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Prion diseases
NEUROSURGICAL ANAESTHESIA
Prion diseases
Learning objectives
Nicholas Hirsch After reading this article you should be able to: C understand the nature of prion diseases C understand how variant CreutzfeldteJakob disease (CJD) differs from sporadic CJD C list the anaesthetic implications of prion diseases.
Abstract The prion diseases are a group of invariably fatal neurodegenerative conditions caused by a structurally abnormal form of the naturally occurring cellular prion protein. Although all are rare, interest over the last 15 years has been intense due to the appearance of a new prion disease e variant CreutzfeldteJakob disease which is caused by ingestion of meat from cattle suffering from bovine spongiform encephalopathy. The disease is transmissible and therefore has implications for the anaesthetist including the use of airway devices, fibreoptic equipment and blood transfusion.
encoded by a single gene (designated PRNP) on chromosome 20. Importantly, the gene is polymorphic at codon 129, encoding either methionine or valine; homozygosity for methionine seems to be a major risk factor for developing human prion disease.
Human prion diseases Keywords Airway devices; blood transfusion; prion disease; variant
The only definitive method of 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 electroencephalographic features, measurement of certain markers in the cerebrospinal fluid (e.g. 14.3.3 protein) and genetic sequencing of the PRNP gene to provide information regarding the codon 129 polymorphism. The human prion disease may be classified into sporadic, inherited and acquired types (Table 1).
CreutzfeldteJakob disease
Introduction The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative conditions which affect both humans and animals. Examples of the latter include scrapie in sheep, transmissible mink encephalopathy and bovine spongiform encephalopathy (BSE) in cattle. Recently, interest in these diseases has burgeoned due to the emergence of a new form of prion disease e variant CreutzfeldteJakob disease (vCJD). The human TSEs are characterized by relentlessly progressive dementia and ataxia and are invariably fatal. Histological examination of affected neural tissue reveals spongiform changes and astrocytic and microglial activation.
Sporadic CJD (sCJD) sCJD has an annual incidence of one in one million of the population and usually affects those between the ages of 55e65. It is characterized by a progressive dementia often accompanied by behavioural and visual disturbances, ataxia, extrapyramidal features and myoclonus. Death usually occurs within 6 months. Definitive diagnosis requires brain biopsy. Genetic analysis reveals 70% are homozygous for methionine at codon 129.
Pathophysiology of prion diseases The changes seen on pathological examination are accompanied by the presence of an abnormal form of the normal cellular prion protein (PrPC); this abnormal species is designated PrPSC (SC for scrapie) and seems to differ from PrPC only in the manner of its folded structure. Infectivity of PrPSC from cell to cell appears to occur by ‘autocatalytic’ conversion of PrPC to PrPSC and therefore is unique in not requiring nucleic acids for replication. Human PrPC is present in high concentrations in neural and associated tissues and in low concentrations in lymphoreticular tissue. No definite function of PrPC has been confirmed although it appears to have a role in combating oxidative stress. It is
Inherited human prion diseases This group of diseases include familial CJD, Gerstmanne Stra¨usslereScheinker syndrome and fatal familial insomnia; although the presentation differs between the conditions, all are due to various mutations of the PRNP gene and are inherited on an autosomal dominant basis. Acquired human prion diseases Iatrogenic CJD: iatrogenic CJD is caused by transfer of PrPSC infected tissue to healthy individuals. Most cases involved the implantation of infected tissue (e.g. dura mater and corneal grafts) or from treatment involving the injection of pituitary extracts taken from affected cadavers. Kuru, a prion disease seen exclusively in the South Fore tribes of Papua New Guinea, is due to the ingestion of infected brain tissue during cannibalistic rites. The route of infection seems to determine the incubation period; thus, patients who have received infected dura mater grafts develop symptoms within 24 months, whereas those who develop Kuru may take up to 50 years to show clinical signs.
Nicholas Hirsch FRCA FRCP is a Consultant Neuroanaesthetist at the National Hospital for Neurology and Neurosurgery and Honorary Senior Lecturer at the Institute of Neurology, London. He qualified from Guy’s Hospital and trained in anaesthesia in London and at Yale University. His research interests involve both neuroanaesthesia and neuromedical critical care. No conflict of interest declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
369
Ó 2010 Elsevier Ltd. All rights reserved.
