PRION DISEASES. RSGKnight,RGWill. i36. copyright.

Transcription

1 i36 PRION See end of artile for authors affiliations Correspondene to: Dr Rihard Knight, National CJD Surveillane Unit, Bryan Matthews Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK; P PRION DISEASES RSGKnight,RGWill J Neurol Neurosurg Psyhiatry 2004; 75(Suppl I):i36 i42. doi: /jnnp rion diseases or transmissible spongiform enephalopathies (table 1) are haraterised by the deposition of PrP S, an abnormal form of a normal ellular protein, PrP C. These diseases exist in sporadi (idiopathi), geneti, and aquired forms. PROTEIN The normal prion protein, PrP C, is enoded by the prion gene (PRNP) on human hromosome 20, with equivalent prion genes in animals. The funtion of PrP C is not known but it may have roles in anti-oxidant systems and ellular opper metabolism. In prion diseases, the normal host gene produes the normal host PrP C but there is then an inompletely understood post-translational onformational hange to a disease related form, PrP S. PrP S is relatively insoluble and relatively protease resistant, and aumulates in tissues forming amyloid strutures. The preise pathogenesis of the neurologial illness is not known, but PrP S deposition is assoiated with the neuropathologial hanges of neuronal loss, astroyti gliosis, and spongiform hange (fig 1). In the aquired prion diseases, material from an affeted host infets another. The infetive agent (termed the prion ) has not been fully haraterised, but PrP S is assoiated with infetivity. Sine the prion protein has suh a entral role, it is not surprising to find that the prion protein gene, PRNP, is also important (even in non-geneti forms of TSE). In human prion diseases, a ommon polymorphism at odon 129 has important effets on suseptibility to disease, the resulting linial harateristis and the inubation period (in aquired forms). At odon 129 of PRNP, an individual may enode for methionine (M) or valine (V) and, therefore, all humans are MM or VV homozygotes or MV heterozygotes. In the normal UK population, the distributions are approximately: MM 40%, VV 10%, MV 50%. Some effets of this polymorphism are disussed in speifi setions below. Two basi fats illustrate the potential importane of this polymorphism: approximately 80% of UK sporadi CJD ases and, to date, all ases of variant CJD, are MM (table 2). This review is onerned with those human prion diseases of relevane to linial neurologial pratie in the UK: Creutzfeld-Jakob disease (CJD), Gerstmann-Sträussler-Sheinker syndrome (GSS), and fatal familial insomnia (FFI). These diseases are very rare but, nonetheless, are of importane and interest. SPORADIC CJD What is sporadi CJD? Most ases of CJD our on a sporadi, worldwide basis without any urrently reognised geneti, iatrogeni or other ause, affeting approximately one person per million per year. Sporadi CJD (scjd) is generally regarded as a spontaneous neurodegenerative illness, arising from either a spontaneous PRNP gene somati mutation or a stohasti PrP protein strutural hange. In either ase, one would expet a ontinuously inreasing inidene with inreasing age, yet, harateristially, scjd has a peak inidene in the seventh deade, with a deline in the very elderly (fig 2). In reent epidemiologial studies, inluding in the UK, there has been an inrease in the inidene in the elderly, and there may have been under-asertainment of ases in this age group. scjd ould be an aquired illness despite failures to identify a definite external ause; two reent ase ontrol studies (in Australia and the UK) have found a relative exess of previous surgery in the ases. Naturally, scjd may not be aetiologially homogenous, with possibly some ases being spontaneous and others possibly being iatrogeni. To date, there is no evidene to support a dietary ause. As stated above, being odon 129 MM is learly a risk fator for sporadi CJD, with MV heterozygosity affording a partial protetion (80% of ases and 40% of normal UK population being MM; 10% of ases and 50% of the normal UK population being MV) (table 2). J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

2 Table 1 Prion diseases Animal diseases Notes Human diseases Notes Srapie Naturally ourring disease of sheep and goats Kuru Confined to Papua New Guinea Related to annibalisti mourning rituals TME Transmissible mink enephalopathy, a disease of farmed mink CWD Chroni wasting disease of deer, onfined to North Ameria BSE Bovine spongiform enephalopathy, disease of attle first reported 1987 BSE related diseases Transmission of BSE to ats (FSE) and other animals What is sporadi CJD like? scjd typially presents with a rapidly progressive dementia. Other neurologial features appear inluding erebellar ataxia and, most harateristially, myolonus. The speed of progression often alarms relatives or friends and may surprise the liniian; initial investigation plans