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Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy: Differential Diagnoses & Workup

Author: Chitharanjan Rao, MD, DM, MRCP, DNB, Assistant Professor, Department of Neurology, University of Pittsburgh School of Medicine
Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Contributor Information and Disclosures

Updated: Apr 27, 2007

Differential Diagnoses

Alzheimer Disease
Neurosyphilis
Confusional States and Acute Memory Disorders
Parkinson Disease
Cortical Basal Ganglionic Degeneration
Parkinson Disease in Young Adults
Dementia in Motor Neuron Disease
Prion-Related Diseases
Frontal and Temporal Lobe Dementia
Striatonigral Degeneration
Frontal Lobe Syndromes
Subdural Hematoma
Herpes Simplex Encephalitis
Systemic Lupus Erythematosus
HIV-1 Encephalopathy and AIDS Dementia Complex
Thyroid Disease
Huntington Disease
Vitamin B-12 Associated Neurological Diseases
Hydrocephalus
Whipple Disease
Metastatic Disease to the Brain
Multi-infarct Dementia

Other Problems to Be Considered

The differential diagnosis includes the following:

Sporadic CJD
Psychiatric disease
Peripheral neuropathy
Wilson disease
Hashimoto encephalopathy
CNS vasculitis
Possible encephalitis lethargica
Inflammatory diseases of the CNS
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes)65

Because psychiatric symptoms and limb pain are common presenting symptoms in variant CJD, a workup for the disease in the early stage may be quite challenging. Therefore, the differential diagnoses include peripheral neuropathy and a variety of psychiatric disorders.

Earlier age of onset necessitates inclusion of disorders such as Wilson disease in the differential diagnosis. Occurrence of the disease in older patients warrants a search for other conventional causes of dementia. However, sporadic CJD is still the most likely differential diagnosis of variant CJD.

Workup

Laboratory Studies

  • The initial workup should include tests for dementia and encephalopathy. Include a serum chemistry profile, liver function tests, vitamin B-12 level, methylmalonic acid level, folate value, thyroid studies, ammonia value, erythrocyte sedimentation rate, C-reactive protein value, and neurosyphilis and HIV tests, in appropriate cases.
  • No blood or serum studies have been found useful in diagnosing variant CJD.
  • CSF workup includes the following:
    • Findings from routine CSF studies are unremarkable; however, studies on brain-specific proteins, such as protein 14-3-3, neuron-specific enolase (NSE), S-100b, and tau protein are helpful.
    • In sporadic CJD, detection of protein 14-3-3 is a reliable and sensitive marker for sporadic CJD, with sensitivity and specificity approaching 96%. In variant CJD, on the other hand, the sensitivity is 50% and the specificity is 91%.
    • CSF tau protein has the best sensitivity (80%) and specificity (94%) of any of the proteins investigated in variant CJD. CSF tau protein is an axonal microtubular phosphoprotein, and why it has a higher sensitivity than the other neuronal markers 14-3-3 and NSE is unclear. The combination of a positive CSF 14-3-3 and/or an increased CSF tau protein has an increased sensitivity (86%) for the detection of variant CJD, with only a slight reduction in specificity (90%).66
    • Recently, a specific reduction in the CSF uric acid levels has been shown in variant CJD but not in sporadic CJD, thus potentially helping in the differential diagnosis of variant CJD.67
    • The 14-3-3 protein test is performed as a service by the Laboratory of CNS Studies, National Institute of Neurologic Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, Maryland (Telephone: 301-496-4821).

Imaging Studies

  • Magnetic resonance imaging
    • MRI demonstrates certain unique features in variant CJD, such as the pulvinar sign and the hockey stick sign.68,69 These findings are specific to variant CJD and, therefore, have been included in the World Health Organization (WHO) criteria for the diagnosis of variant CJD. See the World Health Organization Case Definition for Variant CJD in Staging.
    • In a large study of 86 patients, 71% of T2-weighted images and 100% of fluid-attenuated inversion recovery (FLAIR) images showed positive pulvinar signs, as defined by symmetric hyperintensity of the bilateral pulvinars relative to the anterior putamen (see Media File 5).70 Common additional MRI findings include hyperintensity of dorsomedial thalamic nuclei (93%), periaqueductal gray matter (83%), and caudate head (see Media File 6). Dorsomedial thalamic hyperintensity produces a characteristic hockey stick distribution of hyperintensity, as illustrated in Media File 7.68,69,70
    • In contrast, MRI changes in sporadic CJD are usually more pronounced in the caudate and putamen and the changes can be asymmetric.71,72 Rarely, hyperintensity in the pulvinar relative to other thalamic nuclei has been described in young patients with sporadic CJD, making the pulvinar more conspicuous. While this could be mistaken for variant CJD, the signal intensity of the pulvinar always remains less than that of the anterior putamen.{Ref72}
  • Single-photon emission computed tomography (SPECT) scanning: SPECT scans were studied in 2 patients and showed nonspecific hypoperfusion abnormalities.73