NEUROSURGICAL ANAESTHESIA
The human prion diseases Disease Sporadic CJD
Inherited diseases: Familial CJD GSS FFI Acquired CJD: Iatrogenic CJD Variant CJD
Age of onset (years) 60e70
Mean duration of disease 6 months
Symptoms Dementia, cerebellar ataxia, visual disturbance, extrapyramidal symptoms, myoclonus
50e60 50e60 20e60
6 months 5e6 years 15 months
Similar to sporadic CJD Cerebellar symptoms Autonomic failure, insomnia
e 12e74
6 months 14 months
Similar to sporadic CJD Neuropsychiatric symptoms (depression, anxiety, agitation, social withdrawal). Later dementia
CJD, CreutzfeldteJakob disease; FFI, fatal familial insomnia; GSS, GerstmanneStra¨usslereScheinker syndrome.
Table 1
Variant CJD (vCJD): vCJD was first reported in 1996 and by February 2010 there had been about 200 reported cases from definite or probable vCJD reported. Approximately 170 cases come from the UK. Biochemical, neuropathological and transmission studies show conclusively that the condition is due to the ingestion of meat from cattle suffering from BSE.1 Although the incidence of cases peaked in 2000 and has been declining since, controversy remains about how many people are carrying the infectious prion protein and will eventually develop disease. A recent study of 63,000 pairs of tonsils failed to detect any abnormal prion protein suggesting that the prevalence of vCJD in the British population was zero (but with a large confidence interval of 0e113 per million).2 However, this finding differs from another study of tonsillar and appendix tissue which found deposits of PrPSC in three specimens suggesting a prevalence of 237 cases of asymptomatic vCJD per million. Until December 2009 all cases of vCJD have been homozygous for methionine at the polymorphic codon 129 of the prion protein gene PRNP. However, vCJD has now been reported in an individual heterozygous for the codon and this raises the question of whether such heterozygotes may develop disease but with longer incubation periods. vCJD differs from sCJD in a number of ways and affects mainly young people (Table 2). In contrast to sCJD, PrPSC is not only present in central nervous system 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 vCJD is supported by magnetic resonance imaging findings of increased signal intensity in the pulvinar nuclei and is confirmed by tonsillar biopsy which is 100% sensitive and specific. A recently developed blood test for detection of vCJD is undergoing trials.
Anaesthetic implications of prion disease Contamination of laryngoscope blades and airway devices During routine use, laryngoscope blades become contaminated with lymphoid tissue even when used on patients who have previously undergone tonsillectomy.3 Furthermore, PrPSC has a huge avidity for stainless steel and it has been estimated that only 1 mg of tissue is necessary for infection. Routine cleaning with detergent and autoclaving of blades is not only ineffective at removing protein deposits, it does not destroy prion protein. In view of the potentially large reservoir of asymptomatic but infected individuals, disposable laryngoscope blades should be used whenever possible. Recently introduced blades are as effective as their non-disposable counterparts. Similar considerations apply to Magill forceps, bougies and laryngeal mask airways. Endoscopic equipment Although no case of CJD has been attributed to an endoscopic procedure, there is an unquantifiable risk of PrPSC transmission particularly as a result of biopsying lymphoid material. PrPSC
Differing features of sporadic and variant CJD Sporadic CJD C Dementia prominent
C C
C
Treatment of CJD: no effective treatment for CJD has emerged. Observational trials of intraventricular pentosan polysulphate are proceeding as are trials of quinacrine, but no conclusive benefits have been reported as yet.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
Average age 55e65 years Duration (onset to death) 6 months Abnormal prion protein (PrPSC) confined to brain and spinal cord
Variant CJD Neuropsychiatric symptoms prominent e depression, agitation, social withdrawal C Average age 30 years C Duration (onset to death) 14 months SC C Abnormal prion protein (PrP ) found in brain, spinal cord, tonsil, appendix, blood C
Table 2
370
Ó 2010 Elsevier Ltd. All rights reserved.