may well be overtaken by linial developments. In some ases, the onset is so abrupt as to suggest a stroke, although the subsequent progressive ourse will ause the liniian to reonsider. The ability to walk and speak is often lost early. In a typial ase, the progression ulminates in a terminal akineti mute state with myolonus. There is linial heterogeneity in scjd, espeially at the onset when partiular foal defiits may be present. Highly atypial linial profiles have been reported but suh ases are relatively rare instanes of an already very rare disease. However, linial neurologists should be at least aware of two speifi variations: firstly, presentation with an isolated, progressive erebellar syndrome over several weeks, or oasionally longer, before the appearane of other features inluding dementia seondly, presentation with isolated, progressive visual disturbane ulminating in ortial blindness. The basis for this linial heterogeneity (whih is paralleled to some degree by variations in the neuropathology) is not entirely understood and a detailed disussion is outwith the remit of this review. However, it does, in part, reflet different CJD The most ommon human prion disease. First desribed in 1921 Exists in four forms: Sporadi Geneti Iatrogeni Variant (desribed 1996) GSS Gerstmann-Sträussler-Sheinker syndrome, a rare autosomal dominant hereditary disease FFI Fatal familial insomnia, a rare autosomal dominant hereditary disease odon 129 genotypes, or the type of prion protein deposited in the brain. The median duration of illness in scjd is four months, with around two thirds dying within six months. Fourteen per ent of ases have illness durations of a year or more, and only 5% of two years or more (fig 3). As a general guide, if an individual is still able to walk and talk at a year, then scjd is unlikely. How do I diagnose scjd? The diagnosis should be onsidered in any individual presenting with a rapidly progressive dementia (harateristially developing over weeks) when other more ommon auses have been exluded. The early presene of other neurologial features (espeially erebellar or visual) is helpful, and the development of myolonus is harateristi (although not invariable and, of ourse, not unique to CJD). A general outline of the diagnosti proess is given in table 3. Table 2 PrP odon 129 genotype distributions MM (%) MV (%) VV (%) Normal population scjd (UK ) vcjd Figure 1 Neuropathologial hanges in Creutzfeld-Jakob disease (CJD). (A) scjd: spongiform hange in the frontal ortex (haematoxylin and eosin). (B) scjd: erebral PrP deposition (KG9 antibody). (C) vcjd: thalamus showing glioti hange (glial fibrillary aidi protein antibody). Courtesy of James Ironside and Linda MCardle, National CJD Surveillane Unit. i37 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

3 i38 It is ritial to exlude other possible diagnoses. Quite aside from non-cjd illnesses, it is important to onsider geneti, iatrogeni, and variant forms of CJD. This requires onsideration of the linial profile, a detailed past medial history (to over potential iatrogeni auses), a areful family history, geneti testing, and the use of investigations. There are three investigations of partiular diagnosti utility: the eletroenephalogram (EEG), erebrospinal fluid (CSF) , and magneti resonane imaging (MRI). A definite diagnosis requires neuropathology, but a high degree of linial onfidene an be ahieved in most ases. There are published linial diagnosti riteria (also available on and any ase lassified as probable, aording to these riteria, has around a 95% likelihood of having sporadi CJD. This requires a orret understanding of the riteria and a areful linial assessment, but it represents a greater degree of ertainty that is attahed to the use of the term probable in the linial diagnosis of many other neurologial onditions! Cerebral biopsy an, of ourse, provide neuropathologial onfirmation in life. However, it should be onsidered only if there is a reasonable possibility of it onfirming an alternative, potentially treatable disease, and it is only rarely neessary. Table 3 Diagnosis of sporadi CJD Awareness of scjd A rapidly progressive dementia Other early neurologial features (espeially erebellar or visual) Myolonus Exlusion of other diagnoses (inluding other forms of CJD) MRI Exlusion of other diagnoses Findings suggestive of scjd EEG Periodi disharges CSF Exlusion of other diagnoses (e.g. no pleoytosis) Positive EEG The EEG shows a progressive deterioration in the normal bakground rhythms and, in around two thirds of ases, the appearane of periodi sharp wave omplexes (PSWCs) (fig 4). These important points should be noted: Figure 2 Age at death of variant and sporadi CJD in the UK by five year age groups. The absene of PSWCs does not exlude the diagnosis PSWCs may be present in other onditions (for example, hepati enephalopathy, drug toxiity