● death usually occurs within 1 yr of onset of symptoms
● 3 forms: 1) transmissible (possibly via prions), 2) autosomal dominant inherited, 3) sporadic
● characteristic EEG finding: bilateral sharp wave (0.5–2 per second)
● pathology: status spongiosus without inflammatory response
Creutzfeldt-Jakob disease (CJD) is one of 4 known rare human diseases associated with transmissible spongiform encephalopathy agents, also called prions (proteinaceous infectious particles). Although sometimes also referred to as a “slow virus,” these agents contain no nucleic acids and are also resistant to processes that inactivate conventional viruses.
Prions do not provoke an immune response. The other human prion diseases are kuru, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The protease-resistant protein associated with disease is designated PrPres or PrPSc, and is an isoform of a naturally occurring protease-sensitive protein designated PrPsen or PrPC. In the abnormal state, PrPsen, which is a predominantly alpha-helical structure, undergoes a post-translational conformation change to PrPres, which has large betasheets, and which accumulates in neural cells, disrupting function and leading to cell death and vacuolization. The famous choreographer George Balanchine died of CJD in 1983. CJD occurs in 3 forms: transmissible (possibly via prions), inherited (autosomal dominant) and sporadic
Annual incidence of CJD: 0.5–1.5 per million population with little change over time and no geographic clustering (except in locations with large numbers of familial cases). Over 200 people die of CJD in the U.S. each year.
Natural route of infection is unknown and virulence appears low, with lack of significant dissemination by respiratory, enteric, or sexual contact. There is no increased incidence in spouses (only a single conjugal pair of cases has been verified), physicians, or laboratory workers. There is no evidence of transplacental transmission. The only known cases of horizontal transmission of CJD have occurred iatrogenically. Kuru has been transmitted via handling and ingestion of infected brains in ritualistic funereal cannibalism practiced among the Fore (pronounced: “fore-ay”) linguistic group in the eastern highlands of Papua, New Guinea,14 a practice which was generally abandoned in the 1950s. Kuru is a subacute, uniformly fatal disease involving cerebellar degeneration (the word “kuru” means “to tremble” in the local language. Most noniatrogenically transmitted cases of CJD occur in patients > 50 yrs old, and is rare in age < 30. The incubation period can range from months to decades. The onset of symptoms following direct inoculation is usually faster (common range: 16–28 mos), but still may be much longer (up to 30 years with corneal transplant,16 and 4–21 yrs with hGH transmission). In experimental models of CJD, higher inoculation doses produce shorter incubation periods.
5–15% of cases of CJD occur in an autosomal dominant inheritance pattern with abnormalities in the amyloid gene18 on chromosome 20 with a penetrance of 0.56.
Since familial CJD is dominantly inherited, analysis for the PrP gene is not indicated unless there is a history of dementia in a firstdegree relative.
In ≈ 90% of cases of CJD, no infectious or familial source can be identified, and these cases are considered sporadic. 80% occur in persons 50–70 yrs old.13 Sporadic cases show no abnormality in the PrP gene. There appears to be a genetic susceptibility in the sporadic and iatrogenically transmitted CJD cases, with the majority of these showing specific changes in the human prion protein.
