Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy Workup

  • Author: Florian P Thomas, MD, MA, PhD, Drmed; Chief Editor: Karen L Roos, MD   more...
 
Updated: Jun 21, 2010
 

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.
    • The detection of CSF 14-3-3 is nonspecific.
    • 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%).[71]
    • Ubiquitin has the potential of serving as a CSF marker in CJD.[72]
    • 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.[73]
    • 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).
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Imaging Studies

  • Magnetic resonance imaging
    • MRI demonstrates certain unique features in variant CJD, such as the pulvinar sign and the hockey stick sign.[74, 75] 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.[76] Pulvinar sign of variant Creutzfeldt-Jakob diseasePulvinar sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows marked symmetrical hyperintensity of the pulvinar (posterior) thalamic nuclei, and this sign is present in 100% of cases imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
    • Common additional MRI findings include hyperintensity of dorsomedial thalamic nuclei (93%), periaqueductal gray matter (83%), and caudate head (see image below). Dorsomedial thalamic hyperintensity produces a characteristic hockey stick distribution of hyperintensity, as illustrated in image below.[74, 75, 76] Axial fluid-attenuated inversion recovery (FLAIR) Axial fluid-attenuated inversion recovery (FLAIR) showing periaqueductal gray matter hyperintensity (arrow). Although not a specific sign, periaqueductal hyperintensity is observed in 83% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9. Hockey stick sign of variant Creutzfeldt-Jakob disHockey stick sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows symmetrical pulvinar and dorsomedial thalamic nuclear hyperintensity. This combination produces a characteristic hockey stick appearance and is present in 93% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
    • In contrast, MRI changes in sporadic CJD are usually more pronounced in the caudate and putamen and the changes can be asymmetric.[77, 78] 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.
  • Single-photon emission computed tomography (SPECT) scanning: SPECT scans were studied in 2 patients and showed nonspecific hypoperfusion abnormalities.[79]
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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-Sträussler-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.[80]
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Procedures

  • Lumbar puncture (see Lab Studies)
  • Tonsil and brain biopsy (see Histologic Findings)
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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 image below).[81, 82, 31] The lymphoreticular accumulation of PrPSc, as assessed by immunocytochemistry, has been shown to be a highly specific feature of variant CJD.[83]

Prion protein (PrP) accumulation in the tonsil in Prion protein (PrP) accumulation in the tonsil in variant Creutzfeldt-Jakob disease within follicular dendritic cells and macrophages in a germinal center as demonstrated by PrP immunocytochemistry. From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.

A distinctive PrPSc subtype (ie, 4t) is consistently observed in antemortem and postmortem tonsil examinations in cases of variant CJD.[82, 31] 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.[82]

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.[84, 82, 31] 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 infection[82, 85, 86] , 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.[87] 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.[83]

Neuropathology

The pathology of variant CJD shows relatively uniform morphologic and immunocytochemical characteristics, which are distinct from other forms of CJD (see images below).

The florid plaque in the cerebral cortex in varianThe florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57. The florid plaque in the cerebral cortex in varianThe florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at high magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57. Immunocytochemistry for prion protein (PrP) shows Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57. Immunocytochemistry for prion protein (PrP) shows Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (higher magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.

The diagnostic pathological features are listed as follows (adapted from Ironside et al, 2002[88] ).

  • 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.[89] 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.[90] 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.[89]

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.

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Staging

WHO Case Definition for Variant CJD (adapted from the revision of the WHO surveillance case definition for variant CJD, 2001[91] )

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
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Contributor Information and Disclosures
Author

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; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Amy A Pruitt, MD  Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Hospital of the University of Pennsylvania

Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Neil A Busis, MD  Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

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.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

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: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Chitharanjan V Rao, MD, MRCP, DM to the development and writing of this article.

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Incidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food.
Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.
Time course of epidemic bovine spongiform encephalopathy (BSE) in the United Kingdom, 1986-2000, with dates of major precautionary interventions. SBO stands for specified bovine offal (ie, brain, spinal cord, thymus, spleen, and intestines from cattle aged >6 mo). MBM stands for meat and bone meal (protein residue produced by rendering). From Brown P, Will RG, Bradley R, et al. "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution and current concerns". Emerging Infectious Diseases, 2001;7: 6-16.
Normal fluid-attenuated inversion recovery (FLAIR) image at the level of the basal ganglia shows that the thalamus is normally isointense or slightly hypointense relative to putamen. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Pulvinar sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows marked symmetrical hyperintensity of the pulvinar (posterior) thalamic nuclei, and this sign is present in 100% of cases imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Axial fluid-attenuated inversion recovery (FLAIR) showing periaqueductal gray matter hyperintensity (arrow). Although not a specific sign, periaqueductal hyperintensity is observed in 83% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Hockey stick sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows symmetrical pulvinar and dorsomedial thalamic nuclear hyperintensity. This combination produces a characteristic hockey stick appearance and is present in 93% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Prion protein (PrP) accumulation in the tonsil in variant Creutzfeldt-Jakob disease within follicular dendritic cells and macrophages in a germinal center as demonstrated by PrP immunocytochemistry. From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at high magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (higher magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] )
Psychiatric FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



Dysphoria



Withdrawal



Anxiety



Irritability



Insomnia



Loss of interest



Poor memory



Impaired concentration



Disorientation



Agitation



Less common



n = 25 to < 50



Behavioral changes



Anergia



Poor performance



Tearfulness



Weight loss



Appetite change



Hypersomnia



Confusion



Hallucinations



Impaired self care



Paranoid delusions



Inappropriate affect



Rare



n < 25



Obsessive features



Losing things



Suicidal ideation



Panic attacks



Psychomotor retardation



Diurnal mood variation



Loss of confidence



Bizarre behavior



Paranoid ideation



Recognition impairment



Confabulation



Lack of emotion



Perseveration



Impaired comprehension



Change in eating preferences



Impaired use of devices



Acalculia



Table 2. Neurologic Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] )
Neurologic FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



NoneGait disturbance



Slurring of speech



Hyperreflexia



Impaired coordination



Myoclonus



Incontinence



Eye features



Less common



n = 25 to < 50)



PainParesthesia



Numbness



Chorea



Extensor plantars



Dysphagia



Clonus



Hypertonia



Primitive reflexes



Rare



n < 25



Headaches



Dropping things



Sweatiness



Loss of consciousness



Tremors



Handwriting impairment



Coldness



Odd sensation



Dizziness



Cranial motor weakness



Dysdiadochokinesis



Taste disturbance



Startle response



Hypersensitivity



Peripheral motor weakness



Primitive reflexes



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