and, rarely, Alzheimer s disease) If PSWCs are absent on an initial EEG, repeat EEGs may show their development (repeat testing should be onsidered at around weekly intervals) CSF CSF is a normal neuronal protein that has no speifi onnetion to CJD, being released into the CSF following neuronal damage. It is, therefore, perhaps surprising that it has speifi diagnosti utility in CJD. However, many of the onditions that ause elevated CSF onentrations an be reasonably readily differentiated from sporadi CJD on linial grounds. A positive test may therefore strongly support a linial diagnosis of scjd, but the reported speifiity and sensitivity (both around 94%) are valid only in an appropriate linial ontext. CSF is useful in ases where scjd is a sensible possibility and other possibilities have already been exluded by reasonable neurologial assessment and investigation. The CSF will almost ertainly be examined in any ase in the exlusion of other diagnoses: the test does not usually require a separate investigation, providing CSF has been stored. There is a national laboratory servie run by the National CJD Surveillane Unit (NCJDSU) in Edinburgh (ontat details below). MRI Cerebral imaging is a vital part of the exlusion of other diagnoses, and normal brain imaging, in the fae of a rapidly progressive, devastating enephalopathy, may lead to a onsideration of scjd. However, in some ases, the MRI J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

4 Figure 3 shows a harateristi signal hange in the putamen and audate (fig 5). Oasionally, high signal may be seen in the erebral ortex, generally foal and refleting the partiular linial features at the time of imaging. Signifiant atrophy is unusual if imaging is undertaken within three months of disease onset. GENETIC PRION DISEASES What are geneti prion diseases? The basi definition of geneti prion disease is simple: disease related to an underlying mutation of the prion protein gene (PRNP) on human hromosome 20. However, there are a signifiant number of reognised mutations and a wide variety of linial illness phenotypes. The resulting omplexity is inreased by the use of disease labels (partly eponymous) that have probably outlived their pratial utility (table 4). The underlying abnormalities are point mutations (suh as E200K) and insertions (suh as ins24bp). The latter our in a region of the gene that enodes for a funtionally important otapeptide repeat part of PrP. Insertions in this region lead to expansions of the otapeptide repeat number Table 4 Duration of illness (months) in variant and sporadi CJD. Geneti prion diseases and mutations Geneti prion diseases Geneti CJD FFI GSS Assoiated PRNP mutations E200K, V180I, T183A, H208R, P102L, D178N, M232R, V210I, F198S, 145stop, A117V, Q217R, Q212P Ins24bp, ins48bp, ins96bp, ins120bp, Ins144bp, ins168bp, ins216bp, ins192bp and the size of the insertion affets the linial phenotype (as in Huntington s disease). In general, other geneti fators (partiularly the odon 129 polymorphism) may influene the linial phenotype (inluding age of onset and illness duration) resulting from a given mutation. Most notably, the D178N mutation gives rise to the linial piture of geneti CJD when assoiated with 129-V on the mutant allele and yet results in FFI when assoiated with 129-M. This fat illustrates how the lassial nomenlature of geneti prion diseases should perhaps be abandoned in the light of modern moleular understanding. Overall, the most ommon mutation is E220K. There are important partiular foi of geneti prion disease, most partiularly in Israel, Slovakia, and Chile. In the UK, there are only a few deaths per year from geneti prion disease. Figure 4 CJD. The typial periodi EEG seen in many ases of sporadi i39 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

5 i40 What are they like? Geneti prion diseases are very rare and a detailed desription of their varied linial features is not appropriate for this review. Geneti CJD aused by a point mutation may have a linial profile not dissimilar to that of scjd, although with a lower mean age of onset and a longer mean duration. GSS, in its lassial form, tends to present with a progressive erebellar ataxia, although the definition of GSS has beome a little onfused and inreasingly neuropathologial in nature. FFI presents with prominent sleep and autonomi disturbanes. A few important general points an be made: The linial phenotype of geneti prion disease, inluding the age of onset and illness duration, is extremely variable arising partly (but not entirely) from the different ausative mutations. The linial piture may not be uniform within a given pedigree Many ases of geneti prion disease may be linially indistinguishable from non-geneti forms A family history of geneti prion disease may not be present (for a variety of reasons) These diseases are of autosomal dominant