iatrogenic transmission, although rare, has occurred as described above. 

Familial CJD occurs in patients who inherit mutations of the prion protein gene.

There is no epidemiological evidence to indicate that classical CJD can be transmitted sexually, perinatally, or via blood or blood products.

It is believed that variant CJD emerged after being acquired through dietary exposure to BSE contaminated beef products. Blood transfusions of contaminated blood products have also been recognised as a secondary transmission route for vCJD.

Incubation Period

Variable, typically many years.  Short incubation periods can occur after direct iatrogenic intracerebral inoculation.

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Infectivity and Communicability

In most cases of classical CJD, a thorough analysis of the medical and occupational histories fails to identify clear evidence of an external source or point of infection and the cases are considered to be sporadic CJD, in the absence of a family history.

In a very small number of cases there is clear evidence of iatrogenic transmission as described above. 

Studies of experimentally transmitted classical CJD in non-human primates and other animals have enabled the development of a guide to the infectivity of body tissues and fluids of symptomatic AND asymptomatic patients.  The period of infectivity prior to onset of symptoms is unknown.

High infectivity tissues: brain, dura mater, pituitary, spinal cord, posterior eye (including retina and optic nerve), cranial and dorsal root ganglia, olfactory epithelium

Low or no detectable infectivity tissues: cornea, anterior chamber of eye, CSF, blood and blood products, other body fluids and secretions, kidney, liver, lung, lymph nodes, spleen, placenta, uterus, peripheral nerve and most other organs/tissues.

Susceptibility and Resistance

Susceptibility is assumed to be universal.

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Management

Role of ANCJDR
ANCJDR routinely follows up all cases of CJD in Australia, gathering detailed information and investigating potential causes. Queensland Health and ANCJDR have signed an agreement that ANCJDR will undertake the exposure investigation and final classification of all CJD cases resident in Queensland, and will advise of any public health concerns identified. ANCJDR receives notifications from clinicians and family members, actively corresponds with neurologists and pathologists to enhance case ascertainment and conducts searches of death registries and hospital medical records to assess all notifications have been identified ante-mortem.  ANCJDR seeks detailed clinical information from the referring source and interviews families to identify possible risk factors.  ANCJDR provides specialist support and advice in establishing the diagnosis of CJD, and as it provides sophisticated diagnostic techniques (e.g. it is currently the only provider of 14-3-3 protein CSF testing) there is usually a high degree of cooperation from reporting physicians and the families of people diagnosed with CJD.

Cases

Investigation:
Follow up of cases will normally be carried out in collaboration with the patient's health care providers and ANCJDR.

  • For all cases notified by sources other than ANCJDR check whether the treating clinician or diagnosing neuropathologist has informed ANCJDR.
  • If ANCJDR has not been informed, request the treating clinician or diagnosing neuropathologist do so.  Advise treating clinicians they should seek verbal family consent.
  • If there is reluctance to contact ANCJDR the PHU should liaise with CDB.  CDB protocol is to fax all clinical notifications received to ANCJDR.
  • If the case is identified as suspect variant CJD, inform CDB immediately.
  • Contact the ANCJDR coordinator on 03 8344 1949 to confirm that ANCJDR has been informed.
  • Ascertain if any public health concerns have been identified.
    o If ANCJDR notified the case this information should be available on NOCS.
    o Once ANCJDR is aware of a case notified from another source they will undertake the exposure investigation and notify any concerns.
  • Situations of public health concern include:
    o Any possibility that a case may have been iatrogenically acquired.
    o Any possibility that other people may have been exposed to risk of iatrogenic transmission from a CJD case while infectious.
    o Any case of variant CJD.
  • If situations of public health concern are identified, inform CDB immediately.

Restriction: 
Nil

Infection Control: 
Queensland Health guidelines for management of classical CJD are available.  More extensive guidance is available in the national infection control guidelines (Chapter 31 and Appendix 9).

Contacts

Definition:
Defining and identifying "contacts" is not straightforward. 

