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Prion diseases
NERVOUS SYSTEM INFECTIONS
Prion diseases
What’s new?
Diego Kaski C
The routine use of new MRI sequences, such as DWI and FLAIR, is increasingly recognized in supporting clinical diagnosis
C
The National Prion Clinic in London is running a longitudinal prospective study collecting data from patients with suspected, confirmed, or at-risk of developing all forms of CJD, which will enable the formulation of a staging system against which future therapies could be monitored, in addition to offering insights into the natural history of the disease
C
Prion-like mechanisms are increasingly described in common neurodegenerative diseases like Parkinson’s and Alzheimer’s disease
Simon Mead
Abstract Human prion diseases are a rare and diverse group of neurodegenerative diseases that have long provoked interest from physicians and scientists. Initially, this related to the enigma of a group of diseases with inherited, sporadic and acquired forms, and then subsequently to the proposition that the infectious agent comprised an abnormally folded but widely expressed cell-surface protein. More recently, the epidemic of bovine spongiform encephalopathy in cattle and its transmission to humans as variant CreutzfeldteJakob disease has raised major public health concerns in the UK and other European countries. From a physician’s perspective, prion diseases should be considered in patients with dementia or ataxia that progresses rapidly or dementia associated with neurological or psychiatric features in the early stages. Diagnostic tests such as CSF analysis, MRI, EEG, genetic testing and tonsil biopsy may be useful. However, a diagnostic blood test and an effective therapy remain elusive.
transmission occurs when the disease-associated prion protein acts as a template that encourages conversion of normal host prion protein.
Sporadic prion disease Epidemiology: about 60 cases of sporadic CJD occur each year in the UK. The incidence is similar worldwide and there is no marked difference between the sexes. Peak incidence is in the seventh decade of life, but the disease has been reported in young adults. Despite extensive investigation, no definite environmental risk factors have been found, although there is some evidence for a risk associated with surgery.
Keywords bovine spongiform encephalopathy; CreutzfeldteJakob disease (CJD); dementia; infections; kuru; nervous system infections; neurodegenerative; prion; pulvinar; tonsil; variant CJD
Clinical features: the core clinical feature of sporadic CJD is rapidly progressive dementia; the duration typically ranges from a few weeks to several months from onset to death. Common accompanying clinical features include cerebellar ataxia, pyramidal tract or extrapyramidal signs and myoclonus. Amyotrophy or cortical blindness occurs less commonly. A pre-morbid state of unresponsiveness is often described as ‘akinetic mutism’.
Prion diseases are a diverse group of human and animal neurodegenerative disorders; examples include sheep scrapie, bovine spongiform encephalopathy (BSE) and human Creutzfeldte Jakob disease (CJD). The pathogenesis of these conditions involves a cell-surface glycoprotein, the prion protein. Human prion diseases may be classified as sporadic, inherited or acquired. Doctors should consider them in patients presenting with rapidly progressive dementia, ataxia, and in those with dementia and additional neurological signs or psychiatric symptoms.
Investigations and diagnosis: investigations of particular help in diagnosis include genetic analysis of the prion protein gene,2 EEG, MRI and CSF examination (for 14-3-3 protein). A definitive diagnosis can be made at post-mortem; typical findings are spongiform change (small holes typically found in the cerebral cortex), neuronal loss and astrocytosis (Figure 1). Prion protein deposition may also be demonstrated by immunocytochemistry and by showing partial protease resistance (a biochemical feature of the disease-associated form) by Western blotting of brain homogenate (Figure 2). The diagnosis of sporadic CJD is in doubt if there is a history of dementia of more than two years’ duration, the typical neurological signs are absent, or there is evidence of inflammation on CSF examination. In two-thirds of patients with definite CJD, EEG shows periodic sharp waves and T2-weighted MRI shows high signal in the caudate and putamen. The combined use of diffusion-weighted imaging (DWI) and FLAIR sequences, using high signal in the cortex and/or striatum as suggestive of sCJD is increasingly thought to be a useful investigation for diagnosis.
Molecular basis of prion diseases The infectious agent of prion disease comprises an abnormal isoform of the prion protein. Normal prion protein is found on cell surfaces throughout the body and predominantly has an alpha helix structure; its function is unknown. The disease form of the protein is largely of beta-sheet structure.1 Prion diseases are transmissible between individuals; it is hypothesized that
Diego Kaski MBBS BSc MRCP is a Clinical Research Fellow at the National Prion Clinic at the National Hospital for Neurology in London, UK. Competing interests: none declared. Simon Mead MBBS MRCP PhD is a Consultant Neurologist and lead clinician at the National Prion Clinic at the National Hospital for Neurology in London, UK. Competing interests: none declared.
