1. Creutzfeldt-Jakob disease
충남대병원 신경과
이애영

2. Case : 72 yo female 주소 : 동작이 느리고 말수가 적다 현병력
2003년 1월부터 서서히 진행하는 운동능력저하와 언어표현의 감소
가정주부, 아파트 임대업, 고졸학력
2002년 12월 남편과 사별 후 독거
정신 산만, 모든 일에 걱정,
불면증
기억장애
2003/2/02 우울증 진단, citalopram 20 mg치료
2003/2/28 어눌한 말씨, 느린 행동, 단추 끼우기, 순서대로 옷 입기 장애, 대화 시에 사용하는 단어 수 감소, 기억력 감소
과거력: 고혈압(+), 당뇨(+)
각막이식, 성장호르몬투여, 뇌수술: (-)
한약복용, 장기적인 약물복용, 독성물질 노출: (-)
가족력: 특이사항 없음

3. Physical and neurological examination
BP, 140/80 mmHg; BT, 36.4 C; PR, 80/min; RR 20/min
Alert, fully oriented to time, place, & person
Scanty verbal output, comprehensive, dysarthric
Cranial nerve functions: intact
Motor: GV/GV
Sensory: W.N.L.
DTRs: normoactive
Pathologic reflex: (-)
EPS: fine postural tremor in both hands, intermittent jerky movement in left arm, rigidity
Cerebellar function: W.N.L.
Gait: W.N.L

4. Myoclonus on the limbs

5. Laboratory tests
Routine lab. Including TFT: w.n.l. except mild hyperglycemia & hypercholesterolemia
EKG & echocardiogram: w.n.l.
ApoE genotype 3/3
CSF
Acelluar, normal protein
Neuron specific enolase (NSE) ng/ml
(serum 9.62 ng/ml control <12.5 ng/ml)
protein (+)
No mutation on PRNP gene
Polymorphism: Met/Met on codon 129

6. Cognitive function tests-1
MMSE(03/3/03)
Orientation time 2/5, place 4/5
3 words registration 3/3
Attention 0/5
Recall 0/3
Language naming 2/2
repetition 0/1
following 3 stage command 2/3
read & obey 0/1
writing 0/1
copy design 0/ Total 13/30

7. Cognitive function tests-2
Modified Mini-Mental State Examination (3MS)
Remote memory 5/5 Abstract thinking /6
Registration /3 Repetition /5
Attention /7 Comprehension /3
Primary recall /9 Writing /5
Orientation time 5/15 Drawing pentagon /10
place 4/5 Obey to 3-step order 2/3
Naming /5 Delayed recall /9
Fluency / Total /100

8. Korean-Dementia
Rating Scale (DRS)
(03/3/03)

9. Axial Diffusion weighted image and T2 weighted image at March 3, 2003

10. Serial EEG changes
03/3/04
03/3/15
03/4/15

11. SPECT findings on 03/3/04

12. Name of the disease German neurologists Creutzfeldt & Jakob (1920s)
Miller Fisher (1960)
rapidly progressing dementia, rigidity, akinesia, & mute
state followed by death

13. Definition (prion diseases)
A neurodegenerative condition that is the most common clinicopathologic subtype of transmissible spongiform encephalopathies
(prion diseases)
Transmissible spongiform encephalopathies
abnormal, protease resistant, isoform of a membrane bound glycoprotein (prion protein) deposition in brain
Hankey GJ, Wardlaw JM. Clinical neurology. 2002

14. The structure of human PrPC
Carbohydrates moiety
disulphide bridge
polypeptide backbone of mouse PrPC
glycoinositol phospholipid anchor
J Clin Pasthol: Mol Pathol 2001;54:

15. Physiological functions of PrPC
Receptor or adhesion molecule
Metabolism of neurotransmitters
Protective antioxidant activity