NEUROSURGICAL ANAESTHESIA
proteins have been found in olfactory and respiratory epithelium and in intestinal lymphoid tissue from duodenum to rectum. Guidelines have been published for the safe use and decontamination of endoscopic equipment.4 The use of all fibreoptic equipment must be recorded at each use to permit contact tracing if endoscopic transmission needs to be investigated in the future. Fibreoptic equipment for tracheal intubation and gastrointestinal endoscopy for use in patients with confirmed variant or sporadic CJD is available from the National CreutzfeldteJakob Surveillance Unit in Edinburgh.
removes prion protein is now available and its routine use is being considered. A
REFERENCES 1 Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J. The same prion strain causes vCJD and BSE. Nature 1997; 389: 448e50. 2 Clewey JP, Kelly CM, 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. 3 Hirsch N, Beckett A, Collinge J, Scaravilli F, Tabrizi S, Berry S. Lymphocyte contamination of laryngoscope blades e a possible vector for transmission of variant CreutzfeldteJakob disease. Anaesthesia 2005; 60: 664e7. 4 http://www.dh.gov.uk/ab/ACDP/TSEguidance/index.htm (accessed 9 Jan 2010). 5 Gillies M, Chohan G, Llewelyn CA, et al. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sang 2009; 97: 211e8.
Blood transfusion To date there have been four cases of confirmed transfusionderived vCJD and evidence suggests that this mode of transmission occurs.5 The interval between transfusion and development of symptoms is 5e8 years. The UK’s Transfusion Medicine Epidemiology Review continues to follow recipients of blood products donated by individuals who subsequently developed vCJD. No confirmed test exists to detect blood infected with PrPSC and therefore various measures have been instituted to minimize the risk of transmission. Since 1998 all blood donated has been leukodepleted (which appears to lessen but not eliminate the prion infectivity) and since 1999 all non-cellular blood products (except fresh frozen plasma and cryoprecipitate) is sourced from the USA and Germany. Individuals who have received a blood transfusion after 1980 are no longer accepted as donors. A blood filtration system which
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
FURTHER READING Aguzzi A, Calella AM. Prions: protein aggregation and infectious diseases. Physiol Rev 2009; 89: 1105e52. Sakudo A, Ikuta K. Prion protein functions and dysfunction in prion diseases. Curr Med Chem 2009; 16: 380e9. Zou S, Fang CT, Schonberger LB. Transfusion transmission of human prion diseases. Transfus Med Rev 2008; 22: 58e69.
371
Ó 2010 Elsevier Ltd. All rights reserved.
Prion diseases
Learning objectives
Nicholas Hirsch After reading this article you should be able to: C understand the nature of prion diseases C understand how variant CreutzfeldteJakob disease (CJD) differs from sporadic CJD C list the anaesthetic implications of prion diseases.
Abstract The prion diseases are a group of invariably fatal neurodegenerative conditions caused by a structurally abnormal form of the naturally occurring cellular prion protein. Although all are rare, interest over the last 15 years has been intense due to the appearance of a new prion disease e variant CreutzfeldteJakob disease which is caused by ingestion of meat from cattle suffering from bovine spongiform encephalopathy. The disease is transmissible and therefore has implications for the anaesthetist including the use of airway devices, fibreoptic equipment and blood transfusion.
encoded by a single gene (designated PRNP) on chromosome 20. Importantly, the gene is polymorphic at codon 129, encoding either methionine or valine; homozygosity for methionine seems to be a major risk factor for developing human prion disease.
Human prion diseases Keywords Airway devices; blood transfusion; prion disease; variant
The only definitive method of 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 electroencephalographic features, measurement of certain markers in the cerebrospinal fluid (e.g. 14.3.3 protein) and genetic sequencing of the PRNP gene to provide information regarding the codon 129 polymorphism. The human prion disease may be classified into sporadic, inherited and acquired types (Table 1).
CreutzfeldteJakob disease
Introduction The transmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of neurodegenerative conditions which affect both humans and animals. Examples of the latter include scrapie in sheep, transmissible mink encephalopathy and bovine spongiform encephalopathy (BSE) in cattle. Recently, interest in these diseases has burgeoned due to the emergence of a new form of prion disease e variant CreutzfeldteJakob disease (vCJD). The human TSEs are characterized by relentlessly progressive dementia and ataxia and are invariably fatal. Histological examination of affected neural tissue reveals spongiform changes and astrocytic and microglial activation.
Sporadic CJD (sCJD) sCJD has an annual incidence of one in one million of the population and usually affects those between the ages of 55e65. It is characterized by a progressive dementia often accompanied by behavioural and visual disturbances, ataxia, extrapyramidal features and myoclonus. Death usually occurs within 6 months. Definitive diagnosis requires brain biopsy. Genetic analysis reveals 70% are homozygous for methionine at codon 129.