MEDICINE 37:11
579
Ó 2009 Published by Elsevier Ltd.
NERVOUS SYSTEM INFECTIONS
Figure 1 Panels a and b show haematoxylin and eosin (H&E) stained sections. a, fine vacuolization, commonly also known as spongiform degeneration or spongiosis. The larger nuclei are neuronal and the smaller nuclei are astrocytic. b, Florid plaque. A round amyloid plaque with a dense core is surrounded by multiple small vesicles. In addition, the cortex in variant CJD may also show variable degrees of spongiosis. c, d: Detection of abnormal prion protein using antibody KG9. c, synaptic pattern of prion protein deposition in sporadic CJD. A fine granular distribution of prion protein and occasional intracellular, dendritic deposition are seen. d, the plaques in vCJD are strongly positive for abnormal PrP, but also synaptic deposits are frequently found. Scale bar, 50 mm.
cerebral vasculopathies (ischaemic, amyloid, inflammatory, vascular lymphoma e multiple white-matter lesions seen on MRI) chronic encephalitis (younger patients, including Hashimoto’s encephalitis, some may be steroid responsive) and subacute sclerosing panencephalitis paraneoplastic encephalitis (normally associated with abnormal CSF, specific antineuronal antibodies and detection of the primary tumour) encephalopathy (e.g. anoxic brain damage e obvious from the history and accompanied by watershed infarction) white-matter diseases (e.g. multiple sclerosis e should be indicated by imaging).
In the UK patients should be referred to the National CJD Surveillance Unit, Edinburgh and the National Prion Clinic, London. Differential diagnosis of sporadic CJD includes: Alzheimer’s disease and other neurodegenerative dementias (usually older patients)
Management: there is no known treatment that delays disease progression; several experimental therapies have failed in clinical studies/trials. A number of drugs may be used to control problematic symptoms. For example, myoclonus may be controlled with clonazepam or levetiracetam. Hallucinations may improve with quetiapine. Nurses and carers should be aware that CJD is not contagious in the conventional sense through routine personal care. Possible transmission by invasive procedures and blood transfusion is an important issue, and guidelines are available (http://www.dh.gov.uk/ab/ACDP/TSEguidance/ index.htm).
Figure 2 Western blot of protease-resistant prion protein showing heterogeneity for molecular weight and predominance of different bands, representing different glycosylation states, in sporadic CJD (1e3) and variant CJD (4) (London classification).
MEDICINE 37:11
580
Ó 2009 Published by Elsevier Ltd.
NERVOUS SYSTEM INFECTIONS
Inherited prion disease
products raises important infection control and public health issues.5
Many insertion and point mutations have been described in the prion protein gene that causes familial prion diseases. All are autosomal dominantly inherited, though some pedigrees exhibit reduced penetrance. Clinical presentation ranges from classical CJD to the slowly progressive, ataxic dementia of Gerstmanne StrausslereScheinker syndrome, or the rapidly progressive insomnia and movement disorder seen in familial fatal insomnia.2
Investigations and diagnosis: EEG is often abnormal, but classic periodic sharp waves are not seen generally. T2-weighted MRI often shows high signal in the posterior thalamus (‘pulvinar sign’). While the patient is alive, definite diagnosis is made by tonsil biopsy to detect abnormal prion protein. Definitive diagnosis at post-mortem requires demonstration of florid amyloid plaques in the cerebrum and cerebellum, typical Western blot findings and prion protein deposition in the lymphoreticular system. vCJD shows a marked predilection for a methionine homozygous for genotype at codon 129 of the prion protein gene. A
Acquired prion disease Iatrogenic Prions have been transmitted by human growth hormone supplements prepared from cadaveric pituitary glands, by corneal and dural grafting, and by brain electrodes; however, such cases are rare. Surgeons need advance notice of patients who may have been exposed to infectious material, even if they are asymptomatic, to take necessary precautions. Variant CJD (vCJD) may be transmitted in blood transfusion and possibly by surgical instruments. To date, three cases of vCJD have been identified in recipients of blood products from asymptomatic donors who later developed vCJD.
