Advertisement

Prion diseases

Published:December 18, 2019DOI:https://doi.org/10.1016/j.mpaic.2019.10.014

      Abstract

      The prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of neurodegenerative diseases. They are caused by an abnormal form of a naturally occurring cellular protein, known as prion protein. All prion diseases are fatal and without cure. Although all are rare, interest has increased over the last 20 years due to the appearance of a new prion disease called variant Creutzfeldt-Jakob disease. This disease is transmissible via medical devices and blood and therefore has implications for the anaesthetist, especially where blood transfusions and the use of airway devices and fibreoptic equipment are concerned.

      Keywords

      After reading this article, you should be able to:
      • discuss the nature of prion diseases
      • describe the differences between sporadic and variant Creutzfeldt-Jakob disease
      • explain the implications of prion diseases for anaesthetists

      Introduction

      Prion diseases affect both humans and animals. Those affecting animals include transmissible mink encephalopathy, bovine spongiform encephalopathy (BSE or ‘mad cow disease’) and scrapie, seen in sheep. Scrapie was first described in the 1730s. Its name derives from the way infected sheep scrape their fleeces against hard surfaces to relieve itch. In the 1920s, Creutzfeldt and Jakob described the prion disease that affects humans and that became known as Creutzfeldt-Jakob disease (CJD). Recently, interest in prion diseases has burgeoned due to the emergence of a new form of CJD, known as variant Creutzfeldt-Jakob disease (variant CJD). Variant CJD arose from human ingestion of meat from BSE-infected cattle.

      Pathophysiology

      The unifying features of prion diseases are the neuropathological changes of neuronal loss, gliosis and spongiform change. These changes are caused by an abnormal form of the normal cellular prion protein (PrPC), found on the surface of many cells and particularly neurons. This abnormal form is designated PrPSC (‘sc’ for scrapie). PrPC has a largely alpha-helical structure whereas PrPSC has an increased number of beta-sheets. This conformational change in PrPSC renders it resistant to proteolytic digestion and confers resistance to conventional methods of decontamination. PrPSC is not significantly affected by disinfectants and is resistant to standard autoclaving methods.
      • Ironside J.W.
      Variant Creutzfeldt-Jakob disease: an update.
      Infectivity of PrPSC from cell to cell appears to occur by ‘autocatalytic’ conversion of PrPC to PrPSC. Human PrPC is present in high concentrations in neural tissues and in low concentrations in cells of the immune system. No definite function of PrPC has been confirmed, although it appears to have a role in synaptic transmission. PrPC is encoded by a single gene, which is found on chromosome 20 and known as PRNP. Importantly, the gene is polymorphic at codon 129, encoding either methionine or valine. Homozygosity for methionine or valine seems to be a major risk factor for developing human prion disease.
      The only definitive method for diagnosing prion disease is by biopsy and examination of affected tissue, with subsequent typing of PrPSC using Western blotting techniques. However, the suspicion of disease on clinical grounds can be supported by MRI changes, electroencephalographic features, measurement of certain markers in cerebrospinal fluid (including 14-3-3 protein) and genetic sequencing of the PRNP gene. A more recent test, real time quaking induced conversion (RT-QUiC) has also been developed to aid diagnosis.

      Human prion diseases

      Human prion diseases may be classified into sporadic, inherited and acquired types.

      Sporadic CJD

      Sporadic CJD is the most common form of CJD (85%) with an annual incidence of one per million of the population. Sporadic CJD is found with similar incidence in all documented countries and usually affects people in late middle-age with a typical onset age of 65 years. The trigger for sporadic CJD is unknown. It is characterized by a rapidly progressive dementia, often accompanied by behavioural and visual disturbances, ataxia, extrapyramidal features and myoclonus. There is frequently an insidious onset, then a rapid progressive phase and death within one year. Definitive diagnosis requires a brain biopsy. Genetic analysis of the PRPN gene reveals that 70% of confirmed cases are homozygous for methionine at codon 129. Elevation of 14-3-3 protein in CSF is a non-specific biomarker, and may be a more sensitive test for sporadic CJD than for variant CJD.
      Variably protease sensitive prionopathy, a relatively recently described form of prion disease, is considered a form of sporadic CJD. There have been 17 cases reported in the UK.

