1. Creutzfeldt-Jakob Disease
Moussa A. Chalah, MD

2. CASE PRESENTATION CC: memory problems
HPI: A 52 years old, right-handed gentleman, presented for rapid progressive dementia over 2-3 weeks, manifested initially by difficulties in naming, motor programming, apraxia.
The patient called his daughter sometimes with the name of his sister, he would call things with different names

3. CASE PRESENTATION
HPI: He was seen by the endocrinologist who told him that he is ok. Then, things got worse:
he could not finish a phone conversation with his wife due to inability to identify persons or items; he ended the call upset
He puts objects away and could not find them later
Insomnia is also recently reported
the wife noticed as well new onset tremors and myoclonic jerks

4. CASE PRESENTATION
PMH: borderline hyperglycemia, HTN, DL; he discontinued the antihypertensive medications gradually. Oral hypoglycemic medications were also D/C after his recent weight loss
Medications and allergies:
ATORVASTATIN/EZETIMIBE (D/C)
AMLODIPINE/BENAZEPRIL (D/C)
Recently started with CLOZAPINR (Clozanex 25mg) for new onset insomnia
SH: the patient is a Jeweler, he is currently unable to work
ROS: the patient lost around 15kg

5. CASE PRESENTATION
PE: the patient is alert, awake, quiet, talks when adressed. oriented to day, but not to date.
The patient cannot register nor recall

6. CASE PRESENTATION
He talks and mixes in a sentence items that are previously described, but may have nothing to do with current sentence
TULIA: the patients shows how to hammer a nail, but then continue to hammer the nail instead of combing his hair; apraxia with perseveration
Otherwise, the exam shows no focal neurological deficit

7. CASE PRESENTATION Previous Labs:
CBCD: Hb 14.8, Ht 45, Pt 72000, WBC 6.8
ESR 8/22, INR 1.1
TSH 0.32, FT4 2 ( ), negative thyroid antibodies (microsomal)
RF: 9.3
ANA negative
CRP 2.4
Gliadin IgG negative
Phospholipids Abs normal
C-ANCA, P-ANCA negative

8. CASE PRESENTATION
Previous MRI: cortical ribbon abnormalities on FLAIR bilaterally, but no gad uptake. Not consistent with vasculitis. Bilateral atrophy mostly involving the FT lobes
Previous MRA neck/brain: normal
Previous CSF: IgG index normal, no malignant cells, Glucose 65, protein 59, lactate normal, RBC 940, WBC 8
Previous EEG: no periodic slow waves
TTE: normal

9. CASE PRESENTATION A/P: R/O CJD, repeat EEG, MRI
R/O B12, folate deficiencies
R/O thyroid disease

10. CASE PRESENTATION Vit B12 190 (240-900) Folic acid 10 (4.6-18.7)
TSH 0.723, FT4 1.07
EEG: Sleep deprived EEG which is abnormal with a diffuse moderately severe encephalopathy

11. NEUROIMAGING

13. PRION DISEASES

14. PRION DISEASES Prion: Abnormally shaped membrane-bound protein
Neurodegenerative diseases that have long incubation periods and progress inexorably once clinical symptoms appear

15. HUMAN PRION DISEASES
These human prion diseases share certain common neuropathologic features including neuronal loss, proliferation of glial cells, absence of an inflammatory response, and the presence of small vacuoles within the neuropil, which produces a spongiform appearance.
Johnson, R. “Creutzfeldt-Jakob Disease and Related Transmissible Spongioform Encephalopathies”. NEJM December 31,

16. CJD
sCJD
fCJD
iCJD
vCJD
The vast majority of CJD cases are sporadic (85 to 95 percent), while 5 to 15 percent are due to fCJD; iCJD generally accounts for less than 1 percent

17. EPIDEMIOLOGY
Incidence: 1/1,000,000 per year with a worldwide distribution, No gender predilection for CJD
Mean Age: Between 57 and 62 years, although rare cases in younger and older adults
Patients with vCJD and iCJD tend to be much younger: mode of transmission might be different?
fCJD patients have only a slightly younger age of onset compared with sCJD
In the United States, the incidence of CJD appears to be less in African Americans, American Indians, and Alaska natives compared with the white population, however this observation may have resulted from ascertainment bias

18. PATHOPHYSIOLOGY
Conversion of Normal Prion Proteins to Abnormal Isoforms
Rinne, M. “A Startling Decline”. NEJM 366;9 nejm.org march 1,

19. NEUROPATHOLOGY
On gross examination, most cases show some atrophy with ventricular enlargement
Atrophy may include the deep GM : the caudate, putamen & thalamus, while the hippocampus is spared (V/S AD)
The cerebellum may also show atrophy of the folia due to loss of GM

20. MAIN HISTOLOGIC FEATURES
Spongiform change: The intracytoplasmic vacuolization
Neuronal loss (particularly layers III-V) w/o inflammation
Accumulation of the abnormal prion protein
Synaptic loss
Nissl-Stained Specimens of Tissue from the Cortex (Left) and Striatum (Right) of One of Jakob’s Patients

21. NEUROPATHOLOGY Spongiform vacuolations can occur in other diseases:
End-stages neurodegenerative diseases have severe neuronal loss
status spongiosus as a common feature :coarse microvacuolization with astrocytosis
Vacuoles are:
Larger
More irregular
Concentrated in the upper layers (I-III) of the cerebral cortex
In FT dementias: Vacuoles are in the upper cortical layers of the frontal and temporal lobes

22. NEUROPATHOLOGY
Lewy bodies dementia: vacuoles are usually restricted to the medial temporal lobe
Acute hypoxic ischemic & other metabolic encephalopathies can also give this microscopic appearance
Finally, inadequate tissue fixation or poor processing can cause artifactual changes that resemble prion vacuoles
The clinical history + prion protein IHC generally clearly distinguishes among them

23. PRION PROTEIN IHC Accumulation of the prion protein is detected by IHC
Distribution is in several patterns:
Perivacuolar distribution
Diffuse synaptic distribution
In plaques
The plaque type can be associated with specific prion protein diseases, such as Kuru, GSS, or vCJD.