Other Tests

  • Electroencephalography
    • Periodic sharp and slow wave complexes (PSWCs) are considered characteristic of CJD. They may appear as early as 3 weeks after the onset of the disease and occur in 60-70% of all patients with sporadic CJD during the course of the illness. PSWCs also occur in some cases of familial CJD but are absent in iatrogenic human growth factor hormone–related CJD, fatal familial insomnia, and Gerstmann-Strãussler-Scheinker syndrome.
    • So far, only one patient with variant CJD has been reported to show PSWCs. This was seen in the Japanese patient whose initial EEG showed diffuse slowing and a follow-up EEG performed 2 years later showed periodic complexes typical for sporadic CJD.74

Procedures

Histologic Findings

Tonsil biopsy

Unlike sporadic CJD, in patients with variant CJD, PrPSc is detectable in follicular dendritic cells within germinal centers in lymphoid tissues, including the tonsils, lymph nodes, spleen, thymus, and gut-associated lymphoid tissues in the appendix and small intestine (see Media File 8).75,76,30 The lymphoreticular accumulation of PrPSc, as assessed by immunocytochemistry, has been shown to be a highly specific feature of variant CJD.77

A distinctive PrPSc subtype (ie, 4t) is consistently observed in antemortem and postmortem tonsil examinations in cases of variant CJD.76,30 Type 4t PrPSc in the tonsils differs from type 4 PrPSc observed in brain tissue in variant CJD in the proportion of the prion protein glycoforms, implying the superimposition of tissue- and strain-specific effects of prion protein glycosylation.76

Tonsil biopsy has shown 100% sensitivity and specificity for the diagnosis of variant CJD. It allows diagnosis of variant CJD at an early clinical stage.78,76,30 Therefore, a tonsil biopsy is an important diagnostic test for suspected variant CJD, particularly if characteristic MRI findings are absent.

Furthermore, large-scale anonymous screening of routine surgical tonsillectomy tissues may provide an early warning of a high-level preclinical variant CJD infection76,79,80 , although a relatively small sample of 2000 consecutive tonsillectomy specimens obtained in the United Kingdom did not detect any positive cases on analysis by both high-sensitivity immunoblotting and immunohistochemistry.81 This study was limited by the fact that the median age of tonsillectomy specimens is less than 10 years and most of these patients would not have had a significant exposure to BSE. The second study examined more than 16,000 tonsillectomy and appendectomy specimens from persons aged 10-30 years (the population at highest risk for variant CJD) and found 3 positive results, yielding a prevalence of 237 cases per million population.77

Neuropathology

The pathology of variant CJD shows relatively uniform morphologic and immunocytochemical characteristics, which are distinct from other forms of CJD (see Media Files 9-12). The diagnostic pathological features are listed as follows (adapted from Ironside et al, 200282 ).

  • Multiple florid plaques in hematoxylin and eosin sections; numerous small cluster plaques in prion protein–stained sections; amorphous pericellular and perivascular prion protein accumulation in the cerebral and cerebellar cortex 
  • Severe spongiform change; perineuronal and axonal prion protein accumulation in the caudate and putamen; marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain 
  • Marked astrocytosis and neuronal loss in the posterior thalamic nuclei and midbrain; reticular and perineuronal prion protein accumulation in the gray matter of the brainstem and spinal cord 
  • Reticular and perineuronal prion protein accumulation in the gray matter of the brainstem and spinal cord 
  • PrPSc accumulation in lymphoid tissues throughout the body 
  • Predominance of diglycosylated PrPSc in CNS and lymphoid tissues

Relative uniformity of the pathological and biochemical features in the brain is a striking feature of variant CJD and is in keeping with the relatively consistent clinical phenotype for this disease.

By contrast, for sporadic CJD, at least 6 neuropathological and biochemical subtypes have been identified.83 While the biochemical profile of PrPSc in variant CJD resembles that in BSE and BSE-related disorders in other species, the neuropathology of variant CJD is distinct from BSE.

Florid plaques are a neuropathological, but not uniform, hallmark of variant CJD. However, smaller cluster plaques are observed in all cases and have not been reported in any other type of human prion disease. Rarely, florid plaques have occurred in iatrogenic CJD in dura matter graft recipients in Japan, but these cases do not show any other distinctive neuropathological features of variant CJD.84 Kuru-type amyloid plaques observed in patients with sporadic CJD who are heterozygotes at codon 129 in their PRNP gene can be distinguished from florid plaques by their restricted distribution in the cerebral cortex and cerebellum, smaller size, compact plaque morphology, and absence of the rim of spongiform change in the neuropil.83

The pattern of thalamic neuronal loss and gliosis is distinct. In both familial and sporadic fatal insomnia, anterior thalamic nuclei are predominantly involved, while in variant CJD, pulvinar and dorsomedial nuclei are affected.

