human prion diseases Learning Objectives Overview Introduction Subtypes Clinical Features

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Human Prion DiseasesTom Webb

Tom Webb is a specialist registrar in neurology in the Yorkshire and Humber region. Having completed an MD(Res) research degree at the MRC Prion Unit, Queen Square, London, he maintains an interest in this area as well as cognitive neurology and stroke medicine.

Edited by Prof Tom Solomon and Dr Agam Jung

This session provides an overview of human prion diseases with a summary of disease subtypes, when to consider the diagnosis and how to diagnose them,

as well as infection control issues.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Individual sections• References and

further reading• Questions

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Learning Objectives

By the end of this session you will be able to:

• Describe the different subtypes of human prion disease and state their relative frequency

• List the clinical features suggestive of a diagnosis of the different subtypes of human prion disease

• State the commonly available investigations likely to assist in making a diagnosis of human prion disease

• Explain the infection control issues surrounding human prion disease, list sources of further information and referral in the UK

• Describe the importance of genetics in human prion disease, particularly in the context of otherwise undiagnosed hereditary neurodegenerative disease

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Overview

This session explores human prion diseases. Although rare, these diseases are relentlessly progressive, untreatable and catastrophic for those affected. As a result of Bovine Spongiform Encephalopathy (BSE), prion diseases have affected and may continue to affect the UK more than other parts of the world. The sporadic forms of the illness are commoner than most people believe and are almost certainly underdiagnosed, especially in the elderly.

This session first examines the different subtypes of prion disease occurring in humans, focusing on the clinical features suggesting the diagnosis and the investigations which can aid making it.

The session then explains the infection control issues surrounding prion disease, identifying sources of further information and advice.

Finally, it provides a summary of the genetic factors of relevance to prion diseases in general and in particular the genetic forms of the disease.

The first section begins with an overview of prion diseases in all animals.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Introduction

'Prion' is a shortening for the term 'Proteinaceous infectious particles', associated with prion diseases. This term was coined by Stanley Prusiner in the 1980s as part of his work which led to a Nobel Prize in Medicine in 1997. Prion diseases are a group of neurodegenerative diseases affecting humans and mammals. These diseases are uniformly fatal and currently untreatable. Their biology is unique and fascinating, being associated with sporadic, inherited and transmissible forms.

Prion diseases are associated with abnormal conformations in a widely-expressed and highly evolutionarily conserved endogenous protein (the human prion protein). Although the very similar structure of this protein in animals whose most common recent ancestor is tens of millions of years distant suggests a crucial function in vivo, this has not been elucidated as yet.

Colour-enhanced image showing deposition of the abnormal form of the prion protein (PrPSc) in tissue from an animal with scrapie.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease I

Prions identified in 'lower' life forms transmit biological information and can be shared between strains of yeast, but seem to have an adaptive function and not be pathological, raising the possibility that similar non-pathological prions might be present in 'higher' animals.

In humans, prion diseases can be divided into:

• Sporadic• Acquired• Genetic forms

Sporadic prion disease or sporadic Creutzfeldt-Jakob disease is the most frequent form of the disease.

Subtypes of human prion disease. Note that the syndromic names of inherited prion diseases such as familial CJD are less commonly used now, and molecular mutation designations are preferred such as “P102L”.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease II

Sporadic Creutzfeldt-Jakob Disease

Sporadic Creutzfeldt-Jakob disease (CJD) is the most frequent form of the disease. It occurs with a globally similar frequency of around 1-2 cases per million of the population. We would therefore expect to see between 50 and 100 cases in the United Kingdom in a year. Life time risk of developing sCJD may be as high as 1 in 30,000.

The disease can occur at any age although most cases occur in the sixth decade and beyond. Previously, it was thought that the disease frequency declines in old age. This is biologically difficult to explain and contrary to what is seen in neurodegenerative disease in general.

The apparent decline in incidence may be better explained by a lower diagnosis rate in older populations where other forms of dementia are more common and death may occur relatively earlier before the diagnosis is considered.