24. PRION PROTEIN IHC
The pattern and distribution of prion protein deposition may be specific to the subtype of sCJD
MM1 &MV1 subtypes associated with the synaptic pattern
MV2 and VV2 associated with plaque formation
MM2 associated with perivacuolar & loose plaque-like formatiom
ICJD related to dura mater grafts has also been associated with plaque formation

25. CLINICAL FEATURES Rapidly progressive mental deterioration & Myoclonus
Johnson, R. “Creutzfeldt-Jakob Disease and Related Transmissible Spongioform Encephalopathies”. NEJM December 31,

26. CLINICAL FEATURES: RPMD
Dementia & Behavioral abnormalities
Deficits involving higher cortical function
Concentration, memory & judgment difficulties
Sleep disturbances: hypersomnia, but also insomnia
Mood changes such as apathy and depression
euphoria, emotional lability, and anxiety (less frequently)
Mental deterioration may be manifest as dementia, behavioral abnormalities, and deficits involving higher cortical function. Concentration, memory, and judgment difficulties are frequent early signs [65]. Mood changes such as apathy and depression are common; euphoria, emotional lability, and anxiety occur less frequently. Sleep disturbances, particularly hypersomnia, but also insomnia, are also common, and may be a presenting sign [66,67]. With disease progression, dementia becomes dominant in most patients and can advance rapidly.

27. CLINICAL FEATURES: Myoclonus
Especially provoked by startle
Present in >90 % of patients at some point during the illness
May be absent at presentation, even when dementia is profound
Myoclonus, especially provoked by startle, is present in more than 90 percent of patients at some point during the illness but may be absent at presentation, even when dementia is profound. sCJD should always be considered in a patient with the combination of a rapidly progressive dementia and myoclonus.

28. CLINICAL FEATURES: CST
40-80% of patients
Hyperreflexia, extensor plantar responses & spasticity
Signs of corticospinal tract (pyramidal) involvement develop in 40 to 80 percent of patients, including such findings as hyperreflexia, extensor plantar responses (Babinski sign), and spasticity.

29. CLINICAL FEATURES: EPS
EPS: hypokinesia, cerebellar manifestations including nystagmus & ataxia
Occur in 2/3 of patients
Are the presenting symptoms in %
Isolated cerebellar syndrome early in the disease course of iCJD
Extrapyramidal signs such as hypokinesia and cerebellar manifestations, including nystagmus and ataxia, occur in approximately two-thirds of patients and are the presenting symptoms in 20 to 40 percent [65]. In particular, iatrogenic CJD related to human gonadotrophin and growth hormone treatment as well as to dura mater grafts has a propensity to manifest as a largely isolated cerebellar syndrome early in the disease course [19,63,68].

30. CLINICAL FEATURES In younger patients with sCJD
Psychiatric symptoms are more prominent
Clinical course more prolonged
May suggest vCJD, but CSF protein markers, and neuroimaging, are consistent with sCJD
Younger patients with sCJD have clinical features that are somewhat distinct from the more typical older patient. In one case series of 52 patients younger than 50 years, psychiatric symptoms were more prominent and the clinical course more prolonged than in older patients, features that may suggest variant CJD [69,70]. (See "Variant Creutzfeldt-Jakob disease".) However, test results, CSF protein markers, and neuroimaging, are consistent with sCJD.

31. CLINICAL FEATURES CNs abnormalities sensory abnormalities
Involvement of the PNS
Disturbances of pupillary responses
EOM
trigeminal neuropathy
vestibulocochlear dysfunction
Sensory signs and symptoms are common in vCJD but extremely atypical in human prion diseases
Some clinical findings, although compatible with CJD, should raise the suspicion of an alternative diagnosis, especially if they are among the more prominent features of the illness. These include cranial nerve abnormalities, sensory abnormalities, and involvement of the peripheral nervous system. Disturbances of pupillary responses, extraocular movements, trigeminal neuropathy, and vestibulocochlear dysfunction have all been reported in isolated cases but are not characteristic. Sensory signs and symptoms are common in vCJD but are otherwise extremely atypical in human prion diseases.

32. CLASSIFICATION of cCJD
Subtypes of disease have been defined based upon FND reflecting predominant involvement of individual brain regions
Visual (Heidenhain variant)
Cerebellar (Oppenheimer-Brownell variant)
Thalamic
Striatal
However, a number of variants or subtypes of disease have been defined based upon focal neurologic findings reflecting predominant involvement of individual brain regions. Examples of these include forms with mainly visual (Heidenhain variant), cerebellar (Oppenheimer-Brownell variant), thalamic, and striatal features