Staging

WHO Case Definition for Variant CJD (adapted from the revision of the WHO surveillance case definition for variant CJD, 200185 )

Class I

  • A - Progressive neuropsychiatric disorder
  • B - Duration of illness longer than 6 months
  • C - Routine investigations not suggestive of alternative diagnosis
  • D - No history of iatrogenic exposure
  • E - No history of familial form of TSE

Class II

  • A - Early psychiatric symptoms (ie, depression, anxiety, apathy, withdrawal, delusions)
  • B - Persistent painful sensory symptoms (ie, including frank pain and/or dysesthesia)
  • C - Ataxia
  • D - Myoclonus or chorea or dystonia
  • E - Dementia

Class III

  • A - EEG without typical appearance of sporadic CJD (ie, generalized triphasic periodic complexes at approximately one per second) or no EEG
  • B - Brain MRI showing bilateral symmetrical pulvinar high-signal intensity (relative to the signal intensity of the other deep gray matter nuclei and cortical gray matter; modification of the case definition of the characteristic MRI features [IIIB] to brain MRI shows bilateral symmetrical pulvinar hyperintensity relative to the signal intensity of the anterior putamen is recommended to improve the accuracy of the pulvinar sign in variant CJD)

Class IVA
 
Positive findings on tonsil biopsy (biopsy not routinely recommended and not recommended in cases with EEG appearance typical of sporadic CJD but may be helpful in suspected cases in which the clinical features are compatible with variant CJD without MRI findings of bilateral pulvinar high signal intensity)

Possible diagnoses

  • Definite - Class IA and neuropathologic confirmation of variant CJD (ie, spongiform change and extensive prion protein deposition with florid plaques throughout the cerebrum and cerebellum)
  • Probable - Class I and 4 of 5 of class II and classes IIIA and IIIB or class I and class IVA
  • Possible - Class I and 4 of 5 of class II and class IIIA 

More on Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy

Overview: Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
Differential Diagnoses & Workup: Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
Treatment & Medication: Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
Follow-up: Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
Multimedia: Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
References
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References

  1. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse ME, Watt CJ, Udy HJ, et al. Transmission dynamics and epidemiology of BSE in British cattle. Nature. Aug 29 1996;382(6594):779-88. [Medline].

  2. Donnelly CA, Ferguson NM, Ghani AC, Anderson RM. Implications of BSE infection screening data for the scale of the British BSE epidemic and current European infection levels. Proc R Soc Lond B Biol Sci. Nov 7 2002;269(1506):2179-90. [Medline].

  3. Brown P, Will RG, Bradley R, Asher DM, Detwiler L. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns. Emerg Infect Dis. Jan-Feb 2001;7(1):6-16. [Medline].

  4. Wells GA, Scott AC, Wilesmith JW, Simmons MM, Matthews D. Correlation between the results of a histopathological examination and the detection of abnormal brain fibrils in the diagnosis of bovine spongiform encephalopathy. Res Vet Sci. May 1994;56(3):346-51. [Medline].

  5. Wells GA, Hancock RD, Cooley WA, Richards MS, Higgins RJ, David GP. Bovine spongiform encephalopathy: diagnostic significance of vacuolar changes in selected nuclei of the medulla oblongata. Vet Rec. Nov 18 1989;125(21):521-4. [Medline].

  6. Brown P, Bradley R. 1755 and all that: a historical primer of transmissible spongiform encephalopathy. BMJ. Dec 19-26 1998;317(7174):1688-92. [Medline].

  7. Smith PG, Cousens SN. Is the new variant of Creutzfeldt-Jakob disease from mad cows?. Science. Aug 9 1996;273(5276):748. [Medline].

  8. Brown P. The risk of bovine spongiform encephalopathy ('mad cow disease') to human health. JAMA. Sep 24 1997;278(12):1008-11. [Medline].

  9. Collee JG, Bradley R. BSE: a decade on--Part I. Lancet. Mar 1 1997;349(9052):636-41. [Medline].

  10. Collee JG, Bradley R. Bovine Spongiform Encephalopathy (BSE): a decade on--Part 2. Lancet. Mar 8 1997;349(9053):715-21. [Medline].

  11. Schreuder BE. Animal spongiform encephalopathies--an update. Part 1. Scrapie and lesser known animal spongiform encephalopathies. Vet Q. Oct 1994;16(3):174-81. [Medline].