inheritane Penetrane is typially high and age dependant, but variable. In the ase of E220K, penetrane is reported to be 0.45 by the age of 60 years and 0.96 by 80+ The urrent view is that the underlying mutations are diretly ausal, requiring no external fator for disease. However, the possibility that there are suseptibility fators determining response to some ommon (unidentified) environmental fator annot be entirely dismissed. How do I diagnose geneti prion disease? The fat that a family history may not be present, ombined with the linial variability and the potential for mimiking Table 5 Diagnosis of geneti prion disease Awareness of possibility Awareness of linial Diagnosis of a prion disease (linially phenotypi variability or neuropathologially) Exlusion of other diagnoses Family history Blood test: PRNP mutation sreening Figure 5 Magneti resonane imaging in CJD. (A) scjd: axial FLAIR image at the level of the basal ganglia showing symmetrial high signal in the audate head and anterior putamen (arrows). (B) vcjd: axial FLAIR image at the level of the basal ganglia showing symmetrial high signal in the pulvinar and dorsomedial nulei of the thalamus (arrows). Courtesy of David Summers, National CJD Surveillane Unit. scjd, has one lear impliation: geneti prion disease annot be absolutely exluded unless speifi geneti testing is undertaken. Table 5 presents an outline of the diagnosis. Essentially, one has to suspet a prion disease, obtain a areful family history, and to undertake geneti testing for a reognised PRNP mutation. IATROGENIC CJD What is iatrogeni CJD? Over the past 30 years about 300 ases of CJD have been aused by the transmission of infetion from person to person in the ourse of medial or surgial treatments. The first ase was desribed in 1974 and involved the development of CJD 18 months after the insertion of a orneal graft obtained from a patient who themselves had died of CJD; shortly after this two ases linked to depth EEG eletrodes were identified. In retrospet, transmission of CJD via neurosurgial instruments probably ourred in the 1950s in three ases operated on in the same theatre with instruments previously used in ases of CJD. In the 1980s iatrogeni transmission via human pituitary growth hormone and human dura mater grafts was reognised. Human pituitary hormones were produed from pools ontaining many thousands of adaveri glands and the presumption is that pituitaries from patients with CJD were inadvertently inluded in the prodution proess. Human dura mater grafts were also obtained from adavers and the great majority of ases of CJD linked to this treatment were given a speifi brand of dura, Lyodura. There may have been pooling of glands during prodution with the potential for ross ontamination from a sample of dura mater obtained from a patient with CJD. Variation at odon 129 of PRNP influenes suseptibility to iatrogeni CJD. In ases related to infetion in or adjaent to the brain for example, dura mater grafts odon 129MM is a risk fator, but with peripheral infetion for example, pituitary hormone treatment (whih was administered by injetion) homozygosity, either MM or VV, is a risk fator. What is iatrogeni CJD like? The linial presentation of iatrogeni CJD is determined by the route of exposure. In ases with effetive inoulation into the entral nervous system (CNS) for example, via neurosurgial instruments the linial features are J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

6 indistinguishable from sporadi CJD, with rapidly progressive dementia and myolonus. Survival is usually measured in months. With a peripheral route, suh as human pituitary hormone treatment, there is initially a progressive erebellar syndrome, usually affeting gait in partiular, and other foal signs suh as myolonus only develop later in the linial ourse. Cognitive impairment and/or dementia our only rarely and in many ases meaningful ommuniation is possible until the terminal stages. The mean survival is about a year. In ases related to human dura mater grafts there is heterogeneity, with many ases presenting with linial features similar to sporadi CJD, although in some ases there is early ataxia and relatively prolonged survival. The fat that the linial presentation in iatrogeni CJD is influened by the route of exposure is of sientifi interest as kuru, the disease in Papua New Guinea linked to ritual annibalism, is aused by a peripheral route of exposure and also presents with a predominant erebellar syndrome. That diret CNS infetion results in a linial piture similar to sporadi CJD may be an argument in support of the hypothesis that sporadi CJD develops following the spontaneous generation of disease assoiated prion protein in the brain. How do I diagnose iatrogeni CJD? Cases of iatrogeni CJD may be missed without an awareness of the relevant risk fators, and obtaining a history of potentially