33. CLASSIFICATION of cCJD
Genotype of the prion protein gene (PRNP)
PRNP gene codon 129 genotype
Homozygous or heterozygous for M or V at codon 129
Phenotype: Molecular properties of the pathological prion protein (PrPSc)
Determined by Western blot analysis
classified in the Parchi/Gambetti nomenclature as type 1 or 2 depending on the size & mobility of the protease resistant core fragment (PrPres)
Collinge nomenclature
Variants of sCJD have also been classified based according to the genotype of the prion protein gene (PRNP) and the molecular properties of the pathological prion protein (PrPSc) as will be discussed next.
Molecular subtypes of sCJD — Clinical phenotypes of sporadic CJD have been associated with molecular subtypes determined by the PRNP gene codon 129 genotype and the pathologic prion protein (PrPSc) type. The PRNP genotype is homozygous or heterozygous for methionine (M) or valine (V) at codon 129. The PrPSc type is determined by Western blot analysis and classified in the Parchi/Gambetti nomenclature as type 1 or type 2 depending on the size and electrophoretic mobility of the protease resistant core fragment (PrPres) [72,73

34. CLASSIFICATION of cCJD
6 clinical phenotypes of sCJD have been described:
MM1 &MV1 (myoclonic, Heidenhain variant) account for 70% of cases and correlate with the "cCJD" phenotype of advanced age at onset, a rapidly progressive dementia with early & prominent myoclonus & a short duration of illness (3.9 months)
VV2 (ataxic variant) accounts for 15 % or less of sCJD, presents with ataxia at onset, often as an isolated feature, late dementia & a longer duration of illness (7 -9 months)
MV2 (Kuru plaque variant) accounts for 9 %, presents with ataxia, progressive dementia with prominent psychiatric features, and longer duration (17.1 months)
6 clinical phenotypes of sCJD have been described
MM1 and MV1 (myoclonic, Heidenhain variant) account for about 70 percent of cases and correlate with the "classic CJD" phenotype of advanced age at onset, a rapidly progressive dementia with early and prominent myoclonus, and a short duration of illness (mean 3.9 months). The MM1 phenotype is the one most commonly associated with periodic sharp wave complexes (PSWC) on electroencephalogram (EEG).
VV2 (ataxic variant) accounts for 15 percent or less of sCJD and presents with ataxia at onset, often as an isolated feature, late dementia, and a longer duration of illness (mean 7 to 9 months) [76].
MV2 (Kuru plaque variant) accounts for 9 percent and presents with ataxia, progressive dementia with prominent psychiatric features, and longer duration (mean 17.1 months) [77]. The protein in the CSF is a relatively insensitive marker for the MV2 variant (about 70 percent), and PSWC are only infrequently seen on EEG [75,77-79].
MM2 can present as either a thalamic variant or a cortical variant. Some, but not all, patients have a young age at onset, and the disease course is typically long, with a median disease duration of 14 months in one study [80]. The protein has been reported to be present in 61 to 91 percent of patients with MM2, and periodic sharp wave complexes (PSWCs) on EEG are more often absent than in other MM and MV subtypes [73,75,78-80]. The clinical features of MM2 type sCJD may resemble those of variant CJD. (See "Variant Creutzfeldt-Jakob disease", section on 'Clinical features'.) The thalamic MM2 variant accounts for 2 percent of cases, and mean disease duration is 15.6 months. Insomnia, psychomotor hyperactivity, ataxia, and cognitive impairment are the predominate manifestations, and this phenotype resembles that of fatal familial insomnia (FFI) [81]. (See "Diseases of the central nervous system caused by prions", section on 'Fatal familial insomnia'.) The cortical MM2 variant accounts for 2 percent of cases, with a mean disease duration of 15.7 months. Dementia is the predominate manifestation, while cerebellar and visual signs are rarely described at presentation [82].
VV1 accounts for 1 percent of cases and is notable for progressive dementia and longer duration (mean 15.3 months). A case series of nine patients with this subtype confirmed the slower, more prolonged course (median 21 months) [83]. All patients had elevated CSF levels of the protein, but none had PSWCs on EEG, and cortical rather than basal ganglia abnormalities were more common on MRI.

35. CLASSIFICATION of cCJD
MM2 may resemble those of vCJD
The thalamic MM2 variant accounts for 2 % of cases & mean disease duration is 15.6 months. Insomnia, psychomotor hyperactivity, ataxia, and cognitive impairment are the predominate manifestations; resembles (FFI)
The cortical MM2 variant accounts for 2% of cases & mean disease duration of 15.7 months. Dementia is the predominate manifestation, while cerebellar and visual signs are rarely described at presentation
VV1 accounts for 1 % of cases and is notable for progressive dementia and longer duration (mean 15.3 months)

36. CLASSIFICATION of cCJD

37. Belay, E. “Creutzfeldt-Jakob Disease Surveillance and Diagnosis” CID 2005:41, , 15 September 2005

38. DIFFERENTIAL DIAGNOSIS
It must be distinguished from other dementias:
AD & FT dementia
both can be occasionaly associated with myoclonus and a more rapidly progressive course than is typical
Prominent ataxia or parkinsonism may suggest dementia with Lewy bodies, progressive SNP, or MSA
These dementias virtually never have a disease course that progresses to death within 12 months
DIFFERENTIAL DIAGNOSIS — Creutzfeldt-Jakob disease (CJD) must be distinguished from other dementias. Occasionally Alzheimer disease (AD) and frontotemporal dementia is associated with myoclonus and a more rapidly progressive course than is typical and is therefore mistaken for CJD [93]. Prominent ataxia or parkinsonism when present may suggest dementia with Lewy bodies, progressive supranuclear palsy, or multiple systems atrophy [93-95]. However, even when more rapidly progressive than is usual, the neurodegenerative dementias virtually never have a disease course that progresses to death within 12 months, a time-frame that is typical for CJD [96].