  12. Nathonson N, Wilesmith J, Wells GA. Bovine spongiform encephalopathy and related disorders. In: Pruisner SB, ed. Prion Biology and Diseases. Cold Springs Harbor, NY: Cold Springs Harbor Laboratory Press; 1999.

  13. Sigurdson CJ, Miller MW. Other animal prion diseases. Br Med Bull. 2003;66:199-212. [Medline].

  14. Bradley R. Animal prion diseases. In: Collinge J, Palmer MS. Prion Diseases. Oxford, England: Oxford University Press; 1997:91-127.

  15. Commission of European Communities. Commission Decision. 27 December 2000 amending Decision 2000/418/EC regulating the use of material presenting risks as regards transmissible spongiform encephalopathies. Official Journal of the European Communities. Available at http://europa.eu.int/comm/food/fs/bse/bse23_en.pdf.

  16. Holt TA, Phillips J. Bovine spongiform encephalopathy. Br Med J (Clin Res Ed). Jun 4 1988;296(6636):1581-2. [Medline].

  17. Taylor DM. Bovine spongiform encephalopathy and human health. Vet Rec. Oct 14 1989;125(16):413-5. [Medline].

  18. Dealer SF, Lacey RW. Transmissible spongiform encephalopathies: the threat of BSE to man. Vol 7. Food Microbiology. 1990:253-79.

  19. Bateman D, Hilton D, Love S, Zeidler M, Beck J, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 18-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155-6. [Medline].

  20. Britton TC, al-Sarraj S, Shaw C, Campbell T, Collinge J. Sporadic Creutzfeldt-Jakob disease in a 16-year-old in the UK. Lancet. Oct 28 1995;346(8983):1155. [Medline].

  21. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet. Apr 6 1996;347(9006):921-5. [Medline].

  22. California Emerging Infections Program. California Creutzfeldt-Jakob Disease (CJD) Surveillance Project. California Emerging Infections Program. Available at http://www.ceip.us/cjd.htm.

  23. Will RG. Acquired prion disease: iatrogenic CJD, variant CJD, kuru. Br Med Bull. 2003;66:255-65. [Medline].

  24. Jackson GS, Beck JA, Navarrete C, Brown J, Sutton PM, Contreras M, et al. HLA-DQ7 antigen and resistance to variant CJD. Nature. Nov 15 2001;414(6861):269-70. [Medline].

  25. Bishop MT, Hart P, Aitchison L, Baybutt HN, Plinston C, Thomson V, et al. Predicting susceptibility and incubation time of human-to-human transmission of vCJD. Lancet Neurol. May 2006;5(5):393-8. [Medline].

  26. Beisel CE, Morens DM. Variant Creutzfeldt-Jakob disease and the acquired and transmissible spongiform encephalopathies. Clin Infect Dis. Mar 1 2004;38(5):697-704. [Medline].

  27. Bradley R, Collee JG, Liberski PP. Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 1. Folia Neuropathol. 2006;44(2):93-101. [Medline].

  28. Collee JG, Bradley R, Liberski PP. Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 2. Folia Neuropathol. 2006;44(2):102-10. [Medline].

  29. Foster JD, Hope J, Fraser H. Transmission of bovine spongiform encephalopathy to sheep and goats. Vet Rec. Oct 2 1993;133(14):339-41. [Medline].

  30. Wadsworth JD, Joiner S, Hill AF, Campbell TA, Desbruslais M, Luthert PJ, et al. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet. Jul 21 2001;358(9277):171-80. [Medline].

  31. Bosque PJ, Ryou C, Telling G, Peretz D, Legname G, DeArmond SJ, et al. Prions in skeletal muscle. Proc Natl Acad Sci U S A. Mar 19 2002;99(6):3812-7. [Medline].

  32. Glatzel M, Abela E, Maissen M, Aguzzi A. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N Engl J Med. Nov 6 2003;349(19):1812-20. [Medline].

  33. Head MW, Ritchie D, Smith N, McLoughlin V, Nailon W, Samad S, et al. Peripheral tissue involvement in sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease: an immunohistochemical, quantitative, and biochemical study. Am J Pathol. Jan 2004;164(1):143-53. [Medline].

  34. Peden AH, Ritchie DL, Head MW, Ironside JW. Detection and localization of PrPSc in the skeletal muscle of patients with variant, iatrogenic, and sporadic forms of Creutzfeldt-Jakob disease. Am J Pathol. Mar 2006;168(3):927-35. [Medline].

  35. Blättler T. Transmission of prion disease. APMIS. Jan 2002;110(1):71-8. [Medline].

  36. O'Rourke KI, Huff TP, Leathers CW, Robinson MM, Gorham JR. SCID mouse spleen does not support scrapie agent replication. J Gen Virol. Jun 1994;75 ( Pt 6):1511-4. [Medline].