16. Schematic representation of the possible
molecular events underlying infection with
prions
Schematic representation of the possible molecular events underlying infection with prions. PrPC is shown in dynamic equilibrium with the unfolded PrP (A), from which [beta]-PrP can form upon reduction of the native disulphide bond (B). [beta]-PrP is prone to aggregation and may form a stable seed of PrPSc. Recruitment of either more [beta]-PrP (C) or unfolded PrP (D) leads to irreversible propagation of insoluble PrPSc. Pathogenic mutations may destabilise PrPC and move the equilibrium A to the right. Infection with a preformed seed of PrPSc will lead to recruitment and irreversible propagation directly.
J Clin Pasthol: Mol Pathol 2001;54:

17. Possible pathogenic mechanisms of neuro- -degeneration in prion
diseases
Fig. 1. Possible pathogenic mechanisms of neurodegeneration in prion diseases. PK, proteinase K; ROS, reactive oxygen species; RNS, reactive nitrogen species; Hsp60, heat shock protein 60; NF- B, nuclear factor-kappa B. Mechanism of Ageing and Development 2002;123:

18. Prion disease in human Kuru
Gerstmann-Sträussler-Scheinker disease (GSS)
Fatal familial insomnia (FFI)
Creutzfeldt-Jakob disease (CJD)

19. Unusual properties of prion disease
Extremely long incubation period
No inflammation & no disease-specific immune response
Unrelated 3 different manifestations
Infectious
Inherited
Sporadic

20. Common histopathology of prion disease
Spongiform degeneration of CNS
Reactive gliosis
Neuronal loss
Formation of amyloid plaques

21. Spongiform changes and vacuolation

22. Figure 1. New variant of Creutzfeldt–Jakob disease.
A florid plaque
Figure 1 A and B: Creutzfeldt–Jakob disease. Microscopic lesions in the cerebral cortex. A: Sporadic Creutzfeldt–Jakob disease. Numerous cavities in the neuropile indicate a spongiform change. This characteristic lesion is due to the development of vacuoles in the neuronal cytoplasm, especially in the processes. Paraffin embedding, hematoxylin and eosin stain, Objective × 20. B: New variant of Creutzfeldt–Jakob disease. A florid plaque is shown by PrP immunohistochemistry. A large rounded PrP deposit labelled by the antibodies is surrounded by vacuoles of spongiform change. Paraffin embedding, 12F10 anti PrP monoclonal antibody, generous gift of Dr J. Grassi, CEA, peroxidase-antiperoxidase (AAP) with diaminobenzidine (DAB) as a chromogen. Objective × 100.
Figure2. Neuropathologic (A, B) and immunohistochemical findings by an anti-prion protein (anti-PrP) monoclonal antibody, 3F4 (C through F). (A) The cerebral frontal cortex shows mild to moderate spongiform change, Hematoxylin–eosin. (B) The cerebellar cortex shows a congophilic plaque in the granular cell layer, Congo red. (C) Plaque-like PrP deposits are distributed in the cortex, and diffuse synaptic-type PrP immunoreactivities are detected especially in the deep cortical layers of the cortex. (D) Plaque-like PrP deposits are detected in the cerebellar cortex and cerebellar white matter. (E) Plaque-like PrP deposits are seen in the frontal cortex. (F) There are PrP deposits surrounding the neuronal cell body and processes in the deep layer of the frontal cortex. Scale bars = 50 µm.
Neurlogy 2003;60(3):
Figure 3. Immunocytochemistry for PrPRES in the cerebellum shows strong staining of large rounded plaques, with smaller clusters of plaques (centre) and abundant amorphous PrPRES deposits. KG9 anti-PrP monoclonal antibody, × 180. C.R.Bioloies 2002;325:27-31
Figure 2. immunohistochemical findings
by an anti-prion protein (anti-PrP)
monoclonal antibody
Figure 3. Immunocytochemistry
for PrPRES in the cerebellum

23. Types of CJD Sporadic 85% Iatrogenic fewer than 1%
spontaneous mutation in the gene that encodes for the prion protein
Iatrogenic fewer than 1%
prion-contaminated tissues or instruments such as corneal transplants, cadevaric GH, dura mater, contaminated neurosurgical instruments or stereotactic electrodes
Familial 10%
AD inheritance; point mutation or insertions in the prion protein gene located on the short arm of chromosome 20
nvCJD
recently seen in the UK & Europe, where the disease is likely transmitted from bovine prions