39. DIFFERENTIAL DIAGNOSIS
Autoimmune disorders: paraneoplastic syndromes, demyelinating disease, sarcoidosis, and Hashimoto's encephalopathy
Infections: Viral & postviral encephalitis, fungal, tubercular meningitis & HIV
Malignancy including lymphoma, gliomatosis cerebri, paraneoplastic syndromes
Other entities that have been mistaken for CJD include [93,95,97-103]:
Autoimmune disorders, including paraneoplastic syndromes, demyelinating disease, sarcoidosis, and Hashimoto's encephalopathy
Infections, including viral and postviral encephalitis, fungal and tubercular meningitis, and HIV
Malignancy, including lymphoma, gliomatosis cerebri, and paraneoplastic syndromes
Toxic and metabolic encephalopathies, including alcoholic cerebral degeneration, and methylmalonic acidemia,
Cerebrovascular disease, including cerebral amyloid angiopathy, MELAS, and CADISIL
Psychiatric disease

40. DIFFERENTIAL DIAGNOSIS
Toxic & metabolic encephalopathies, including alcoholic cerebral degeneration, methylmalonic acidemia
Cerebrovascular disease, including cerebral amyloid angiopathy, MELAS & CADASIL
Psychiatric disease

41. DIAGNOSIS: BIOPSY
Brain biopsy remains the gold standard diagnostic test
Figure 1.
Histopathological Changes in Creutzfeldt–Jakob Disease.
Panel A shows a plastic-embedded section of a brain-biopsy specimen from a patient with sporadic Creutzfeldt–Jakob disease,
showing intracytoplasmic vacuoles containing fragments and loops of membranes (arrow). (Cresyl violet, ¬300.)
Panel B shows a paraffin-embedded section of a brain-biopsy specimen from a 28-year-old woman with new-variant Creutzfeldt–
Jakob disease, showing a large fibrillary amyloid plaque surrounded by patchy spongiform changes (arrows). (Hematoxylin and
eosin, ¬100; provided by Dr. James Ironside, Edinburgh, Scotland.)
Intracytoplasmic vacuoles containing fragments and loops of membranes
Large fibrillary amyloid plaque surrounded by patchy spongiform changes
Johnson, R. “Creutzfeldt-Jakob Disease and Related Transmissible Spongioform Encephalopathies”. NEJM December 31,

42. DIAGNOSIS: BIOPSY
Brain biopsy remains the gold standard diagnostic test
Figure 1.
Histopathological Changes in Creutzfeldt–Jakob Disease.
Panel A shows a plastic-embedded section of a brain-biopsy specimen from a patient with sporadic Creutzfeldt–Jakob disease,
showing intracytoplasmic vacuoles containing fragments and loops of membranes (arrow). (Cresyl violet, ¬300.)
Panel B shows a paraffin-embedded section of a brain-biopsy specimen from a 28-year-old woman with new-variant Creutzfeldt–
Jakob disease, showing a large fibrillary amyloid plaque surrounded by patchy spongiform changes (arrows). (Hematoxylin and
eosin, ¬100; provided by Dr. James Ironside, Edinburgh, Scotland.)
Patchy vacuolization in the cortical neuropil that is evidentat low and higher magnification
Images courtesy of Rebecca Folkerth, M.D., Brigham and Women’s Hospital, Boston

43. DIAGNOSIS: NEUROIMAGING
The recommended MR imaging protocol for assessment of patients with suspected CJD include:
T2 and proton density axial images with 3 mm slice thickness
FLAIR axial and sagittal images at 3 mm slice thickness
T1 images
DWI
The recommended MR imaging protocol for assessment of patients with suspected CJD include T2 and proton density axial images with 3 mm slice thickness, FLAIR axial and sagittal images at 3 mm slice thickness, T1 images, and diffusion-weighted images (DWI)

44. DIAGNOSIS: NEUROIMAGING
The gray-scale indicates the frequency in which the region shows hyperintensity, ranging from slight gray (postcentral gyrus, 28%) to dark gray (insula and superior frontal and cingulate gyri, 95%)
Tschampa, A. “Pattern of Cortical Changes in Sporadic Creutzfeldt-Jakob Disease” Tschampa AJNR 28 Jun-Jul

45. A, Axial FLAIR image shows insular cortex slightly hyperintense to neocortex
B, More superior axial FLAIR image shows relative hyperintensity in cingulate cortex
C, Axial DWI shows hyperintensity in bilateral insular cortex
D, More superior DWI shows relative hyperintensity cingulate cortex
Young, G. “Diffusion-Weighted and Fluid-Attenuated Inversion Recovery Imaging in Creutzfeldt-Jakob Disease: High Sensitivity and Specificity for Diagnosis”. AJNR Am J Neuroradiol 26:1551–1562, June/July 2005

46. DIAGNOSIS: NEUROIMAGING
T2 and FLAIR :Abnormally increased signal intensity in the putamen and head of the caudate, less commonly in the globus pallidus, thalamus, cerebral and cerebellar cortex & white matter
DWI is the most sensitive technique, especially for cortical changes & for the early stages of disease, showing abnormalities before the onset of characteristic clinical findings (myoclonus) & PSWC (EEG)
MRI abnormalities may vary with the clinical syndrome and molecular subtype