  37. Beekes M, McBride PA, Baldauf E. Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol. 79 (Pt 3):601-7. [Medline].

  38. McBride PA, Beekes M. Pathological PrP is abundant in sympathetic and sensory ganglia of hamsters fed with scrapie. Neurosci Lett. Apr 16 1999;265(2):135-8. [Medline].

  39. Houston F, Foster JD, Chong A, Hunter N, Bostock CJ. Transmission of BSE by blood transfusion in sheep. Lancet. Sep 16 2000;356(9234):999-1000. [Medline].

  40. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature. Oct 24 1996;383(6602):685-90. [Medline].

  41. Lasmezas CI, Deslys JP, Demaimay R, Prusiner SB. BSE transmission to macaques. Nature. Jun 27 1996;381(6585):743-4. [Medline].

  42. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature. Oct 2 1997;389(6650):498-501. [Medline].

  43. Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J, et al. The same prion strain causes vCJD and BSE. Nature. Oct 2 1997;389(6650):448-50, 526. [Medline].

  44. Lasmézas CI, Fournier JG, Nouvel V, Boe H, Marcé D, Lamoury F, et al. Adaptation of the bovine spongiform encephalopathy agent to primates and comparison with Creutzfeldt-- Jakob disease: implications for human health. Proc Natl Acad Sci U S A. Mar 27 2001;98(7):4142-7. [Medline].

  45. Llewelyn CA, Hewitt PE, Knight RS, Amar K, Cousens S, Mackenzie J, et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet. Feb 7 2004;363(9407):417-21. [Medline].

  46. UK Health Protection Agency. Health protection agency press release: new case of variant CJD associated with blood transfusion. Available at http://www.hpa.org.uk/hpa/news/articles/press_releases/2006/060209_cjd.htm.

  47. Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. Aug 7-13 2004;364(9433):527-9. [Medline].

  48. Cousens SN, Vynnycky E, Zeidler M, Will RG, Smith PG. Predicting the CJD epidemic in humans. Nature. Jan 16 1997;385(6613):197-8. [Medline].

  49. Ghani AC, Ferguson NM, Donnelly CA, Anderson RM. Predicted vCJD mortality in Great Britain. Nature. Aug 10 2000;406(6796):583-4. [Medline].

  50. d'Aignaux JN, Cousens SN, Smith PG. Predictability of the UK variant Creutzfeldt-Jakob disease epidemic. Science. Nov 23 2001;294(5547):1729-31. [Medline].

  51. Valleron AJ, Boelle PY, Will R, Cesbron JY. Estimation of epidemic size and incubation time based on age characteristics of vCJD in the United Kingdom. Science. Nov 23 2001;294(5547):1726-8. [Medline].

  52. Andrews NJ, Farrington CP, Ward HJ, Cousens SN, Smith PG, Molesworth AM, et al. Deaths from variant Creutzfeldt-Jakob disease in the UK. Lancet. Mar 1 2003;361(9359):751-2. [Medline].

  53. Lorains JW, Henry C, Agbamu DA, Rossi M, Bishop M, Will RG, et al. Variant Creutzfeldt-Jakob disease in an elderly patient. Lancet. Apr 28 2001;357(9265):1339-40. [Medline].

  54. Cooper JD, Bird SM. Predicting incidence of variant Creutzfeldt-Jakob disease from UK dietary exposure to bovine spongiform encephalopathy for the 1940 to 1969 and post-1969 birth cohorts. Int J Epidemiol. Oct 2003;32(5):784-91. [Medline].

  55. Huillard d'Aignaux JN, Cousens SN, Maccario J, Costagliola D, Alpers MP, Smith PG, et al. The incubation period of kuru. Epidemiology. Jul 2002;13(4):402-8. [Medline].

  56. Swerdlow AJ, Higgins CD, Adlard P, Jones ME, Preece MA. Creutzfeldt-Jakob disease in United Kingdom patients treated with human pituitary growth hormone. Neurology. Sep 23 2003;61(6):783-91. [Medline].

  57. Aguzzi A, Glatzel M. Prion infections, blood and transfusions. Nat Clin Pract Neurol. Jun 2006;2(6):321-9. [Medline].

  58. Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study. Vox Sang. Oct 2006;91(3):221-30. [Medline].

  59. Spencer MD, Knight RS, Will RG. First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review of early psychiatric and neurological features. BMJ. Jun 22 2002;324(7352):1479-82. [Medline].

  60. Zeidler M, Stewart GE, Barraclough CR, Bateman DE, Bates D, Burn DJ, et al. New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet. Sep 27 1997;350(9082):903-7. [Medline].

  61. Zeidler M, Johnstone EC, Bamber RW, Dickens CM, Fisher CJ, Francis AF, et al. New variant Creutzfeldt-Jakob disease: psychiatric features. Lancet. Sep 27 1997;350(9082):908-10. [Medline].