Classical CJD:
Potential contacts include:

  • Recipients of corneal transplants, dura-mater grafts or pituitary hormones from an infectious case.
  • Those exposed to instruments/equipment potentially contaminated during procedures conducted on an infectious case involving exposure to high-infectivity tissue (e.g. invasive neurological investigations, neurosurgery, spinal cord surgery, or ophthalmic surgery) and not subjected to documented and sufficient additional re-processing as described in Queensland Health and Australian Government infection control guidelines.

While occupational exposure is theoretically possible e.g. inoculation of infectious tissue via an injury from a contaminated instrument, no such cases have been conclusively documented, and there is no epidemiological evidence that health care workers are at increased occupational risk

Variant CJD:
Potential contacts include:

  • Recipients of blood product or other tissue donated by an infectious case.
  • Those exposed to instruments/equipment potentially contaminated following surgery/invasive procedures on a case and not subjected to sufficient cleaning and re-processing for the inactivation of the infectious agent for CJD, such as described in Queensland Health and Australian Government infection control guidelines.

While occupational exposure is theoretically possible e.g. inoculation of infectious tissue via an injury from a contaminated instrument, no such cases have been conclusively documented.

Look-back investigations
Any decision to trace and disclose potential exposure to people identified as potential contacts should be made in consultation with CDB and after a careful risk assessment and consultation with the CDNA CJD incident panel. The risk of psychiatric injury due to the disclosure of a possible risk of contracting a fatal disease with a long incubation period and no cure must be considered, along with other issues.

Prophylaxis:
Nil available at present.

Counselling:
If a look-back investigation is conducted, contacts should be advised not to donate blood or body parts, and to alert health care workers to their increased risk of CJD.  Appropriate counselling should be offered, and the person informed of relevant support groups.

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Preventive Measures

Australia's actions to prevent TSEs of animals include:

  • since 1996, importation of meat and bone meal into Australia has been prohibited from all countries other than New Zealand, which is free of TSEs
  • Australia imports cattle only from New Zealand and new Caledonia, which are free of BSE
  • An extensive quarantine policy relating to sheep, goats, deer and biological materials of bovine origin
  • a voluntary ban on the feeding of ruminant material to ruminants (1996)
  • active and passive surveillance for TSEs in animals.

Australia's actions to protect human health include:

  • a certification system to ensure all beef products entering Australia are derived from BSE-free animals
  • a ban of blood donations from anyone who lived in the UK for a cumulative total of six months or more between 1980 and 1996 or who received a blood transfusion in the UK from 1980 onwards
  • registration of CJD as a nationally notifiable disease.

Feedback

Report to notifying agency.

Summary

Prepare a report for the Communicable Diseases Branch, Queensland Health.

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References

Australian Government Department of Health and Ageing. The Variant Creutzfeldt-Jakob Disease Contingency Plan.
This document includes:

  • Australian Government Department of Health and Ageing. A Variant Creutzfeldt-Jakob Disease Clinical Response Plan for Australia.
  • Australian Government Department of Health and Ageing. A Variant Creutzfeldt-Jakob Disease Infection Control Response Plan for Australia.

Australian Government Department of Health and Ageing.  Infection Control Guidelines for the Prevention of Transmission of Infectious Diseases in the Health Care Setting.

Robotin M.  Evaluation of the Australian CJD surveillance system.  Communicable Diseases Intelligence 2002;26:265-272.

Belay ED.  Transmissible spongiform encephalopathies in humans.  Annual Reviews in Microbiology.  1999;53:283-314.

Klug GM, Boyd A, Lewis V et al.  Surveillance of Creutzfeldt-Jakob disease in Australia, 2008 Communicable Diseases Intelligence 2008;32:232-236.

Queensland Health.  Guidelines for Management of Classical Creutzfeldt-Jakob Disease.

Will RG, Ironside JW, Zeidler M et al.  A new variant of Creutzfeldt-Jakob disease in the UK.  Lancet 1996;347:921-925.

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Last updated: 21 September 2011