47. DIAGNOSIS: NEUROIMAGING
Evolution of MRI abnormalities 
Early CJD is characterized by increased DWI signal in cortex or deep gray matter (the caudate nucleus & anterior putamen) or both, ay be unilateral or bilateral, focal, multifocal or diffuse, and asymmetrical or symmetrical
Intermediate CJD is characterized on DWI by progression of unilateral/asymmetrical lesions to greater contralateral/symmetrical involvement and progression of caudate lesions to involve the putamen
Late or terminal CJD is characterized by prominent generalized atrophy and ventricular dilatation. Limited data suggest that loss of abnormal cortical and basal ganglionic DWI high signal may occur in some but not all cases

48. DIAGNOSIS: NEUROIMAGING
MRI is better than CT in detecting abnormalities in sCJD
CT scan is generally normal & serves to exclude other diagnoses
Serial CT scans performed over several months may show rapid ventricular enlargement & progressive cortical atrophy
Abnormal PET: Thalamic hypometabolism
SPECT: Hypoperfusion on cerebral blood

49. DIAGNOSIS: EEG
A characteristic EEG pattern of periodic synchronous bi- or triphasic PSWC is observed in 67-95% percent of patients with sCJD
PSWCs have a very high specificity for the diagnosis of sCJD
Similarity of PSWCs in sCJD to the EEG pattern seen in preterm newborns
Electroencephalogram — An electroencephalogram (EEG) can provide supportive but not definitive evidence for CJD. A characteristic EEG pattern of periodic synchronous bi- or triphasic sharp wave complexes (PSWC) is observed in 67 to 95 percent of patients with sCJD at some time during the course of the illness.
PSWCs have a very high specificity for the diagnosis of sCJD. Objective diagnostic EEG criteria proposed in 1996 were found to have a sensitivity and specificity of 67 and 86 percent, respectively for the diagnosis of CJD [131]. In addition, interobserver variability was very low. The PSWCs typical of sCJD were characterized by the following features [131]:
Strictly periodic cerebral potentials, the majority with a duration of 100 to 600 milliseconds and an intercomplex interval of 500 to 2000 milliseconds
Generalized and lateralized complexes permitted
At least five repetitive intervals with a duration difference of <500 milliseconds required to exclude semiperiodic activity
In a subsequent report from the same investigators, a much larger series of autopsy confirmed (n=150) or autopsy excluded (n=56) cases of CJD were studied [132]. Objective EEG criteria for sCJD showed a sensitivity and specificity of 64 and 91 percent, respectively, and positive and negative predictive values were 95 and 49 percent. In this study, there were five false-positive EEG results; four had Alzheimer disease, and one had vascular dementia. However, applying combined EEG criteria with clinical criteria yielded an overall specificity of 98 percent and resulted in only one false-positive case among the 56 excluded from CJD by autopsy.
The mechanism of PSWCs is speculative, but attention has been called to the similarity of PSWCs in sCJD to the EEG pattern seen in preterm newborns [ ]; cortical degeneration due to sCJD may erode the normal physiologic sleep architecture, which is replaced by activity driven from an underlying midline pacemaker, possibly thalamic, and involved with the ascending reticulothalamocortical activating system [135].
PSWCs are helpful in the differentiation of sCJD from other prion disease [132].
PSWCs are occasionally found in patients with fCJD, although PSWCs are found more commonly in patients with fCJD who have the codon 200 mutation [136].
PSWCs are not found in patients with new variant CJD (vCJD).
PSWCs are also not found in patients with kuru, Gerstmann-Straüssler-Scheinker syndrome, or fatal familial insomnia.
Other factors may contribute to the sensitivity of the PSWC finding.
Molecular subtype. In particular, PSWCs may be more commonly absent in the thalamic variant of MM2 sCJD, as well as the MV2 and VV2 subtypes [75,77,137].
Disease duration. PSWCs may not be recorded in the initial stages of the illness. The probability of recording PSWCs corresponds to the amount of neuronal loss, and serial EEG recording may be useful in patients suspected of having sCJD when initial EEG recordings are negative [133]. PSWCs typically disappear in later stages of sCJD, which is characterized by low voltage activity followed by electrocerebral inactivity [75,138].
Age. One analysis of 2083 patients with pathologically confirmed CJD found that the presence of PSWCs steadily increased with age, from 22 percent in individuals <50 years old to 67 percent in those >70 years [75].
Drugs such as barbiturates and benzodiazepines can mask PSWCs.
Iatrogenic CJD may also be less likely to be associated with PSWCs [63].