      Inherited human prion diseases

      Inherited or familial prion diseases arise from mutations of the PRNP gene and are inherited on an autosomal dominant basis. More than thirty PRNP mutations have been identified, resulting in varied presentations. This group of diseases includes familial CJD, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. Once an initial diagnosis of inherited CJD has been made, family members must be considered for testing. Some may not wish to know whether they will develop an incurable disease later in life. The choice is personal and appropriate counseling should be available.

      Acquired human prion diseases

      There are several ways prion diseases may be acquired.
      Kuru: A prion disease seen exclusively in the South Fore tribes of Papua New Guinea, kuru arises from the ingestion of infected brain tissue during cannibalistic mortuary rites. Its incidence is diminishing with the abolition of cannibalism and education. Women were historically infected more than men, probably because women were the primary participants in mortuary rites. Kuru victims were a highly regarded source of food, because the layer of fat on the victims, who died quickly, was felt to resemble pork.
      Iatrogenic CJD: arises from the transfer of PrPSC-infected tissue to healthy individuals. Since 1990 there have been 82 deaths due to iatrogenic CJD.
      Transfer of infected tissue may occur in the following ways:
      • Implantation of cadaver-sourced dura mater or corneal grafts: Prior to 1992, patients undergoing spinal or cranial operations that resulted in large dural defects would have the defect repaired using dural grafts. These were sourced from cadavers, a small percentage of which were infected with CJD. Dural grafts are no longer sourced from cadavers: they are now synthetically produced. A small number of people have been infected with CJD following corneal grafts.
      • Administration of growth hormone (GH) and gonadotrophin: Prior to 1985, GH was given to children with restricted growth. The GH was extracted from pituitaries from cadavers, some of which were infected with CJD. Incubation periods may span many decades and presently 2–6 cases are diagnosed each year. Some women with fertility problems have received gonadotrophin supplements derived from cadavers infected with CJD. A very small number have developed CJD. Artificially synthesized GH and gonadotrophin are now available and in use.
      • Infected surgical instruments: There have been no documented cases of transmission via this route since 1976. The risk nonetheless still exists. The surgical instruments used on CJD patients having high-risk operations must be incinerated or quarantined for use on CJD patients only. Similarly, surgical instruments must be incinerated or quarantined for those patients at increased risk of having CJD, until such time as they are proved to be free of the disease. All instruments must be trackable. Patients undergoing neurosurgical procedures who were born after 1997 should not be exposed to instruments that have previously been used on patients born before 1997. This is to protect the substantially lower variant CJD risk of patients born since 1997, when BSE-contaminated beef products were removed from the UK food chain.