24. Risk factors Iatrogenic routes of exposure Growth hormone deficiency
Family history
Homozygosity for the valine or methionine
allele at codon 129 of the PrP gene
Mutations in the PrP gene
Occupational exposure to bovine prions

25. Epidemiology Incidence
1/million/year in general population, 5/million in persons older than 60 years
Gender : M=F
Age
median age of onset : 61 years
rare in < 30 years or > 80 years

26. Six types of CJD
3 genotypes of M/V polymorphism at codon 129 of PrP gene &
2 types of protease-resistant prion protein (types 1 & 2)
New classification (MM1, MM2, MV1, MV2, VV1, VV2) is well correlated to CJD phenotype

27. Clinical features Insidious onset Early behavioral abnormalities (10%)
personality change, withdrawal, apathy, depression, sleep disturbance, agitation, fear, paranoia
Rapidly progressive dementia
Myoclonus, stimulus-sensitive ( > 80%)
Motor abnormalities
cerebellar ataxia, extrapyramidal sign, pyramidal sign
Generalized seizure

28. Clinical variants New variant CJD Heidenhain variant
Brownell-Oppenheimer variant
Thalamic variant
Spastic paralysis with dementia
(Worster-Drought)
Amyotrophic form
More chronic & indolent form

29. New variant CJD (nvCJD)-1
Linked causally to bovine spongiform encephalopathy (BSE)
Younger onset age (<42 years, mean 26 years)
Early behavioral/psychiatric disturbance
Absence of typical EEG changes
HSI in pulvinar of thalamus on T2WI
More prolonged clinical course
Specific neuropathologic profile with extensive formation of cerebellar prion plaques
Homozygous for methionine at codon 129 of PrP gene

30. Possible routes for prion neuroinvasion?
=postulated routes

31. CJD: Infective body tissues or fluid
MEDIUM RISK CSF
Kidney
Liver
Lymph node
Spleen
HIGH RISK Brain
Dura mater
Cornea
LOW RISK TO NO RISK Adrenal gland Nasal mucus
Bone marrow Pph. nerve
Feces Saliva
Gingiva Sputum
Heart Tears
Muscle Urine
CONTROVERSIAL Blood
Am J Infect Control 2002;30:

32. Diagnostic criteria for classical CJD
Definite :
Neuropathologically confirmed and/or
Immunocytochemically confirmed PrP positive (Western blot) and/or
Scrapie-associated fibrils (SAF).
Probable :
Progressive dementia.
Typical EEG.
At least two of the following clinical features:
myoclonus, visual or cbll disturbance,,pyramidal/extrapyramidal dysfunction,,akinetic mutism
Possible :
Progressive dementia.
Two of the clinical features listed above.
No EEG done or atypical EEG.
Duration < 2 yrs.

33. Accidentally transmitted CJD
Progressive cbll syndrome in a pituitary hormone recipient.
Sporadic CJD with a recognized exposure risk
Familial CJD
Definite or probable CJD plus definite or probable CJD in a first-degree relative.
Neuropsychiatric disorder plus disease-specific prion protein (PRNP) mutation.

34. Diagnostic criteria for nvCJD
1. (a) Progressive neuropsychiatric disorder.
(b) Duration of illness > 6 months.
(c) Routine investigations do not suggest an alternative diagnosis.
(d) No history of potential iatrogenic exposure.
2. (a) Early psychiatric symptoms.
(b) Persistent painful sensory symptoms.
(c) Ataxia.
(d) Myoclonus or chorea or dystonia.
(e) Dementia.
3. (a) no typical EEG (or no EEG performed)
(b) Post. Thalamic HSI on T2WI
Definite : 1(a) & neuropathologic confirmation of nvCJD.
Probable : 1 & four-fifths of 2 & 3(a) & 3(b).
Possible : 1 & four-fifths of 2.