50. J Neurol Neurosurg Psychiatry2004;75:i36-i42 doi:10. 1136/jnnp. 2004

51. DIAGNOSIS: EEG
The PSWCs typical of sCJD were characterized by the following features:
Strictly periodic cerebral potentials, the majority with a duration of 100 to 600 ms and an intercomplex interval of 500 to 2000 ms
Generalized and lateralized complexes permitted
At least five repetitive intervals with a duration difference of <500 ms required to exclude semiperiodic activity
Electroencephalogram — An electroencephalogram (EEG) can provide supportive but not definitive evidence for CJD. A characteristic EEG pattern of periodic synchronous bi- or triphasic sharp wave complexes (PSWC) is observed in 67 to 95 percent of patients with sCJD at some time during the course of the illness.
PSWCs have a very high specificity for the diagnosis of sCJD. Objective diagnostic EEG criteria proposed in 1996 were found to have a sensitivity and specificity of 67 and 86 percent, respectively for the diagnosis of CJD [131]. In addition, interobserver variability was very low. The PSWCs typical of sCJD were characterized by the following features [131]:
Strictly periodic cerebral potentials, the majority with a duration of 100 to 600 milliseconds and an intercomplex interval of 500 to 2000 milliseconds
Generalized and lateralized complexes permitted
At least five repetitive intervals with a duration difference of <500 milliseconds required to exclude semiperiodic activity
In a subsequent report from the same investigators, a much larger series of autopsy confirmed (n=150) or autopsy excluded (n=56) cases of CJD were studied [132]. Objective EEG criteria for sCJD showed a sensitivity and specificity of 64 and 91 percent, respectively, and positive and negative predictive values were 95 and 49 percent. In this study, there were five false-positive EEG results; four had Alzheimer disease, and one had vascular dementia. However, applying combined EEG criteria with clinical criteria yielded an overall specificity of 98 percent and resulted in only one false-positive case among the 56 excluded from CJD by autopsy.
The mechanism of PSWCs is speculative, but attention has been called to the similarity of PSWCs in sCJD to the EEG pattern seen in preterm newborns [ ]; cortical degeneration due to sCJD may erode the normal physiologic sleep architecture, which is replaced by activity driven from an underlying midline pacemaker, possibly thalamic, and involved with the ascending reticulothalamocortical activating system [135].
PSWCs are helpful in the differentiation of sCJD from other prion disease [132].
PSWCs are occasionally found in patients with fCJD, although PSWCs are found more commonly in patients with fCJD who have the codon 200 mutation [136].
PSWCs are not found in patients with new variant CJD (vCJD).
PSWCs are also not found in patients with kuru, Gerstmann-Straüssler-Scheinker syndrome, or fatal familial insomnia.
Other factors may contribute to the sensitivity of the PSWC finding.
Molecular subtype. In particular, PSWCs may be more commonly absent in the thalamic variant of MM2 sCJD, as well as the MV2 and VV2 subtypes [75,77,137].
Disease duration. PSWCs may not be recorded in the initial stages of the illness. The probability of recording PSWCs corresponds to the amount of neuronal loss, and serial EEG recording may be useful in patients suspected of having sCJD when initial EEG recordings are negative [133]. PSWCs typically disappear in later stages of sCJD, which is characterized by low voltage activity followed by electrocerebral inactivity [75,138].
Age. One analysis of 2083 patients with pathologically confirmed CJD found that the presence of PSWCs steadily increased with age, from 22 percent in individuals <50 years old to 67 percent in those >70 years [75].
Drugs such as barbiturates and benzodiazepines can mask PSWCs.
Iatrogenic CJD may also be less likely to be associated with PSWCs [63].

52. DIAGNOSIS: EEG
PSWCs:
Are not found in patients with new variant CJD, kuru, GSS syndrome, or FFI; Less likely in iCJD
May be more commonly absent in the thalamic variant of MM2, MV2 & VV2 subtypes
May not be recorded in the initial stages of the illness: corresponds to the amount of neuronal loss
Typically disappear in later stages of sCJD, which is characterized by low voltage activity followed by electrocerebral inactivity
Its presence steadily increased with age, drugs such as barbiturates & benzodiazepines can mask PSWCs

53. DIAGNOSIS: CSF MARKERS
7 distinct isoforms of the protein, with two phosphorylated subtypes, have been found in neurons
CSF assays for 1 > of the specific isoforms may have improved specificity for distinguishing sCJD from other dementias V/S the standard commercial assay
Elevated CSF levels of most isoforms are described in AD, vascular dementia, metabolic and viral encephalopathies, and paraneoplastic syndromes
Protein markers — Several reports have suggested that abnormal CSF proteins may serve as a marker of this illness.
protein — One abnormal protein, the protein, has been advanced as a sensitive and specific diagnostic test for sCJD [139,140]. In one study, a modified western blot technique for CSF protein had a positive predictive value of 95 and 93 percent, respectively, for patients with definite and probable sCJD [140]. However, subsequent reports have found somewhat lower sensitivities and specificities of 53 to 88 percent [75, ].
In addition, "false positive" elevations in CSF have been noted in patients with a variety of neurologic diseases including herpes simplex encephalitis, hypoxic encephalopathy, cerebral metastases, paraneoplastic disease, and metabolic encephalopathies [79,140,144,145]. False-positive results are less likely in neurodegenerative disease [79]. Another report examined expression of this protein in cell cultures of neural and nonneural tissues and found the protein in all cell types, suggesting that the protein may be a marker of brain cell death rather than CJD [145].
Seven distinct isoforms of the protein, with two phosphorylated subtypes, have been found in neurons. It has been suggested that CSF assays for one or more of the specific isoforms may have improved specificity for distinguishing sCJD from other dementias compared with the standard commercial assay [146,147]. However, elevated CSF levels of most isoforms are described in a variety of other conditions including Alzheimer disease, vascular dementia, metabolic and viral encephalopathies, and paraneoplastic syndromes, indicating that none of these is clearly diagnostic of prion disease.