      Variant CJD

      Variant CJD was first reported in 1996. There have been 178 definitive and probable deaths from variant CJD in the UK. Biochemical, neuropathological and transmission studies show conclusively that the agent responsible for prion disease in cows, BSE, is the same agent responsible for variant CJD.
      • Hill A.F.
      • Desbruslais M.
      • Joiner S.
      • et al.
      The same prion strain causes vCJD and BSE.
      Most people who have developed variant CJD have lived in the UK. Many those who were diagnosed in other countries had previously resided in the UK and been exposed to BSE-infected meat. Exposure is mostly likely through consumption of bovine meat products contaminated with infected bovine brain or other central nervous system tissue.
      Although the incidence of variant CJD cases peaked in 2000 and has since been declining, controversy remains about how many people carry the infectious prion protein and will eventually develop disease. A study of 63,000 pairs of tonsils failed to detect any abnormal prion protein, suggesting that the prevalence of variant CJD in the British population was zero.
      • Clewey J.P.
      • Kelly C.M.
      • Andrews N.
      • et al.
      Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey.
      Another study
      • Hilton D.A.
      • Ghani A.C.
      • Conyers L.
      • et al.
      Prevalence of lymphoreticular prion protein accumulation in UK tissue samples.
      of 12,674 tonsillar and appendix tissue samples found deposits of PrPSC in three specimens, suggesting a prevalence of 237 cases of asymptomatic variant CJD per million people. A further study
      • Gill O.N.
      • Spencer Y.
      • Richard-Loendt A.
      • et al.
      Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey.
      looking at 32,441 appendices found an incidence between 412 and 733 per million. On balance, the published studies suggest a prevalence of between one per 4000 and one per 10,000 of the UK population. These rates far exceed those of proven variant CJD cases. This may be explained by the existence of a hypothetical long asymptomatic carrier state.
      Before December 2009, all definite cases of variant CJD had been homozygous for methionine at the polymorphic codon 129 of PRNP. However, a possible case of variant CJD has now been reported in an individual heterozygous for the codon. This raises the question of whether such heterozygotes may develop disease with longer incubation periods. This patient did not have a post-mortem and consequently the diagnosis was not confirmed. Abnormal protein from appendiceal specimens in asymptomatic individuals, were all homozygous for valine.
      • Gill O.N.
      • Spencer Y.
      • Richard-Loendt A.
      • et al.
      Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey.
      Variant CJD differs from sporadic CJD in a number of ways. It affects mainly young people (Table 1). In contrast to sporadic CJD, PrPSC is not only present in CNS tissue but also in the tonsils and other lymph glands and in the appendix and other intestinal tissue. PrPSC is also expressed in the cellular elements of blood. Diagnosis of variant CJD is supported by MRI findings of a characteristic abnormality seen in the posterior thalamic region, the so-called pulvinar sign. Diagnosis is confirmed by tonsillar biopsy, which is both sensitive and specific. Examination of the CSF may be unremarkable. The 14-3-3 test is not as sensitive for variant CJD as for sporadic CJD and is consequently not routinely used in clinical diagnosis.
      Table 1Differing features of sporadic and variant CJD
      FeaturesSporadic CJDVariant CJD
      Typical age of death68 years28 years
      Duration of illness6 months13–14 months
      SymptomsDementia, early neurological signsEarly behavioural signs, delayed neurological signs
      PrPSC presenceBrain and spinal cordBrain, spinal cord, tonsil appendix and other lymphoid tissue
      Tissue diagnosisBrain biopsyTonsillar or brain biopsy
      Periodic sharp waves on EEGOften presentOften absent
      Pulvinar sign on MRINot reportedMostly reported
      CJD, Creutzfeldt-Jakob disease; EEG, electroencephalogram; MRI, magnetic Resonance Imaging.
      A blood test has been developed to detect prion infection in variant CJD. This prototype blood test could facilitate a large screening programme for asymptomatic prion infection.
      • Jackson G.S.
      • Burk-Rafel J.
      • Edgeworth J.A.
      • et al.
      Population screening for variant creutzfeldt-jakob disease using a novel blood test.
      Given the absence of treatment options, the utility of a positive test remains unclear. Effective screening may enable cost reductions in sourcing blood products from overseas if the risks of variant CJD transmission can be eliminated.
      No effective treatment for CJD has emerged. Various drugs have been studied, including intraventricular pentosan polysulphate, quinacrine, tetracycline compounds and flupirtine. No trial drug has shown either cure or definitive halting of disease progression. Since 2018, a few patients have received a new drug, PRN100. This is a manufactured antibody, which binds to the normal proteins in the brain, preventing the abnormal prion protein binding and could potentially halt progression of the disease. The treatment is new and no conclusions with regards to efficacy can made.

      Implications for anaesthetists

      Contamination of airway devices

      Laryngoscope blades come into contact with lymphoid tissue routinely during conventional laryngoscopy. Contamination with lymphoid tissue occurs even if a person has undergone a tonsillectomy.
      • Hirsch N.P.
      • Beckett A.
      • Collinge J.
      • et al.
      Lymphocyte contamination of laryngoscope blades a possible vector for transmission of variant Creutzfeldt-Jakob disease.
      Prion protein adheres to stainless steal avidly and is not removed or destroyed by conventional autoclaving. It follows that prion protein can be transmitted from person to person via re-useable laryngoscope blades.
      It is estimated that only one gram of infected tissue is required for transmission. The wide availability and use of good quality single-use laryngoscopy blades reduces the risk of transmission by this route.
      Many videolaryngoscopes are available. Several of these have a disposable blade component. There are however some designs which are entirely re-useable. Supraglottic devices, including laryngeal masks and intubating laryngeal masks, are available as single use items, as are bougies and magill forceps. Single use items should be used wherever possible.