relevant exposures is ritial to raising the possibility of a diagnosis of iatrogeni CJD. In ases of suspet CJD and in patients with an unexplained progressive neurologial disorder, speifi enquiry should be made about previous neurosurgial or eye operations and about prior pituitary hormone treatment. In ases with a potential iatrogeni risk fator it is essential to arry out appropriate investigation as neurologial deterioration may reflet a reurrene of the ondition for whih the original treatment was given rather than CJD. For example, human growth hormone treatment may have been given following resetion of a primary brain tumour and reurrene may result in a linial piture similar to iatrogeni CJD, partiularly if the tumour is in the erebellum. Reommendations for the investigation of iatrogeni CJD are the same as for sporadi ases. The EEG may show periodi omplexes in ases with entral infetion, but these appearanes are rarely, if ever, found in pituitary hormone related CJD. There is limited information on the utility of CSF assay in iatrogeni CJD, but there are preliminary data to suggest that this investigation an be helpful in all forms of iatrogeni CJD, inluding ases related to growth hormone treatment. There are also limited data on MRI san, but high signal in the putamen and audate have been found in a signifiant proportion of growth hormone related ases. VARIANT CJD What is variant CJD? In ases of CJD were identified in the UK with novel linial and pathologial features, and it was hypothesised that this new variant of CJD (now alled variant CJD) was aused by human infetion with bovine spongiform enephalopathy (BSE). Subsequent researh, inluding laboratory transmission studies in mie, has provided onvining evidene that variant CJD is indeed aused by the BSE agent; the failure to find ases of CJD with a similar phenotype in arhives in the UK and other ountries strongly Table 6 Differenes between sporadi and variant CJD scjd vcjd Mean age at death 66 years 29 years Median duration of 4 months 14 months illness Thalami MRI high Caudate/putamen Pulvinar 90% signal 60% EEG Typial 70% Typial 0% Neuropathology Plaques 10% Florid plaques 100% supports the hypothesis that this is indeed a new disease. To date over 140 ases of variant CJD have been identified in the UK and a small number of ases have been found in other ountries, inluding Frane, Ireland, Italy, the USA, and Canada. It is of note that, although some of these ases may have been exposed to BSE infetion indigenously, the single ases in the USA and Canada had a history of residene in the UK in the 1980s when human exposure to BSE was most likely. The favoured hypothesis is that variant CJD is the result of infetion through dietary exposure to BSE and probably to bovine CNS tissues, whih ontained high levels of infetivity in the 1980s. There was onern about the possibility of a major epidemi of variant CJD; although there remain many unertainties, reent analyses suggest that the annual mortality rate in the UK may have peaked. All tested ases of variant CJD, to date, have been odon 129MM. It is, however, possible that ases with an alternative odon 129 genotype may our in the future as variations at this lous an influene inubation period. There is also the possibility that the linial and pathologial features in suh ases might differ from variant CJD with an MM bakground. What is variant CJD like? Variant CJD affets young people, with a mean age at death of 29 years (range years) in ontrast to a mean age at death in sporadi CJD of 65 years (fig 2). The early linial ourse is dominated by psyhiatri symptoms, inluding depression, withdrawal, and anxiety, although a minority of ases have early neurologial symptoms in the form of ognitive impairment and, notably, persistent painful sensory symptoms. After a mean of six months ataxia develops and this is assoiated with involuntary movements, whih may be horeiform, dystoni, or myoloni. There is progressive ognitive impairment and other foal signs may our, inluding dysphasia, rigidity, hyperreflexia, and primitive reflexes. The later stages are similar to sporadi CJD, with terminal akineti mutism in many ases. The mean survival is 14 months, but some patients have survived over three years from the first symptom (fig 3). How do I diagnose variant CJD? Early diagnosis of variant CJD may be impossible as the psyhiatri features are indistinguishable from ommon psyhiatri disorders. In a minority of ases the ombination of psyhiatri symptoms with painful sensory symptoms and/ or ognitive problems may raise the suspiion of an underlying neurologial disorder, but the possibility of a diagnosis of variant CJD usually depends on the evolution of neurologial features and, in partiular, the development of ataxia and involuntary movements. The ombination of early i41 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.