Coronal FLAIR MRI showing cortical high-signal in a case of sporadic CJD (also sometimes called cortical “ribboning”).

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease IIIa

Variant CJD

Acquired prion diseases comprise variant CJD (vCJD) and iatrogenic forms of the disease where exposure to infected tissue (blood, central nervous system-derived products, or contaminated surgical instruments) is associated with development of the disease.

vCJD was first reported in 1996 in the UK following surveillance specifically looking for evidence of human disease associated with BSE. Globally there have been around 200 cases to date, the majority occurring in UK citizens or in people who resided in the UK at some time. A link with BSE is confirmed by prion strain typing and while the exact route of infection is uncertain a dietary route (as opposed to cosmetic or pharmaceutical products for example) is the likeliest.

Cow affected by BSE.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease IIIb

vCJD Cases

BSE cases have fallen significantly but have not disappeared. There is ongoing concern that a significant proportion of the UK population may be harbouring subclinical or preclinical infection with vCJD. Recently identified cases of transmission of vCJD via blood transfusions has continued to focus efforts to monitor the disease in spite of the fact that so far numbers have not been high.

Some prion scientists remain concerned that the long incubation periods seen in prion disease could lead to new cases occurring (hopefully only in small numbers) for decades to come.

Dark green areas are countries that have confirmed human cases of variant Creutzfeldt-Jakob disease and light green are countries that have bovine spongiform encephalopathy cases.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease IV

Iatrogenic Prion Disease

Iatrogenic prion disease was identified following transmission of sCJD via neurosurgical procedures, dura mater and corneal grafting and the use of cadaver derived growth hormone in the 1970s and 80s. Increased awareness, quarantining of surgical instruments where prion disease is suspected, and the move to recombinant growth hormone means that these cases are becoming rarer. In most, a history of exposure (e.g. to human derived growth hormone) is known and the diagnosis apparent.

The identification of blood-transfusion transmission of vCJD (having received blood products from donors who later developed vCJD) has led to the recognition of a small number of individuals who may be at risk of developing vCJD as a result of having received blood transfusions.

Leucocyte depletion, and the use of blood derived products (for example immunoglobulins) from areas where BSE exposure is much lower aim to reduce the risk of further cases. Techniques designed to screen blood products for abnormal prions are under development.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Subtypes of Human Prion Disease V

Genetic or Inherited Prion Disease

Genetic or inherited prion disease forms around 15% of cases of prion disease and is associated with around 30 known mutations in the prion protein gene. These diseases are inherited in an autosomal dominant fashion and exhibit nearly 100% penetrance in those carrying the abnormal mutation. Although rare, they are probably underdiagnosed as a result of the wide phenotype associated with them.

Traditionally named syndromically (familial CJD, familial fatal insomnia, Gerstmann-Straussler-Scheinker syndrome) the same mutation can present with different syndromes and therefore categorisation by mutation subtype is now more common. Genetic counselling is important in families confirmed to carry mutations associated with inherited prion disease making the involvement of geneticists important. Theoretical risks of disease transmission (confirmed in animal models) also means that affected patients should notify medical staff and be advised not to donate blood or organs. Additional surgical precautions are advisable.      

Protein structure of the normal prion protein (PrP)

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Clinical Features Suggestive of a Diagnosis I

sCJD typically presents with a progressive dementia (often rapidly progressive). Multiple brain regions (pyramidal, extrapyramidal, cerebellar, visual system) are affected leading to a mixture of clinical features.

Initial stageInitially, the condition may mimic stroke, starting with a single apparent lesion site, but spreading to include multiple regions.

Later stagesLater stages of the disease lead to akinetic-mutism. This is a non-specific end point of neurodegenerative disease but myoclonus is often marked and the rapid progression to this point is often suggestive of sCJD.

Disease courseTypically the disease course is months but can be as little as a few weeks to as much as two years (and longer cases with pathological confirmation do exist).