      Endoscopes

      Endoscopes are frequently in contact with high-risk tissue, for example, lymphoid and pituitary tissue. Historically, all endoscopes were autoclaved and re-used. These two facts combined have given rise to concern that CJD may be transmitted by endoscopes. No patient infection by this route has been documented despite the theoretical risk. For tracheal intubation, similar concerns have largely been abated with the introduction of high-quality fibreoptic endoscopes, which are disposable. If re-useable endoscopes or gastroscopes are used, this should be recorded. The serial numbers of the endoscopes used should be entered into patients’ notes and into a register, in order to facilitate subsequent tracing of equipment. Endoscopes that have been contaminated with CJD should be sent to the National Creutzfeldt-Jakob Surveillance Unit in Edinburgh, where they are made available only for use on patients with confirmed CJD.

      Assessment of CJD risk

      Identifying patients at increased risk of CJD is the responsibility of the entire medical team. All surgical patients should be asked screening questions in the pre-assessment clinic.
      Increased risk patients include:
      • those who had operations on their spinal cord or brain prior to 1992 and who may have had dural grafts
      • those who received growth hormone or gonadotrophin replacement prior to 1985
      • those who have received blood from 300 or more donors. In practical terms, this means patients with haemaglobinopathies or bleeding disorders
      • history of familial CJD.
      If a patient does not attend pre-assessment, they should be screened on admission.

      Blood transfusion

      Prior to 31 December 2014, there were four patients who developed CJD from infected blood transfusions and one patient with a bleeding disorder who was infected with CJD from UK-sourced plasma products. These patients have all died. There is no CJD test for blood in use. Since 1998, all donated blood donated is leukodepleted, potentially decreasing the prion infectivity risk. All blood donors are screened. Nobody may donate blood if they themselves have received a blood donation in the UK after 1980. People assessed as having an increased risk of CJD are not permitted to donate blood. All plasma products administered in the UK are sourced from the USA. If a CJD patient is found to have a history of donating blood, its recipients are notified and followed by UK's Transfusion Medicine Epidemiology team for signs and symptoms of CJD.

      WHO checklist

      This safety checklist, published by the World Health Organization (WHO), is used in surgical theatre perioperatively. WHO encourages the addition of items to the checklist to improve patient safety. UK hospitals should adopt (and some have already adopted) the practice of considering whether the patient has moderate or increased risk of CJD as part of their WHO checklist procedure. This assessment, together with the type of operation, dictates whether surgical instruments should be autoclaved and re-used, quarantined or incinerated.

      References

        • Ironside J.W.
        Variant Creutzfeldt-Jakob disease: an update.
        Folia Neuropathol. 2012; 50: 50-56
      1. (accessed on 5 September 2019)
      2. (accessed on 26 February 2016)
        • Hill A.F.
        • Desbruslais M.
        • Joiner S.
        • et al.
        The same prion strain causes vCJD and BSE.
        Nature. 1997; 389: 448-450
        • Clewey J.P.
        • Kelly C.M.
        • Andrews N.
        • et al.
        Prevalence of disease related prion protein in anonymous tonsil specimens in Britain: cross sectional opportunistic survey.
        Br Med J. 2009; 338 (b1442)
        • Hilton D.A.
        • Ghani A.C.
        • Conyers L.
        • et al.
        Prevalence of lymphoreticular prion protein accumulation in UK tissue samples.
        J Pathol. 2004 Jul; 203: 733-739
        • Gill O.N.
        • Spencer Y.
        • Richard-Loendt A.
        • et al.
        Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey.
        BMJ. 2013; 347: f5675
      3. (accessed on 5 September 2019)
        • Jackson G.S.
        • Burk-Rafel J.
        • Edgeworth J.A.
        • et al.
        Population screening for variant creutzfeldt-jakob disease using a novel blood test.
        JAMA Neurol. 2014 Apr; 71: 421-428
        • Hirsch N.P.
        • Beckett A.
        • Collinge J.
        • et al.
        Lymphocyte contamination of laryngoscope blades a possible vector for transmission of variant Creutzfeldt-Jakob disease.
        Anaesthesia. 2005; 60: 664-667