35. Diagnostic procedure Neuroimaging EEG CSF: 14-3-3 protein, NSE
Molecular genetic analysis
Tonsil biopsy
Brain biopsy

36. Comparison of FLAIR, DWI, & ADC map
Arch Neurol 2002;59:

37. Correlation of DWI with neuropathology in CJD
Case 2(56 yo w)
Case 1(65 yo m)
Arch Neurol 2002;59:

38. AJNR 2002;23:
Serial MR images of the evolution of ribbon-like cortical signal intensity abnormalities
4 mo
5.5 mo
6 mo
               
DWI in the early diagnosis and monitoring of the progression;
Corresponded to the localization of periodic sharp-wave

39. Evolution of lesions in CJD
Predominant striatal lesions
in the early stage
(3 mo,A & B)
Images were obtained at
5 months from the onset
AJNR 2002;23:

40. Chronological changes in striatal lesions
At 1 month from the onset
At 3 month from the onset
Chronological changes
in striatal lesions
At 1 mo.
At 3 mo.
At 3 mo.
At 5 mo.
AJNR 2002;23:

41. cortical lesions in DWI
At 2.5 month from
the onset
At 2 month from the
Onset: hyperintense
cortical lesions in DWI
AJNR 2002;23:

42. Chronologic changes in ADC in a striatal lesion
DWI
ADC
At 7 months
At 8 months
AJNR 2002;23:

43. Chronologic ADC changes in cortical lesions
DWI
ADC
DWI
ADC
At 7 months
At 8 months
AJNR 2002;23:

44. Comparison of FLAIR & T2WI for detection of lesions in CJD
Figure. 1 Fluid attenuated inversion recovery (FLAIR) axial MR images (left column: repetition time [TR], 7,282 msec; echo time [TE], 120 msec; inversion time, 2,000 msec; turbo factor, 13) and T2-weighted spin-echo axial MR images (right column: TR, 2,612 msec; TE, 100 msec) of the brain. Extensive hyperintense areas in the cerebral cortex are clearly visible on FLAIR MRI. On T2-weighted spin-echo MRI, changes are seen that could have been considered normal without knowledge of the findings on the FLAIR images. The bilateral basal ganglia and thalami show a normal signal intensity.
Neurology 2000;55:

45. Axial T2-weighted images.
These images reveal
abnormal high signal
intensities in both
caudate nucleus,
putamen and thalamus

46. MRI in CJD Bilateral symmetric high signal intensities affecting the
caudate and the putamen on T2WI:
67% SN & 93% SP for the diagnosis of CJD
DWI
- superior to that of T2WI, especially in early stages of
the illness (cortical abnormalities)
- useful to monitor the progression of the disease
- correlate well with clinical findings
- initial accumulation of abnormal cytoplasmic vacuoles
preceding the development of spongiform degeneration &
gliosis
- gliosis: high signal intensity seen on T2 & proton-density
Arch Neurol 2002;59:

47. SPECT findings in CJD

48. SPECT using a Maxicamera
in cases 1–5 and a Prism
IRIX in cases 6 and 7

49. Bursts of sharp, generalized, symmetric,
biphasic or triphasic waves during REM sleep

50. CSF 14-3-3 protein Specificity: 95% Sensitivity: 45-85%
False positive: viral encephalitis, multi-infarct dementia, stroke within one month, SAH, Rett’s syndrome, carcinomatous meningitis with SCLC

51. Differential diagnosis
Alzheimer’s disease with myoclonus
Non-convulsive status epilepticus
Metabolic/toxic encephalopathy
Bilateral subdural hematoma
CNS vasculitis
Subacute sclerosing panencephalitis
Infiltrating corpus callosum glioma
Huntington’s disease
Motor neuron disease
Psychiatric illness

52. Treatment Phenothiazine Antibacterial activity Antiviral activity
Inhibiting in vitro formation of scrapie
prions (2001, Stanley Prusiner)
Hypothetical mechanism
prion binds to a membrane bound receptor of cell followed by the activation of an endocytic process that brings the prion into the cellphenothiazines to block access of large molecules