REFERENCES 1 Pan KM, Baldwin MA, Nguyen J, et al. Conversion of a-helices into b-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 1993; 90: 10962e6. 2 Mead S. Prion disease genetics. Eur J Hum Genet 2006; 14: 273e81. 3 Collinge J, Sidle KCL, Meads J, et al. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 1996; 383: 685e90. 4 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant CreutzfeldteJakob disease. Ann Neurol 2000; 47: 575e82. 5 Wroe SJ, Pal S, Siddique S, et al. Clinical presentation and pre-mortem diagnosis of variant CreutzfeldteJakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061e7.
Kuru Kuru is a fatal ataxic disease that occurred as a result of ritualistic cannibalism by the Fore people of Papua New Guinea before 1960. The disease may have a remarkably long incubation period and is only now disappearing. vCJD Epidemiology: prion protein typing has shown beyond reasonable doubt that vCJD is the human form of BSE.3 By 2008, more than 160 cases had been described in the UK; the eventual size of the outbreak is unknown, although the peak incidence occurred in 2000 and there has since been a gradual decline. vCJD appears to affect younger individuals than sporadic CJD (typically age 14e50 years), though older patients have been reported.
FURTHER READING Collinge J. Molecular neurology of prion disease. J Neurol Neurosurg Psychiatry 2005; 76(7): 906e19. Poser S, Mollenhauer B, Krauss A, et al. How to improve the clinical diagnosis of CreutzfeldteJakob disease. Brain 1999; 122: 2345e51. (Analysis of the diagnosis of sporadic CJD.)
Clinical features: vCJD presents as a progressive neuropsychiatric disorder (chronic depression, social withdrawal, and occasionally psychotic features) with peripheral pain or dysaesthesia followed by cognitive decline. A number of patients also develop chorea or dystonia; myoclonus is less common.4 Progression is less rapid than in sporadic CJD; the mean duration is 14 months. The demonstration that vCJD can be transmitted via blood
MEDICINE 37:11
Acknowledgements The authors thank Professor John Collinge, Sebastian Brandner, Ray Young and colleagues at the National Prion Clinic and MRC Prion Unit.
581
Ó 2009 Published by Elsevier Ltd.
Prion diseases
What’s new?
Diego Kaski C
The routine use of new MRI sequences, such as DWI and FLAIR, is increasingly recognized in supporting clinical diagnosis
C
The National Prion Clinic in London is running a longitudinal prospective study collecting data from patients with suspected, confirmed, or at-risk of developing all forms of CJD, which will enable the formulation of a staging system against which future therapies could be monitored, in addition to offering insights into the natural history of the disease
C
Prion-like mechanisms are increasingly described in common neurodegenerative diseases like Parkinson’s and Alzheimer’s disease
Simon Mead
Abstract Human prion diseases are a rare and diverse group of neurodegenerative diseases that have long provoked interest from physicians and scientists. Initially, this related to the enigma of a group of diseases with inherited, sporadic and acquired forms, and then subsequently to the proposition that the infectious agent comprised an abnormally folded but widely expressed cell-surface protein. More recently, the epidemic of bovine spongiform encephalopathy in cattle and its transmission to humans as variant CreutzfeldteJakob disease has raised major public health concerns in the UK and other European countries. From a physician’s perspective, prion diseases should be considered in patients with dementia or ataxia that progresses rapidly or dementia associated with neurological or psychiatric features in the early stages. Diagnostic tests such as CSF analysis, MRI, EEG, genetic testing and tonsil biopsy may be useful. However, a diagnostic blood test and an effective therapy remain elusive.
transmission occurs when the disease-associated prion protein acts as a template that encourages conversion of normal host prion protein.
Sporadic prion disease Epidemiology: about 60 cases of sporadic CJD occur each year in the UK. The incidence is similar worldwide and there is no marked difference between the sexes. Peak incidence is in the seventh decade of life, but the disease has been reported in young adults. Despite extensive investigation, no definite environmental risk factors have been found, although there is some evidence for a risk associated with surgery.
Keywords bovine spongiform encephalopathy; CreutzfeldteJakob disease (CJD); dementia; infections; kuru; nervous system infections; neurodegenerative; prion; pulvinar; tonsil; variant CJD
Clinical features: the core clinical feature of sporadic CJD is rapidly progressive dementia; the duration typically ranges from a few weeks to several months from onset to death. Common accompanying clinical features include cerebellar ataxia, pyramidal tract or extrapyramidal signs and myoclonus. Amyotrophy or cortical blindness occurs less commonly. A pre-morbid state of unresponsiveness is often described as ‘akinetic mutism’.