  62. Allroggen H, Dennis G, Abbott RJ, Pye IF. New variant Creutzfeldt-Jakob disease: three case reports from Leicestershire. J Neurol Neurosurg Psychiatry. Mar 2000;68(3):375-8. [Medline].

  63. Dervaux A, Vicart S, Lopes F, Le Borgne MH. Psychiatric features of vCJD similar in France and UK. Br J Psychiatry. Mar 2001;178:276. [Medline].

  64. Will RG, Stewart G, Zeidler M. Psychiatric features of new variant Creutzfeldt-Jakob disease. Psychiatric Bull. 1999;23:264-7.

  65. Isozumi K, Fukuuchi Y, Tanaka K, Nogawa S, Ishihara T, Sakuta R. A MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) mtDNA mutation that induces subacute dementia which mimicks Creutzfeldt-Jakob disease. Intern Med. Sep 1994;33(9):543-6. [Medline].

  66. Green AJ, Thompson EJ, Stewart GE, Zeidler M, McKenzie JM, MacLeod MA, et al. Use of 14-3-3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry. Jun 2001;70(6):744-8. [Medline].

  67. Lekishvili T, Sassoon J, Thompsett AR, Green A, Ironside JW, Brown DR. BSE and vCJD cause disturbance to uric acid levels. Exp Neurol. Nov 2004;190(1):233-44. [Medline].

  68. Sellar RJ, Will RG, Zeidler M. MR imaging of new variant Creutzfeldt-Jakob disease: the Pulvinar sign. Neuroradiology. 1997;39:S53.

  69. Zeidler M, Sellar RJ, Collie DA, Knight R, Stewart G, Macleod MA, et al. The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease. Lancet. Apr 22 2000;355(9213):1412-8. [Medline].

  70. Collie DA, Summers DM, Sellar RJ, Ironside JW, Cooper S, Zeidler M, et al. Diagnosing variant Creutzfeldt-Jakob disease with the pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases. AJNR Am J Neuroradiol. Sep 2003;24(8):1560-9. [Medline].

  71. Finkenstaedt M, Szudra A, Zerr I, Poser S, Hise JH, Stoebner JM, et al. MR imaging of Creutzfeldt-Jakob disease. Radiology. Jun 1996;199(3):793-8. [Medline].

  72. Urbach H, Klisch J, Wolf HK, Brechtelsbauer D, Gass S, Solymosi L. MRI in sporadic Creutzfeldt-Jakob disease: correlation with clinical and neuropathological data. Neuroradiology. Feb 1998;40(2):65-70. [Medline].

  73. de Silva R, Patterson J, Hadley D, Russell A, Turner M, Zeidler M. Single photon emission computed tomography in the identification of new variant Creutzfeldt-Jakob disease: case reports. BMJ. Feb 21 1998;316(7131):593-4. [Medline].

  74. Yamada M, Variant CJD Working Group, Creutzfeldt-Jakob Disease Surveillance Committee, Japan. The first Japanese case of variant Creutzfeldt-Jakob disease showing periodic electroencephalogram. Lancet. Mar 11 2006;367(9513):874. [Medline].

  75. Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet. Jan 11 1997;349(9045):99-100. [Medline].

  76. Hill AF, Butterworth RJ, Joiner S, Jackson G, Rossor MN, Thomas DJ, et al. Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet. Jan 16 1999;353(9148):183-9. [Medline].

  77. Hilton DA, Sutak J, Smith ME, Penney M, Conyers L, Edwards P, et al. Specificity of lymphoreticular accumulation of prion protein for variant Creutzfeldt-Jakob disease. J Clin Pathol. Mar 2004;57(3):300-2. [Medline].

  78. Collinge J. Variant Creutzfeldt-Jakob disease. Lancet. Jul 24 1999;354(9175):317-23. [Medline].

  79. Ironside JW, Hilton DA, Ghani A, Johnston NJ, Conyers L, McCardle LM, et al. Retrospective study of prion-protein accumulation in tonsil and appendix tissues. Lancet. May 13 2000;355(9216):1693-4. [Medline].

  80. Hilton DA, Ghani AC, Conyers L, Edwards P, McCardle L, Penney M, et al. Accumulation of prion protein in tonsil and appendix: review of tissue samples. BMJ. Sep 21 2002;325(7365):633-4. [Medline].

  81. Frosh A, Smith LC, Jackson CJ, Linehan JM, Brandner S, Wadsworth JD, et al. Analysis of 2000 consecutive UK tonsillectomy specimens for disease-related prion protein. Lancet. Oct 2-8 2004;364(9441):1260-2. [Medline].