54. DIAGNOSIS: CSF MARKERS
The test characteristics of protein test may be influenced by several factors
sensitivity was significantly lower (62%) in patients with fCJD:
sensitivity of CSF protein was high in the classical subtypes MMI and MV1 ( %) and relatively low in most of the nonclassical subtypes, especially MM2 and MV2 (57 to 68 %)
The test characteristics of protein test may be influenced by several factors:
In one preliminary report, based on the NIH experience, the sensitivity was significantly lower (62 percent) in patients with fCJD. Based upon this report, caution should be used in interpreting negative test results in patients with possible fCJD.
The clinical and molecular heterogeneity of sCJD may also affect the results of protein testing. Studies in patients with sCJD have found that the sensitivity of CSF protein was high in the classical subtypes MMI and MV1 (91 to 100 percent) and relatively low in most of the nonclassical subtypes, especially MM2 and MV2 (57 to 68 percent) [75,77-79]. These results suggest that the CSF protein test may be helpful for diagnosis of the classical subtypes of sCJD but may be falsely negative for the nonclassical subtypes. Small numbers of patients for most of the nonclassical subtypes in this study limit the strength of these findings. In one study, a second lumbar puncture (LP) at later stages of the disease improved the sensitivity of this test [79].
In one analysis of 1032 assays for the protein, a positive result was significantly less likely when obtained more than 12 months after disease onset, compared with earlier in the disease (72 versus 92 percent) [75].

55. DIAGNOSIS: CSF MARKERS
A variety of other CSF diagnostic tests have been reported in small series:
S100 protein
Neuron specific enolase
Tau protein
A blood test, misfolded prion protein diagnostic assay, is also in development
These are of unproven diagnostic utility at present.

56. DIAGNOSIS: ROUTINE TESTS
Routine tests — Routine laboratory studies are normal in CJD with the occasional exception of LFTs
The CSF contains no cells and usually has normal glucose. An elevated CSF protein may occur in about 40 % of patients

57. DIAGNOSIS & RESEARCH
Extraneural PrPSc: Diagnosing of prion diseases by detecting abnormal prions outside of the CNS remains a major research goal
A study reported that protease-resistant prion protein isoform was detected in the urine of hamsters, cattle, and humans affected with prion disease
Subsequent study failed to confirm the presence of PrPSc by Western blot analysis in urine from patients with sporadic, familial, or variant CJD
Extraneural PrPSc — Establishing the diagnosis of prion diseases by detecting abnormal prions outside of the CNS remains a major research goal. Although a number of methods have been reported, none have been validated as diagnostic tests in human prion diseases.
One study reported that protease-resistant prion protein isoform was detected in the urine of hamsters, cattle, and humans affected with prion disease [152]. However, a subsequent study failed to confirm the presence of PrPSc by Western blot analysis in urine from patients with sporadic, familial, or variant CJD [153].
In nine patients with sCJD, PrPSc was detected at autopsy in the olfactory mucosa and cilia, but not in the respiratory mucosa and not in olfactory tissue from control patients or those with other neurodegenerative conditions [154]. This small study raises the possibility that a nasal biopsy might provide tissue for diagnosis.
Another report, using differential precipitation to concentrate PrPSc prior to performing a Western blot, found evidence of this protein in spleen and skeletal muscle specimens in approximately one-third of 36 patients with known sCJD; all patients had positive tests for PrPSc in brain tissue [155]. Patients with PrPSc detectable in spleen, muscle, or both specimens had a longer history of the disease and were more likely to have uncommon molecular variants.
PrPSc deposits were detected at autopsy in dorsal root ganglia and superficial peroneal nerve from one of three patients with sCJD [156].
The development of a streptomycin precipitation protocol holds promise in its ability to improve the rapid detection of PrPSc in extraneural tissue; as yet, this has only been demonstrated in cerebral tissues [157].

58. DIAGNOSIS & RESEARCH
In 9 patients with sCJD, PrPSc was detected at autopsy in the olfactory mucosa and cilia V/S absent in control patients or with others neurodegenerative diseases
Another report found evidence of this protein in spleen & skeletal muscle specimens in approximately 1/3 of 36 patients with known sCJD
Patients with PrPSc in spleen, muscle, or both specimens had a longer history of the disease & were more likely to have uncommon molecular variants

59. Diagnosis CDC outline the following criteria for probable sCJD:
Progressive dementia
At least 2 /4 clinical features: myoclonus, visual or cerebellar disturbance, PS/EPS, akinetic mutism
Atypical EEG during an illness of any duration
and/or a CSF assay with a clinical duration to death less than two years
and/or MRI high signal abnormalities in caudate nucleus
and/or putamen on diffusion-weighted imaging DWI or FLAIR
Routine investigations should not suggest an alternative diagnosis
The Centers for Disease Control and Prevention (CDC) outline the following criteria for probable sporadic CJD [161]:
Progressive dementia and
At least two out of the following four clinical features: myoclonus; visual or cerebellar disturbance; pyramidal/extrapyramidal dysfunction; akinetic mutism and
Atypical electroencephalogram (EEG) during an illness of any duration, and/or a positive cerebrospinal fluid (CSF) assay with a clinical duration to death less than two years, and/or magnetic resonance imaging (MRI) high signal abnormalities in caudate nucleus and/or putamen on diffusion-weighted imaging (DWI) or fluid attenuated inversion recovery (FLAIR) and
Routine investigations should not suggest an alternative diagnosis

60. Diagnosis
A definitive diagnosis requires these features in combination with one or more of the following neuropathologic findings:
Loss of neurons, gliosis, spongiform degeneration, or plaques positive for PrPSc on histopathology of brain tissue
Positive PrPSc staining following pretreatment of brain tissue with proteinase K to destroy PrPC reactivity
Positive histoblotting of brain tissue extracts for PrPSc after treatment with proteinase to destroy PrPC reactivity
Transmission of characteristic neurodegenerative disease to experimental animals
Demonstration of PRNP gene mutations
However, a definitive diagnosis requires these features in combination with one or more of the following neuropathologic findings:
Loss of neurons, gliosis, spongiform degeneration, or plaques positive for PrPSc on histopathology of brain tissue
Positive PrPSc staining following pretreatment of brain tissue with proteinase K to destroy PrPC reactivity
Positive histoblotting of brain tissue extracts for PrPSc after treatment with proteinase to destroy PrPC reactivity
Transmission of characteristic neurodegenerative disease to experimental animals
Demonstration of PRNP gene mutations