Prion diseases are a diverse group of human and animal neurodegenerative disorders; examples include sheep scrapie, bovine spongiform encephalopathy (BSE) and human Creutzfeldte Jakob disease (CJD). The pathogenesis of these conditions involves a cell-surface glycoprotein, the prion protein. Human prion diseases may be classified as sporadic, inherited or acquired. Doctors should consider them in patients presenting with rapidly progressive dementia, ataxia, and in those with dementia and additional neurological signs or psychiatric symptoms.
Investigations and diagnosis: investigations of particular help in diagnosis include genetic analysis of the prion protein gene,2 EEG, MRI and CSF examination (for 14-3-3 protein). A definitive diagnosis can be made at post-mortem; typical findings are spongiform change (small holes typically found in the cerebral cortex), neuronal loss and astrocytosis (Figure 1). Prion protein deposition may also be demonstrated by immunocytochemistry and by showing partial protease resistance (a biochemical feature of the disease-associated form) by Western blotting of brain homogenate (Figure 2). The diagnosis of sporadic CJD is in doubt if there is a history of dementia of more than two years’ duration, the typical neurological signs are absent, or there is evidence of inflammation on CSF examination. In two-thirds of patients with definite CJD, EEG shows periodic sharp waves and T2-weighted MRI shows high signal in the caudate and putamen. The combined use of diffusion-weighted imaging (DWI) and FLAIR sequences, using high signal in the cortex and/or striatum as suggestive of sCJD is increasingly thought to be a useful investigation for diagnosis.
Molecular basis of prion diseases The infectious agent of prion disease comprises an abnormal isoform of the prion protein. Normal prion protein is found on cell surfaces throughout the body and predominantly has an alpha helix structure; its function is unknown. The disease form of the protein is largely of beta-sheet structure.1 Prion diseases are transmissible between individuals; it is hypothesized that
Diego Kaski MBBS BSc MRCP is a Clinical Research Fellow at the National Prion Clinic at the National Hospital for Neurology in London, UK. Competing interests: none declared. Simon Mead MBBS MRCP PhD is a Consultant Neurologist and lead clinician at the National Prion Clinic at the National Hospital for Neurology in London, UK. Competing interests: none declared.
MEDICINE 37:11
579
Ó 2009 Published by Elsevier Ltd.
NERVOUS SYSTEM INFECTIONS
Figure 1 Panels a and b show haematoxylin and eosin (H&E) stained sections. a, fine vacuolization, commonly also known as spongiform degeneration or spongiosis. The larger nuclei are neuronal and the smaller nuclei are astrocytic. b, Florid plaque. A round amyloid plaque with a dense core is surrounded by multiple small vesicles. In addition, the cortex in variant CJD may also show variable degrees of spongiosis. c, d: Detection of abnormal prion protein using antibody KG9. c, synaptic pattern of prion protein deposition in sporadic CJD. A fine granular distribution of prion protein and occasional intracellular, dendritic deposition are seen. d, the plaques in vCJD are strongly positive for abnormal PrP, but also synaptic deposits are frequently found. Scale bar, 50 mm.
cerebral vasculopathies (ischaemic, amyloid, inflammatory, vascular lymphoma e multiple white-matter lesions seen on MRI) chronic encephalitis (younger patients, including Hashimoto’s encephalitis, some may be steroid responsive) and subacute sclerosing panencephalitis paraneoplastic encephalitis (normally associated with abnormal CSF, specific antineuronal antibodies and detection of the primary tumour) encephalopathy (e.g. anoxic brain damage e obvious from the history and accompanied by watershed infarction) white-matter diseases (e.g. multiple sclerosis e should be indicated by imaging).
In the UK patients should be referred to the National CJD Surveillance Unit, Edinburgh and the National Prion Clinic, London. Differential diagnosis of sporadic CJD includes: Alzheimer’s disease and other neurodegenerative dementias (usually older patients)
Management: there is no known treatment that delays disease progression; several experimental therapies have failed in clinical studies/trials. A number of drugs may be used to control problematic symptoms. For example, myoclonus may be controlled with clonazepam or levetiracetam. Hallucinations may improve with quetiapine. Nurses and carers should be aware that CJD is not contagious in the conventional sense through routine personal care. Possible transmission by invasive procedures and blood transfusion is an important issue, and guidelines are available (http://www.dh.gov.uk/ab/ACDP/TSEguidance/ index.htm).