7 i42 psyhiatri symptoms followed by progressive ognitive and neurologial deterioration should raise the possibility of the diagnosis of variant CJD. The EEG never shows periodi omplexes in variant CJD and the CSF assay is positive in only about 50% of ases. The MRI san is the most helpful non-invasive investigation, showing high signal in the posterior thalamus, the pulvinar sign, on T2 and espeially FLAIR sequenes in about 90% of ases (fig 5). Diagnosti riteria for variant CJD have been formulated (available on and, to date, a diagnosis of probable variant CJD has had 100% speifiity. Tonsil biopsy may allow the identifiation of the disease assoiated prion protein, but, like brain biopsy, is an invasive proedure with potential risks. Table 6 lists some important distintions between variant and sporadi CJD. WHAT SHOULD I DO? The potential for iatrogeni transmission of sporadi CJD underlines the importane of human prion diseases for publi health. The risks from variant CJD may be greater beause the disease assoiated prion protein is found at higher levels in lymphoretiular tissues in this ondition than in other human prion diseases, and a number of poliies have been instituted to redue the risk of onward transmission for example, universal leuodepletion of blood donations. CJD is not a notifiable disease, but there is a need to follow guidelines to protet publi health. The Department of Health has reently issued revised advie, whih is available at Of partiular importane is the reommendation to inform the loal onsultant in ommuniable disease ontrol of any suspet ase of CJD and to inform the CJD Inidents Panel (CJD Inidents Panel, Health Protetion Ageny, CDSC, 61 Colindale Avenue, London NW9 5EQ; tel ex8074, fax ) of any ase of CJD in whih there is a risk that surgial instruments may have been ontaminated and re-used. There is no proven treatment for CJD. Press reports of a benefit from treatment with quinarine and/or hlorpromazine have not been substantiated on the basis of anedotal reports and a review by the Frenh drug ageny (available on Following a High Court hearing pentosan polysulfate has been given to one patient by intraventriular infusion (this drug does not ross the blood brain barrier), but the outome is not yet known. Sine 1990 the Department of Health has funded the National CJD Surveillane Unit with a remit to study the linial harateristis, neuropathology, and epidemiology of CJD. The national CSF laboratory is situated within the unit. All ases of suspet CJD should be referred to: National CJD Surveillane Unit, Bryan Matthews Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU; tel , fax ; r.knight@ed.a.uk or r.g.will@ed.a.uk. A National Care Pakage for all forms of CJD is also based at the unit, with a remit to optimise the are of patients with CJD and their families. The ontat details are: National Care Team, National CJD Surveillane Unit, Bryan Matthews Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU; tel ; fax ; susan.madonald@ed.a.uk Support for patients and their families is also available from the following organisations: Mrs Gillian Turner, CJD Support Network, PO Box 346, Market Drayton, Shropshire, TF9 4WN; tel Helpline; info@jdsupport.net Mrs Franes Hall, Human BSE Foundation Helpline, 99 Warkworth Avenue, Chester Le Street, County Durham, DH2 3TW; tel /4004; fax ; hbsef@btinternet.om The Prion Researh Group at the National Hospital, Queen Square and the Prion Clini at St Mary s Hospital have a longstanding interest in researh in many aspets of human prion disease, inluding basi sientifi researh, geneti disease, and treatment trials. Contat details are: Dr Angus Kennedy, National Prion Clini, Department of Neurology, St Mary s Hospital, Praed Street, London W2 1NY; tel (0207) or 6883; fax (0207) ; help.prion@st-marys.nhs.uk Professor J Collinge, MRC Prion Unit, Department of Neurodegenerative Diseases, National Hospital for Neurology & Neurosurgery, Queen Square, London WC1N 3BG; tel (0207) National Hospital; fax (0207) ; j.ollinge@prion.ul.a.uk... Authors affiliations R S G Knight, R G Will, National CJD Surveillane Unit, Western General Hospital, Edinburgh, UK REFERENCES 1 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant Creutzfeldt- Jakob disease. Ann Neurol 2000;47: A review of the diagnosis of vcjd, inluding the internationally adopted linial diagnosti riteria. Contains details of the linial features and the utility of investigations, partiularly the MRI. 2 Collie DA, Sellar RJ, Zeidler M, et al. MRI of Creutzfeldt-Jakob disease: imaging features and reommended MRI protool. Clin Radiol 2001;56: A review of the MRI findings in CJD, inluding reommended imaging protools. Contains useful examples of images. 3 Brown P, Preee M, Brandel J-P, et al. Iatrogeni Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55: A omprehensive review of iatrogeni CJD, listing all reported ases (as at 2000) with disussion of linial features, and a referene list of partiular ase reports and other relevant papers. 4 Kovas GG, Trabattoni G, Hainfellner JA, et al. Mutations of the prion protein gene: phenotypi spetrum. J Neurol 2002;249: A omprehensive review of geneti CJD, listing the reognised mutations and the reported linial phenotypes. A full referene list of reported ases and other relevant papers is supplied. 5 Will RG, Alpers MP, Dormont D, et al. Infetious and sporadi prion diseases. In: Prusiner SB, e, eds. Prion biology and diseases. New York: Cold Spring Harbour Laboratory Press, 1999: A review of the linial, epidemiologial, and other features of sporadi, variant, and iatrogeni CJD with a omprehensive referene list. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 20 February Downloaded from on 7 September 2018 by guest. Proteted by opyright.