61. Diagnosis
IHC techniques such as ELISA and (CDI) can detect the presence and levels of disease-causing PrPSc in human brain tissue at autopsy or biopsy
The CDI method appears to have a much higher sensitivity for the diagnosis of sCJD disease compared with routine neuropathologic examination and IHC
CDI’s specificity remains to be established
Immunohistochemistry techniques such as ELISA and conformation-dependent immunoassay (CDI) can detect the presence and levels of disease-causing PrPSc in human brain tissue at autopsy or in biopsy samples. (See "Biology and genetics of prions", section on 'Demonstration of PrPSc'.) The CDI method appears to have a much higher sensitivity for the diagnosis of sCJD disease compared with routine neuropathologic examination and immunohistochemistry [162], but its specificity remains to be established.

62. TREATMENT & PROGNOSIS
There is no effective treatment for CJD which is uniformly fatal
Death usually occurs within one year of symptom onset
TREATMENT AND PROGNOSIS — There is no effective treatment for CJD which is uniformly fatal. Death usually occurs within one year of symptom onset [64]. An overview of past and ongoing efforts to find a treatment for CJD and other prion diseases is presented separately. (See "Diseases of the central nervous system caused by prions", section on 'Treatment of prion diseases'

63. Take-Home Message
CJD although rarem is the most frequent of the human prion diseases
1/ 1,000,000 case /year, mean age of onset between years
Clinical phenotypes of sporadic CJD have been associated with molecular subtypes: PRNP gene codon 129 genotype & the pathologic PrPSc type
Rapidly progressive mental deterioration & myoclonus are the two cardinal clinical manifestations of sCJD. EPS (hypokinesia and cerebellar manifestations) are also common
Creutzfeldt-Jakob disease (CJD) is the most frequent of the human prion diseases, although it is still rare. Approximately one case of sporadic CJD occurs per 1,000,000 population per year. The mean age of onset is between 57 and 62 years. (See 'Epidemiology and risk factors' above.)
Iatrogenic CJD has followed administration of cadaveric human pituitary hormones, dural graft transplants, use of dural mater in radiographic embolization procedures, corneal transplants, liver transplants, and the use of contaminated neurosurgical instruments or stereotactic depth electrodes. No definite cases of transfusion-associated CJD are known to have occurred; although transfusion-related variant CJD has been described. (See 'Iatrogenic CJD' above and "Variant Creutzfeldt-Jakob disease", section on 'Transfusion-related vCJD'.)
The main histologic features of prion disease are spongiform change, neuronal loss (particularly of cortical layers III-V) without inflammation, and accumulation of the abnormal prion protein. Accumulation of the prion protein is detected by immunohistochemical techniques. (See 'Neuropathology' above.)
Rapidly progressive mental deterioration, often with behavioral abnormalities, and myoclonus are the two cardinal clinical manifestations of sCJD. Extrapyramidal signs such as hypokinesia and cerebellar manifestations are also common. (See 'Clinical features' above.)
Clinical phenotypes of sporadic CJD have been associated with molecular subtypes determined by the PRNP gene codon 129 genotype and the pathologic prion protein (PrPSc) type. (See 'Molecular subtypes of sCJD' above.)
CJD is distinguished from more common causes of dementia by its rapidly progressive course with prominent myoclonus and gait disturbance. Other autoimmune, infectious, malignant, and toxic-metabolic etiologies should be considered in the differential diagnosis. (See 'Differential diagnosis' above.)
While brain biopsy is the gold standard test for diagnosis, it is often unnecessary. A typical clinical presentation with corroborating findings on magnetic resonance imaging, electroencephalography, and cerebrospinal fluid are in most cases sufficient to exclude other causes and establish CJD as the probable diagnosis. (See 'Diagnosis' above.)
MRI should be performed according to a suggested protocol and in typically shows abnormal signal in the putamen and head of the caudate. Sensitivity and specificity for typical MRI findings range between 83 to 92 percent and 87 to 95 percent respectively. (See 'MR imaging' above.)
A finding of periodic sharp wave complexes on EEG has a high specificity for the diagnosis of CJD, but a low sensitivity. (See 'Electroencephalogram' above.)
The protein test in cerebrospinal fluid is a specific test finding for CJD, but its sensitivity can be low, particularly in some molecular subtypes. (See ' protein' above.)
There is no effective treatment for CJD which is uniformly fatal. Death usually occurs within one year of symptom onset

64. Take-Home Message
Brain biopsy is the gold standard test for diagnosis, but it is often unnecessary
A typical clinical presentation with corroborating findings on:
MRI (abnormal signal in putamen and head of the caudate)
EEG (PSWC)
CSF ( protein)
Autoimmune, infectious, malignant, and toxic-metabolic etiologies should be considered in the differential diagnosis
There is no effective treatment for CJD which is uniformly fatal
Death usually occurs within one year of symptom onset

65. WORKS CITED
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Tschampa, A. Pattern of Cortical Changes in Sporadic Creutzfeldt-Jakob Disease. Tschampa AJNR 2007; 28:
Johnson, R. Creutzfeldt-Jakob Disease and Related Transmissible Spongioform Encephalopathies. NEJM. 1998; 339:
Rinne, M. A Startling Decline”. NEJM 2012; 366:e11