Clinical Features and Diagnosis of Human Prion Diseases

  • Richard KnightEmail author
Part of the Neuromethods book series (NM, volume 129)


Human prion diseases are rare fatal neurodegenerative conditions that occur as sporadic, inherited, and acquired disorders. Despite clinico-pathological variations, there are common clinical features and characteristic neuropathological changes accompanied by the accumulation of a disease-associated form of the prion protein in the brain (and, in variant, CJD also in lymphoid tissues). While neuropathological examination of the brain is required for an absolutely definite diagnosis, probable or highly probable clinical diagnosis is possible in the majority of cases.

In this chapter, the clinical assessment of human prion disease is reviewed with emphasis on the role of clinical features and relevant clinical investigations in their diagnosis.

Key words

Human prion disease CJD Clinical features Clinical diagnosis Diagnostic tests MRI CSF proteins: EEG Genetic tests 


  1. 1.
    Parchi P, Giese A, Capellari S et al (1999) Classification of sporadic Creutzfeldt–Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46(2):224–233CrossRefPubMedGoogle Scholar
  2. 2.
    Brown P, Brandel J-P, Sato T et al (2012) Iatrogenic Creutzfeldt-Jakob disease, final assessment. Emerg Infect Dis 18(6):901–907CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Liberski PP (2013) Kuru: a journey back in time from Papua New Guinea to the Neanderthals’ extinction. Pathogens 2(3):472–505CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C et al (1997) Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389(6650):498–501CrossRefPubMedGoogle Scholar
  5. 5.
    Hewitt PE, Llewelyn CA, Mackenzie J et al (2006) Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiology Review study. Vox Sang 91(3):221–230CrossRefPubMedGoogle Scholar
  6. 6.
    Peden A, McCardle L, Head MW, Love S, Ward HJT, Cousens SN, Keeling DM, Millar CM, Hill FGH, Ironside JW (2010) Variant CJD infection in the spleen of a neurologically asymptomatic UK adult patient with haemophilia. Haemophilia 16(2):296–304CrossRefPubMedGoogle Scholar
  7. 7.
    Kovács G, Puopolo M, Ladogana A, Pocchiari M, Budka H et al (2005) Genetic prion disease: the EUROCJD experience. Hum Genet 118(2):166–174CrossRefPubMedGoogle Scholar
  8. 8.
    Gambetti P, Puoti G, Zou WG (2011) Variably protease-sensitive prionopathy: a novel disease of the prion protein. J Mol Neurosci 45(3):422–424CrossRefPubMedGoogle Scholar
  9. 9.
    Head MW, Yull HM, Ritchie DL, Ironside JW et al (2013) Variably protease-sensitive prionopathy in the UK: a retrospective review 1991–2008. Brain 136(4):1102–1115CrossRefPubMedGoogle Scholar
  10. 10.
  11. 11.
    Gill ON, Spencer Y, Richard-Loendt A et al (2013) Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey. BMJ 347:f5675CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Garske T, Ghani AC (2010) Uncertainty in the tail of the variant Creutzfeldt-Jakob disease epidemic in the UK. PLoS One 5(12):e15626CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Knight R (2008) Clinical features and diagnosis of human prion diseases. Future Neurol 3(4):473–481CrossRefGoogle Scholar
  14. 14.
    Heath CA, Cooper SA, Murray K, Knight RSG, Will RG et al (2010) Validation of diagnostic criteria for variant CJD. Ann Neurol 67(6):761–770PubMedGoogle Scholar
  15. 15.
    Rudge P et al (2015) Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years. Brain 138(11):3386–3399CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Will RG, Alpers MP, Dormont D, Schonberger LB (2004) In: Prusiner SB (ed) Infectious and sporadic prion diseases. Prion biology and diseases. Cold Spring Harbor Laboratory Press, New York, pp 629–671Google Scholar
  17. 17.
    Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG (2006) Sporadic Creutzfeldt–Jakob disease with cerebellar ataxia at onset in the UK. J Neurol Neurosurg Psychiatry 77(11):1273–1275. doi: 10.1136/jnnp.2006.088930 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cooper SA, Murray KL, Heath CA, Will RG, Knight RSG (2005) Isolated visual symptoms at onset in sporadic Creutzfeldt-Jakob disease: the clinical phenotype of the “Heidenhain variant”. Br J Ophthalmol 89(10):1341–1342. doi: 10.1136/bjo.2005.074856 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Parchi P, Strammiello R, Notari S et al (2009) Incidence and spectrum of sporadic Creutzfeldt–Jakob disease variants with mixed phenotype and co-occurrence of PrPSc types: an updated classification. Acta Neuropathol 118(5):659–671. doi: 10.1007/s00401-009-0585-1 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Spencer MD, Knight RSG, Will RG (2002) First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features. BMJ 324(7352):1479–1482CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Collie DA, Sellar RJ, Zeidler M, Colchester A, Knight RSG, Will RG (2001) MRI of Creutzfeldt±Jakob disease: imaging features and recommended MRI protocol. Clin Radiol 56(9):726–739CrossRefPubMedGoogle Scholar
  22. 22.
    Collie DA, Summers DM, Sellar RJ et al (2003) Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathlogically confirmed cases. Am J Neuroradiol 24(8):1560–1569PubMedGoogle Scholar
  23. 23.
    Zerr I, Pocchiari M, Collins S, Brandel J-P, de Pedro Cuesta J, Knight RS et al (2000) Analysis of EEG and CSF 14-3-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 55(6):811–815CrossRefPubMedGoogle Scholar
  24. 24.
    G Chohan G, Pennington C, Mackenzie JM, Andrews M, Everington D, Will RG, Knight RSG, Green AJE (2010) The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review. J Neurol Neurosurg Psychiatry 81(11):1243–1248CrossRefGoogle Scholar
  25. 25.
    McGuire L, Peden AH, Orru CD (2012) Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt–Jakob disease. Ann Neurol 72(2):278–285CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Edgeworth JA, Farmer M, Sicilia A (2011) Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet 377(9764):487–493CrossRefPubMedGoogle Scholar
  27. 27.
    Hill AF, Zeidler M, Ironside J, Collinge J (1997) Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 349(9045):99–100CrossRefPubMedGoogle Scholar
  28. 28.
    Moda F, Gambetti P, Notari S, Concha-Marambio L, Catania M, Park KW, Maderna E, Suardi S, Haïk S, Brandel JP, Ironside J, Knight R, Tagliavini F, Soto C (2014) Prions in the urine of patients with variant Creutzfeldt-Jakob disease. N Engl J Med 371(6):530–539CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Orru C et al (2014) A test for Creutzfeldt-Jakob disease using nasal brushings. New Engl J Med 371(6):519–529. doi: 10.1056/NEJMoa1315200 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Meissner B, Kallenberg K, Sanchez-Juan P, Collie D, Summers DM et al (2009) MRI lesion profiles in sporadic Creutzfeldt_Jakob disease. Neurology 72(23):1994–2001CrossRefPubMedGoogle Scholar
  31. 31.
    Steinhoff BJ, Racker S, Herrendorf G, Poser S, Grosche S et al (1996) Accuracy and reliability of periodic sharp wave complexes in Creutzfeldt-Jakob disease. Arch Neurol 53(2):162–166CrossRefPubMedGoogle Scholar
  32. 32.
    Yamada M, Variant CJD Working Group (2006) The first Japanese case of variant Creutzfeldt-Jakob disease showing periodic electroencephalogram. Lancet 367(9513):874CrossRefPubMedGoogle Scholar
  33. 33.
    Binelli S, Agazzi P, Giaccone G, Will RG, Bugiani O, Franceschetti S, Tagliavin F (2006) Periodic electroencephalogram complexes in a patient with variant Creutzfeldt-Jakob disease. Ann Neurol 59(2):423–427CrossRefPubMedGoogle Scholar
  34. 34.
    Sanchez-Juan P, Green A, Ladogana A et al (2006) CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 67(4):637–643CrossRefPubMedGoogle Scholar
  35. 35.
    Shibuya S, Higuchi J, Shin RW, Tateishi J, Kitamoto T (1998) Codon 219 Lys allele of PRNP is not found in sporadic Creutzfeldt-Jakob disease. Ann Neurol 43(6):826–828CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.National CJD Research & Surveillance UnitCentre for Clinical Brain Sciences, School of Clinical Sciences, University of Edinburgh, Western General HospitalEdinburghUK

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