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Clinical Features Suggestive of a Diagnosis II

Younger Age Group

vCJD often begins with a non-specific neuropsychiatric disorder such as depression and or anxiety. Deep-seated unexplained lower limb pain can be seen in early stages. The presentation is classically in a significantly younger age group than sCJD (but cases of vCJD in older people are well recognised).

• AtaxiaAtaxia with initially subtle cognitive decline develops and progresses subacutely.

• Late stage diseaseLate stage disease is also akinetic-mutism with myoclonus.

• Disease courseThe disease course is typically >6 months and previously fit younger patients have survived for years.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Clinical Features Suggestive of a Diagnosis III

Inherited Prion Disease

The clinical features of inherited prion disease are varied and heterogenous, even within the same family, obviously affected by the same mutation. Some present with sCJD-like symptoms, albeit with a longer clinical course.

Other presentations include Huntington's disease-like presentations with movement disorders and cognitive decline as well as a progressive ataxia without significant cognitive impairment in early stages.

This variability can make identification of affected families difficult, especially where more commonly recognised genetic abnormalities are tested for but prove absent.

Family tree of large kindred affected by the P102L mutation in the prion protein gene.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Management Options

Symptomatic treatment

Symptomatic treatment for human prion disease includes the use of low dose atypical antipsychotic medication as well as antiepileptic medication to control myoclonus.

No established treatment has been shown to halt or even slow disease progression in patients. However, recent work on preventing prion replication in vitro and in animal models is becoming promising.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Available Investigations to Assist in Making a Diagnosis of Human Prion Disease I

Routine serological tests are usually unremarkable and therefore unhelpful except in excluding other possible causes of cognitive decline early in the diagnostic process.

EEG recording in sCJD (and sometimes in vCJD and inherited prion disease) can show characteristic abnormalities known as periodic sharp wave complexes. These are useful in typical cases to improve diagnostic certainty but are not specific to prion disease and may not be seen in a single EEG recording early in the disease.

EEG showing periodic sharp wave complexes associated with sCJD

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Available Investigations to Assist in Making a Diagnosis of Human Prion Disease IICT Scans

CT brain scans are usually only helpful in excluding alternative causes of cognitive decline/reduced mobility early on in diagnostic process (e.g. subdural haematoma).

MRI in sCJD can show basal ganglia and cortical high signal. In vCJD characteristic high signal in the thalamus (known as the pulvinar sign) is seen but can also occur in other conditions.

CSF examination for protein 14-3-3 can improve diagnostic certainty in suggestive cases. However, it is a non-specific marker of neuronal cell death and therefore the identification of raised CSF 14-3-3 in otherwise atypical cases may not be helpful.

Axial FLAIR MRI demonstrating high signal in the thalamus, the so-called “pulvinar” sign. Note that the thalamic signal is higher than in the basal ganglia. High signal in the thalamus which is of an equal degree to the basal ganglia is probably not clinically relevant.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Available Investigations to Assist in Making a Diagnosis of Human Prion Disease IIIBiopsy

Tonsil biopsy can be performed in suspected vCJD cases. The discovery of the disease-associated form of the prion protein in clinical cases consistent with vCJD can help confirm the diagnosis. Although some would argue that only identification of the abnormal prion protein in central nervous system tissue confirms the diagnosis, given the rarity of this finding in tonsillectomy tissue screening studies, the co-existence of this with a suggestive clinical picture outside of vCJD is very unlikely.

According to World Health Organization criteria, the only way of confirming human prion disease of any type is by identification of the hallmarks of prion disease in central nervous system tissue either from brain biopsy or on post mortem examination. The classical pathological triad consists of astrocytosis, neuronal cell death and deposition of the disease associated form of the prion protein.