Pathophysiology of prion diseases The changes seen on pathological examination are accompanied by the presence of an abnormal form of the normal cellular prion protein (PrPC); this abnormal species is designated PrPSC (SC for scrapie) and seems to differ from PrPC only in the manner of its folded structure. Infectivity of PrPSC from cell to cell appears to occur by ‘autocatalytic’ conversion of PrPC to PrPSC and therefore is unique in not requiring nucleic acids for replication. Human PrPC is present in high concentrations in neural and associated tissues and in low concentrations in lymphoreticular tissue. No definite function of PrPC has been confirmed although it appears to have a role in combating oxidative stress. It is
Inherited human prion diseases This group of diseases include familial CJD, Gerstmanne Stra¨usslereScheinker syndrome and fatal familial insomnia; although the presentation differs between the conditions, all are due to various mutations of the PRNP gene and are inherited on an autosomal dominant basis. Acquired human prion diseases Iatrogenic CJD: iatrogenic CJD is caused by transfer of PrPSC infected tissue to healthy individuals. Most cases involved the implantation of infected tissue (e.g. dura mater and corneal grafts) or from treatment involving the injection of pituitary extracts taken from affected cadavers. Kuru, a prion disease seen exclusively in the South Fore tribes of Papua New Guinea, is due to the ingestion of infected brain tissue during cannibalistic rites. The route of infection seems to determine the incubation period; thus, patients who have received infected dura mater grafts develop symptoms within 24 months, whereas those who develop Kuru may take up to 50 years to show clinical signs.
Nicholas Hirsch FRCA FRCP is a Consultant Neuroanaesthetist at the National Hospital for Neurology and Neurosurgery and Honorary Senior Lecturer at the Institute of Neurology, London. He qualified from Guy’s Hospital and trained in anaesthesia in London and at Yale University. His research interests involve both neuroanaesthesia and neuromedical critical care. No conflict of interest declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
369
Ó 2010 Elsevier Ltd. All rights reserved.
NEUROSURGICAL ANAESTHESIA
The human prion diseases Disease Sporadic CJD
Inherited diseases: Familial CJD GSS FFI Acquired CJD: Iatrogenic CJD Variant CJD
Age of onset (years) 60e70
Mean duration of disease 6 months
Symptoms Dementia, cerebellar ataxia, visual disturbance, extrapyramidal symptoms, myoclonus
50e60 50e60 20e60
6 months 5e6 years 15 months
Similar to sporadic CJD Cerebellar symptoms Autonomic failure, insomnia
e 12e74
6 months 14 months
Similar to sporadic CJD Neuropsychiatric symptoms (depression, anxiety, agitation, social withdrawal). Later dementia
CJD, CreutzfeldteJakob disease; FFI, fatal familial insomnia; GSS, GerstmanneStra¨usslereScheinker syndrome.
Table 1
Variant CJD (vCJD): vCJD was first reported in 1996 and by February 2010 there had been about 200 reported cases from definite or probable vCJD reported. Approximately 170 cases come from the UK. Biochemical, neuropathological and transmission studies show conclusively that the condition is due to the ingestion of meat from cattle suffering from BSE.1 Although the incidence of cases peaked in 2000 and has been declining since, controversy remains about how many people are carrying the infectious prion protein and will eventually develop disease. A recent study of 63,000 pairs of tonsils failed to detect any abnormal prion protein suggesting that the prevalence of vCJD in the British population was zero (but with a large confidence interval of 0e113 per million).2 However, this finding differs from another study of tonsillar and appendix tissue which found deposits of PrPSC in three specimens suggesting a prevalence of 237 cases of asymptomatic vCJD per million. Until December 2009 all cases of vCJD have been homozygous for methionine at the polymorphic codon 129 of the prion protein gene PRNP. However, vCJD has now been reported in an individual heterozygous for the codon and this raises the question of whether such heterozygotes may develop disease but with longer incubation periods. vCJD differs from sCJD in a number of ways and affects mainly young people (Table 2). In contrast to sCJD, PrPSC is not only present in central nervous system 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 vCJD is supported by magnetic resonance imaging findings of increased signal intensity in the pulvinar nuclei and is confirmed by tonsillar biopsy which is 100% sensitive and specific. A recently developed blood test for detection of vCJD is undergoing trials.