  82. Ironside JW, McCardle L, Horsburgh A, Lim Z, Head MW. Pathological diagnosis of variant Creutzfeldt-Jakob disease. APMIS. Jan 2002;110(1):79-87. [Medline].

  83. Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeffer W, Windl O, et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol. Aug 1999;46(2):224-33. [Medline].

  84. Shimizu S, Hoshi K, Muramoto T, Homma M, Ironside JW, Kuzuhara S, et al. Creutzfeldt-Jakob disease with florid-type plaques after cadaveric dura mater grafting. Arch Neurol. Mar 1999;56(3):357-62. [Medline].

  85. World Health Organization. The revision of the surveillance case definition for variant Creutzfeldt-Jakob Disease (vCJD). Report of a WHO consultation Edinburgh, United Kingdom 17 May 2001. World Health Organization. Available at http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_EPH_2001_5/en/.

  86. Trevitt CR, Collinge J. A systematic review of prion therapeutics in experimental models. Brain. Sep 2006;129(Pt 9):2241-65. [Medline].

  87. Korth C, May BC, Cohen FE, Prusiner SB. Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. Aug 14 2001;98(17):9836-41. [Medline].

  88. Doh-ura K, Ishikawa K, Murakami-Kubo I, Sasaki K, Mohri S, Race R, et al. Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models. J Virol. May 2004;78(10):4999-5006. [Medline].

  89. Otto M, Cepek L, Ratzka P, Doehlinger S, Boekhoff I, Wiltfang J, et al. Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study. Neurology. Mar 9 2004;62(5):714-8. [Medline].

  90. Wisniewski T, Sigurdsson EM, Aucouturier P. Conformation as a therapeutic target in the prionoses and other neurodegenerative conditions. In: Molecular and Cellular Pathology in Prion Disease. 2001.

  91. Sigurdsson EM, Brown DR, Daniels M, Kascsak RJ, Kascsak R, Carp R, et al. Immunization delays the onset of prion disease in mice. Am J Pathol. Jul 2002;161(1):13-7. [Medline].

  92. Race R, Chesebro B. Scrapie infectivity found in resistant species. Nature. Apr 23 1998;392(6678):770. [Medline].

  93. Race R, Raines A, Raymond GJ, Caughey B, Chesebro B. Long-term subclinical carrier state precedes scrapie replication and adaptation in a resistant species: analogies to bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease in humans. J Virol. Nov 2001;75(21):10106-12. [Medline].

  94. Hill AF, Joiner S, Linehan J, Desbruslais M, Lantos PL, Collinge J. Species-barrier-independent prion replication in apparently resistant species. Proc Natl Acad Sci U S A. Aug 29 2000;97(18):10248-53. [Medline].

  95. Taylor D. Inactivation of the BSE agent. C R Acad Sci III. Jan 2002;325(1):75-6. [Medline].

  96. Collins SJ, Lawson VA, Masters CL. Transmissible spongiform encephalopathies. Lancet. Jan 3 2004;363(9402):51-61. [Medline].

  97. Aguzzi A, Polymenidou M. Mammalian prion biology: one century of evolving concepts. Cell. Jan 23 2004;116(2):313-27. [Medline].

  98. Aguzzi A, Glatzel M. vCJD tissue distribution and transmission by transfusion--a worst-case scenario coming true?. Lancet. Feb 7 2004;363(9407):411-2. [Medline].

  99. Castilla J, Saa P, Soto C. Detection of prions in blood. Nat Med. Sep 2005;11(9):982-5. [Medline].

  100. Glatzel M, Ott PM, Linder T, Gebbers JO, Gmür A, Wüst W. Human prion diseases: epidemiology and integrated risk assessment. Lancet Neurol. Dec 2003;2(12):757-63. [Medline].

  101. Alabama BSE Investigation. Final Epidemiology Report (USDA, APHIS). Available at http://www.aphis.usda.gov/newsroom/hot_issues/bse/downloads/EPIFinal5-2-06.pdf.

  102. APHIS. Bovine Spongiform Encephalopathy (BSE). Available at: http://www.aphis.usda.gov/. Available at http://www.aphis.usda.gov/lpa/issues/bse/bse.html.

  103. Bovine Spongiform Encephalopathy (BSE) Inquiry. The BSE Inquiry. Available at http://www.bseinquiry.gov.uk/.

  104. Centers for Disease Control and Prevention. Fact Sheet: New Variant Creutzfeldt-Jakob Disease. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/.

  105. Centers for Disease Control and Prevention. Questions and Answers Regarding Bovine Spongiform Encephalopathy (BSE) and Creutzfeldt-Jakob Disease (CJD). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/.

  106. Centers for Disease Control and Prevention. Update 2002: Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease. Centers for Disease Control and Prevention; 2002. Available at http://www.cdc.gov/.