.Tonsil histology after biopsy demonstrating abnormal form of the prion protein identified by immunostaining.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Infection Control Issues Surrounding Human Prion DiseasesCJD appears limited in extent to brain and spinal cord. Only procedures involving those tissues (and by extension CSF) are thought likely to risk transmission of prion disease. Conventional medical and nursing care of patients with suspected sCJD therefore requires only usual infection control precautions.

vCJD has been demonstrated in a wider range of tissues and transmission from blood transfusion confirmed. For this reason more caution is required in patients with suspected vCJD.

In iatrogenic and inherited prion diseases transmission risks are likely to be similar to sCJD and therefore, outside of handling brain, spinal cord or fluid, special precautions are probably not necessary.

.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Sources of Further information and Referral in the UKAny patients suspected to have human prion disease should inform medical professionals and dentists. They should be advised not to donate blood or tissue. In the case of inherited prion disease this may extend to at risk family members who have not been tested for the mutation.

Further advice on these issues is available from the Health Protection Agency, the National CJD Surveillance Unit and the National Prion Clinic. Please see the end of the session for links.

.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Importance of Genetics in Human Prion Disease IA polymorphism in the human prion protein gene affects susceptibility to prion disease. Codon 129 can be:

• Methionine (M) or• Valine (V)

Individuals are therefore MM or VV homozygotes or MV heterozygotes. In the UK the proportions of these genotypes are roughly 40%, 10% and 50% respectively.

Those homozygous for the codon 129 polymorphism are over-represented in sporadic and iatrogenic cases of prion disease. Until recently, all confirmed vCJD cases have occurred in MM homozygotes, although a single case of vCJD in an MV heterozygote has been reported.

There have been suggestions that more people from other genetic groups may be affected, providing a possible explanation for longer incubation periods and a theoretical concern for there being a larger proportion of the population affected by vCJD in the future.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Importance of Genetics in Human Prion Disease IIIn inherited prion disease, the possible syndromic presentations are varied. The differential is wide therefore, and there are more common genetic causes for some of the syndromes (Huntington's, Freidreich's, SCA mutations).

However in cases with clear family history who have tested negative for the more common causes, it is worth screening for prion protein mutations as this is relatively straightforward and inexpensive to perform.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Key Points

• Prion diseases are biologically intriguing

• Human prion diseases are rare but underdiagnosed and of particular relevance to the UK

• The diagnosis of prion disease carries important infection control implications

• Testing the prion protein gene for mutations associated with inherited prion disease is worthwhile in those with inherited dementia or ataxia where more common mutations have not been identified

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Learning Objectives and Further Reading

Having completed this session you will now be able to:• Describe the different subtypes of human prion disease

and state their relative frequency• List the clinical features suggestive of a diagnosis of the different

subtypes of human prion disease• State the commonly available investigations likely to assist in making a

diagnosis of human prion disease• Explain the infection control issues surrounding human prion disease,

list sources of further information and referral in the UK• Describe the importance of genetics in human prion disease,

particularly in the context of otherwise undiagnosed hereditary neurodegenerative disease

Further Reading• National CJD Surveillance Unit. View• National Prion Clinic and MRC Prion Unit. View• 'Variant CJD: where has it gone, or has it?' Bob Will, Pract Neurol

2010; 10: 250–251.• 'Molecular neurology of prion disease' John Collinge, J Neurol

Neurosurg Psychiatry 2005 Jul;76(7):906-19

LinksFurther advice on these issues is available from the Health Protection Agency, the National CJD Surveillance Unit and the National Prion Clinic.

HUMAN PRION DISEASES

• Learning Objectives• Overview• Introduction• Subtypes• Clinical Features• Management Optio

ns• Investigations• Infection Control• Sources of F

urther Information & Referral

• Importance of Genetics

• Key Points• Learning Objectives

and Further Reading

• Self Assessment

Self Assessment

Question 1

Which one of the following statements is correct?

A. Variant CJD is the commonest human prion diseaseB. Prions are formed primarily from DNAC. Inherited prion disease accounts for around 15% of prion dise

ase casesD. Iatrogenic CJD cannot occur via blood transfusion