Anaesthetic implications of prion disease Contamination of laryngoscope blades and airway devices During routine use, laryngoscope blades become contaminated with lymphoid tissue even when used on patients who have previously undergone tonsillectomy.3 Furthermore, PrPSC has a huge avidity for stainless steel and it has been estimated that only 1 mg of tissue is necessary for infection. Routine cleaning with detergent and autoclaving of blades is not only ineffective at removing protein deposits, it does not destroy prion protein. In view of the potentially large reservoir of asymptomatic but infected individuals, disposable laryngoscope blades should be used whenever possible. Recently introduced blades are as effective as their non-disposable counterparts. Similar considerations apply to Magill forceps, bougies and laryngeal mask airways. Endoscopic equipment Although no case of CJD has been attributed to an endoscopic procedure, there is an unquantifiable risk of PrPSC transmission particularly as a result of biopsying lymphoid material. PrPSC
Differing features of sporadic and variant CJD Sporadic CJD C Dementia prominent
C C
C
Treatment of CJD: no effective treatment for CJD has emerged. Observational trials of intraventricular pentosan polysulphate are proceeding as are trials of quinacrine, but no conclusive benefits have been reported as yet.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
Average age 55e65 years Duration (onset to death) 6 months Abnormal prion protein (PrPSC) confined to brain and spinal cord
Variant CJD Neuropsychiatric symptoms prominent e depression, agitation, social withdrawal C Average age 30 years C Duration (onset to death) 14 months SC C Abnormal prion protein (PrP ) found in brain, spinal cord, tonsil, appendix, blood C
Table 2
370
Ó 2010 Elsevier Ltd. All rights reserved.
NEUROSURGICAL ANAESTHESIA
proteins have been found in olfactory and respiratory epithelium and in intestinal lymphoid tissue from duodenum to rectum. Guidelines have been published for the safe use and decontamination of endoscopic equipment.4 The use of all fibreoptic equipment must be recorded at each use to permit contact tracing if endoscopic transmission needs to be investigated in the future. Fibreoptic equipment for tracheal intubation and gastrointestinal endoscopy for use in patients with confirmed variant or sporadic CJD is available from the National CreutzfeldteJakob Surveillance Unit in Edinburgh.
removes prion protein is now available and its routine use is being considered. A
REFERENCES 1 Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J. The same prion strain causes vCJD and BSE. Nature 1997; 389: 448e50. 2 Clewey JP, Kelly CM, 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. 3 Hirsch N, Beckett A, Collinge J, Scaravilli F, Tabrizi S, Berry S. Lymphocyte contamination of laryngoscope blades e a possible vector for transmission of variant CreutzfeldteJakob disease. Anaesthesia 2005; 60: 664e7. 4 http://www.dh.gov.uk/ab/ACDP/TSEguidance/index.htm (accessed 9 Jan 2010). 5 Gillies M, Chohan G, Llewelyn CA, et al. A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions. Vox Sang 2009; 97: 211e8.
Blood transfusion To date there have been four cases of confirmed transfusionderived vCJD and evidence suggests that this mode of transmission occurs.5 The interval between transfusion and development of symptoms is 5e8 years. The UK’s Transfusion Medicine Epidemiology Review continues to follow recipients of blood products donated by individuals who subsequently developed vCJD. No confirmed test exists to detect blood infected with PrPSC and therefore various measures have been instituted to minimize the risk of transmission. Since 1998 all blood donated has been leukodepleted (which appears to lessen but not eliminate the prion infectivity) and since 1999 all non-cellular blood products (except fresh frozen plasma and cryoprecipitate) is sourced from the USA and Germany. Individuals who have received a blood transfusion after 1980 are no longer accepted as donors. A blood filtration system which
ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:9
FURTHER READING Aguzzi A, Calella AM. Prions: protein aggregation and infectious diseases. Physiol Rev 2009; 89: 1105e52. Sakudo A, Ikuta K. Prion protein functions and dysfunction in prion diseases. Curr Med Chem 2009; 16: 380e9. Zou S, Fang CT, Schonberger LB. Transfusion transmission of human prion diseases. Transfus Med Rev 2008; 22: 58e69.
371
Ó 2010 Elsevier Ltd. All rights reserved.