Figure 2 Western blot of protease-resistant prion protein showing heterogeneity for molecular weight and predominance of different bands, representing different glycosylation states, in sporadic CJD (1e3) and variant CJD (4) (London classification).
MEDICINE 37:11
580
Ó 2009 Published by Elsevier Ltd.
NERVOUS SYSTEM INFECTIONS
Inherited prion disease
products raises important infection control and public health issues.5
Many insertion and point mutations have been described in the prion protein gene that causes familial prion diseases. All are autosomal dominantly inherited, though some pedigrees exhibit reduced penetrance. Clinical presentation ranges from classical CJD to the slowly progressive, ataxic dementia of Gerstmanne StrausslereScheinker syndrome, or the rapidly progressive insomnia and movement disorder seen in familial fatal insomnia.2
Investigations and diagnosis: EEG is often abnormal, but classic periodic sharp waves are not seen generally. T2-weighted MRI often shows high signal in the posterior thalamus (‘pulvinar sign’). While the patient is alive, definite diagnosis is made by tonsil biopsy to detect abnormal prion protein. Definitive diagnosis at post-mortem requires demonstration of florid amyloid plaques in the cerebrum and cerebellum, typical Western blot findings and prion protein deposition in the lymphoreticular system. vCJD shows a marked predilection for a methionine homozygous for genotype at codon 129 of the prion protein gene. A
Acquired prion disease Iatrogenic Prions have been transmitted by human growth hormone supplements prepared from cadaveric pituitary glands, by corneal and dural grafting, and by brain electrodes; however, such cases are rare. Surgeons need advance notice of patients who may have been exposed to infectious material, even if they are asymptomatic, to take necessary precautions. Variant CJD (vCJD) may be transmitted in blood transfusion and possibly by surgical instruments. To date, three cases of vCJD have been identified in recipients of blood products from asymptomatic donors who later developed vCJD.
REFERENCES 1 Pan KM, Baldwin MA, Nguyen J, et al. Conversion of a-helices into b-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A 1993; 90: 10962e6. 2 Mead S. Prion disease genetics. Eur J Hum Genet 2006; 14: 273e81. 3 Collinge J, Sidle KCL, Meads J, et al. Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 1996; 383: 685e90. 4 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant CreutzfeldteJakob disease. Ann Neurol 2000; 47: 575e82. 5 Wroe SJ, Pal S, Siddique S, et al. Clinical presentation and pre-mortem diagnosis of variant CreutzfeldteJakob disease associated with blood transfusion: a case report. Lancet 2006; 368: 2061e7.
Kuru Kuru is a fatal ataxic disease that occurred as a result of ritualistic cannibalism by the Fore people of Papua New Guinea before 1960. The disease may have a remarkably long incubation period and is only now disappearing. vCJD Epidemiology: prion protein typing has shown beyond reasonable doubt that vCJD is the human form of BSE.3 By 2008, more than 160 cases had been described in the UK; the eventual size of the outbreak is unknown, although the peak incidence occurred in 2000 and there has since been a gradual decline. vCJD appears to affect younger individuals than sporadic CJD (typically age 14e50 years), though older patients have been reported.
FURTHER READING Collinge J. Molecular neurology of prion disease. J Neurol Neurosurg Psychiatry 2005; 76(7): 906e19. Poser S, Mollenhauer B, Krauss A, et al. How to improve the clinical diagnosis of CreutzfeldteJakob disease. Brain 1999; 122: 2345e51. (Analysis of the diagnosis of sporadic CJD.)
Clinical features: vCJD presents as a progressive neuropsychiatric disorder (chronic depression, social withdrawal, and occasionally psychotic features) with peripheral pain or dysaesthesia followed by cognitive decline. A number of patients also develop chorea or dystonia; myoclonus is less common.4 Progression is less rapid than in sporadic CJD; the mean duration is 14 months. The demonstration that vCJD can be transmitted via blood
MEDICINE 37:11
Acknowledgements The authors thank Professor John Collinge, Sebastian Brandner, Ray Young and colleagues at the National Prion Clinic and MRC Prion Unit.
581
Ó 2009 Published by Elsevier Ltd.