Described only in cases of direct contact with infected organs, tissues, or surgical instruments. Has been reported with: corneal transplants, intracerebral EEG electrodes sterilized with 70% alcohol and formaldehyde vapor after use on a CJD patient, operations in neurosurgical ORs after procedures on CJD patients, in recipients of pituitary-derived human growth hormone (hGH) (most cases have occurred in France; there is no longer a risk of CJD with growth hormone in the U.S. since distribution of pituitary derived hGH was halted in 1985 and current hGH is obtained from recombinant DNA technology), and dural graft with cadaveric dura mater (Lyodura®) (most cases have occurred in Japan). Ethylene oxide, autoclaving, formalin, and ionizing radiation do not inactivate the CJD agent
1. imaging: no characteristic CT or MR finding. These studies are frequently normal, but are essential to rule out other conditions, (e.g. herpes-simplex encephalitis, recent stroke…). Diffuse atrophy may be present, especially late. MRI may show increased intensity on T2WI in areas typically involved (basal ganglion, striatum) in up to 79% of cases (retrospectively). This is nonspecific but may help differentiate CJD from SDAT
2. blood tests: serum assays for S-100 protein are so insensitive and nonspecific that it can only be used as a diagnostic adjunct
a) routine labs: usually normal, although protein may occasionally be elevated
b) abnormal proteins:
● abnormal proteins (designated 130 & 131) have been identified in the CSF of patients with CJD,33 but the assay is technically difficult and is therefore not practical for routine clinical use ● proteins 130/131 were identified as the normal neuronal protein 14–3-3, and a relatively simple immunoassay for this was developed for use on as little as 50 mcl of CSF. Detection of the 14–3-3 protein in the CSF has 96% sensitivity and specificity for CJD among patients with dementia. False positives may occur in other conditions involving extensive neuronal destruction including: acute stroke, herpes encephalitis, multi-infarct dementia, primary CNS lymphoma and rarely SDAT (most cases of SDAT test negative). Requires CSF (cannot be done on blood)
4. EEG: characteristic finding of bilateral, symmetrical, periodic bi- or triphasic synchronous sharpwave complexes, AKA periodic spikes, AKA pseudoperiodic sharp-wave complexes (0.5–2 per second) have ≈ 70% sensitivity and 86% specificity. They resemble PLEDs, but are responsive to noxious stimulus (may be absent in familial CJD19 and in the recent UK variant
5. SPECT scan: may be abnormal in vCJD even when EEG is normal36; however, the findings are not specific for vCJD
6. brain biopsy:
7. tonsillar biopsy: patients with variant CJD (vCJD) may have detectable levels of variant type 4 of the abnormal prion protein (PrPSc) in their lymphoreticular system, which may be accessed by a 1cm wedge-biopsy of one palatine tonsil (using careful aseptic precautions)
Four patients who received dural grafts of cadaveric origin in the course of posterior fossa procedures subsequently developed Creutzfeldt-Jakob disease (CJD). The interval from dural placement to clinical onset of CJD ranged from 16 months to nine years. Initial clinical presentation consisted of cerebellar symptoms, with dementia and myoclonus developing in later stages of the disease. EEGs showed diffuse slowing that evolved to a periodic activity pattern. CT and MRI were unremarkable in the early stages but pronounced cerebral and cerebellar atrophy with widened sulci and collections of fluid over the convexities were seen in the late stages of disease. The diagnosis was histologically proved by brain biopsy in all four cases. Molecular genetic analysis showed that the four patients were homozygous for methionine at codon 129 of the PrP gene. From this experience, and from six previous descriptions of this occurrence in the literature, it is manifest that awareness of the means of iatrogenic transmission of CJD, and the adoption of preventive measures, constitute the only effective way to stop the spread of CJD among patients who have neurosurgery 1)
Fujioka H, Soejima Y, Izumihara A, Yamashita K. [A Case of Creutzfeldt-Jakob Disease before Trepanation Presenting as a Chronic Subdural Hematoma]. No Shinkei Geka. 2017 Nov;45(11):1011-1014. doi: 10.11477/mf.1436203637. Japanese. PubMed PMID: 29172208 2).
A 10-year-old boy underwent a posterior fossa craniectomy for removal of a grade 2 cerebellar astrocytoma. Dural closure was achieved by the placement of a dural graft. Eight years later the patient developed dementia and myoclonus. Electroencephalography demonstrated generalized slow activity that evolved into a pattern of periodic triphasic waves. Computed tomography scan and magnetic resonance imaging were unremarkable. Brain biopsy confirmed spongiform encephalopathy of the Creutzfeldt-Jakob type. In the light of previous reports of four similar occurrences, and of our own experience with two further cases of this disease, we believe that the cadaveric dura was the source of transmission of Creutzfeld-Jakob disease in our patient. The authors remark the importance of the awareness of this late complication of dural substitutes, both for the diagnosis of possible future cases and for taking preventive measures to stop the spread of the disease 3)