  107. Croes EA, Roks G, Jansen GH, Nijssen PC, van Duijn CM. Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone. J Neurol Neurosurg Psychiatry. Jun 2002;72(6):792-3. [Medline].

  108. Department for Environment Food and Rural Affairs. BSE: Other TSEs - Creutzfeldt-Jakob Disease (CJD). Department for Environment, Food, and Rural Affairs UK. Available at http://www.defra.gov.uk/animalh/bse/othertses/cjd.html. Accessed July 12, 2004.

  109. Haïk S, Brandel JP, Oppenheim C, Sazdovitch V, Dormont D, Hauw JJ, et al. Sporadic CJD clinically mimicking variant CJD with bilateral increased signal in the pulvinar. Neurology. Jan 8 2002;58(1):148-9. [Medline].

  110. Knight RSG. Potential Treatments for Creutzfeldt-Jakob Disease. The National Creutzfeldt-Jakob Disease Surveillance Unit. Available at http://www.cjd.ed.ac.uk/TREAT.htm. Accessed February 25, 2005.

  111. MRC Clinical Trials Unit. PRION-1: Randomised trial of quinacrine in human prion disease. Available at http://www.ctu.mrc.ac.uk/studies/cjd.asp. Accessed July 6, 2005.

  112. Office International des Epizooties. Bovine Spongiform Encephalopathy (BSE). Office International des Epizooties. Available at http://www.oie.int/eng/info/en_esb.htm. Accessed December 24, 2004.

  113. UK Blood Transfusion Services. UK Blood Transfusion & Tissue Transplantation Guidelines. UK Blood Transfusion & Tissue Transplantation Services. Available at http://www.transfusionguidelines.org.uk.

  114. UK Department of Health. CJD. Available at http://www.dh.gov.uk/Home/fs/en.

  115. UK National Creutzfeldt-Jakob Disease Surveillance Unit. National Creutzfeldt-Jakob Disease Surveillance Unit. University of Edinburgh. Available at http://www.cjd.ed.ac.uk. Accessed July 19, 2005.

  116. United States Department of Agriculture. Veneman Announces Additional Protection Measures To Guard Against BSE. Available at http://www.usda.gov/. Accessed December 30, 2003.

  117. United States Department of Health and Human Services. Expanded "Mad Cow" Safeguards Announced To Strengthen Existing Firewalls Against BSE Transmission. Available at http://www.hhs.gov/news/press/2004pres/20040126.html. Accessed January 26, 2004.

  118. US Food and Drug Administration. Bovine Spongiform Encephalopathy (BSE). US-FDA. Available at http://www.fda.gov/.

  119. US Food and Drug Administration. Guidance for Industry - Revised Preventative Measures to Reduce the Possible Risk of Transmssion of Creuztfeldt-Jakob Disease (CJD) and variant Creuztfeldt-Jakob Disease (vCJD) by Blood and Blood Products. US-FDA. Available at http://www.fda.gov/cber/gdlns/cjdvcjd.pdf. Accessed January, 2002.

  120. US National Prion Disease Pathology Surveillance Center. The National Creutzfeldt-Jakob Disease Surveillance Unit. US National Prion Disease Pathology Surveillance Center. Available at http://www.cjdsurveillance.com/. Accessed June 6, 2005.

  121. Wisniewsky T. Prion-Related Diseases. Available at: http://www.emedicine.com/neuro/topic662.htm. eMedicine by WebMD [serial online]. 2004:[Full Text].

  122. World Health Organization. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies. Report of a WHO Consultation, Geneva, Switzerland, 23-26 March 1999. World Health Organization. Available at http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000_3/en/.

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Further Reading

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Keywords

transmissible spongiform encephalopathies, TSE, prion diseases, prionosis, prionoses, PrP diseases, Creutzfeldt-Jakob disease, CJD, sporadic CJD, sCJD, new variant CJD, nvCJD, variant CJD, vCJD, bovine spongiform encephalopathies, BSE, mad cow disease, mad cow, mad cows, scrapie, kuru, Gerstmann-Strãussler-Scheinker disease, GSS, familial fatal insomnia, FFI, sporadic fatal insomnia, SFI, chronic wasting disease, CWD

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Contributor Information and Disclosures

Author

Chitharanjan Rao, MD, DM, MRCP, DNB, Assistant Professor, Department of Neurology, University of Pittsburgh School of Medicine
Chitharanjan Rao, MD, DM, MRCP, DNB is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association, Medical Council of India, and Royal College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

Amy A Pruitt, MD, Program Director, Assistant Professor, Department of Neurology, University of Pennsylvania
Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, University of Pittsburgh Medical Center - Shadyside, Clinical Associate Professor, Department of Neurology, University of Pittsburgh School of Medicine
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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