Sporadic Creutzfeldt-Jakob disease in adults over 80 years: a 10-year review of United Kingdom surveillance.

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68 years. Age-specific incidence declines after 80 years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. OBJECTIVE: To phenotype the clinical features and investigation profile of sCJD in adults >80 years. METHODS: We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011-2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. RESULTS: 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3 months; P < 0.001). Pyramidal signs (48.3% vs 34.2%; P = 0.008) and akinetic mutism (55.1% vs 33.2%; P < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P = 0.01) and cerebellar signs (65.4% vs 78.6%, P = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P = 0.006) and MRI was inferior (67.8% vs 91.4%; P < 0.001). CONCLUSIONS: Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive.

Sporadic Creutzfeldt-Jakob Disease in 2 Plasma Product Recipients, United Kingdom.

Sporadic Creutzfeldt-Jakob disease (sCJD) has not been previously reported in patients with clotting disorders treated with fractionated plasma products. We report 2 cases of sCJD identified in the United Kingdom in patients with a history of extended treatment for clotting disorders; 1 patient had hemophilia B and the other von Willebrand disease. Both patients had been informed previously that they were at increased risk for variant CJD because of past treatment with fractionated plasma products sourced in the United Kingdom. However, both cases had clinical and investigative features suggestive of sCJD. This diagnosis was confirmed in both cases on neuropathologic and biochemical analysis of the brain. A causal link between the treatment with plasma products and the development of sCJD has not been established, and the occurrence of these cases may simply reflect a chance event in the context of systematic surveillance for CJD in large populations.

Intensity of human prion disease surveillance predicts observed disease incidence.

BACKGROUND: Prospective national screening and surveillance programmes serve a range of public health functions. Objectively determining their adequacy and impact on disease may be problematic for rare disorders. We undertook to assess whether objective measures of disease surveillance intensity could be developed for the rare disorder sporadic Creutzfeldt-Jakob disease (CJD) and whether such measures correlate with disease incidence. METHOD: From 10 countries with national human prion disease surveillance centres, the annual number of suspected prion disease cases notified to each national unit (n=17,610), referrals for cerebrospinal fluid (CSF) 14-3-3 protein diagnostic testing (n=28,780) and the number of suspect cases undergoing diagnostic neuropathological examination (n=4885) from 1993 to 2006 were collected. Age and survey year adjusted incidence rate ratios with 95% CIs were estimated using Poisson regression models to assess risk factors for sporadic, non-sporadic and all prion disease cases. RESULTS: Age and survey year adjusted analysis showed all three surveillance intensity measures (suspected human prion disease notifications, 14-3-3 protein diagnostic test referrals and neuropathological examinations of suspect cases) significantly predicted the incidence of sporadic CJD, non-sporadic CJD and all prion disease. CONCLUSIONS: Routine national surveillance methods adjusted as population rates allow objective determination of surveillance intensity, which correlates positively with reported incidence for human prion disease, especially sporadic CJD, largely independent of national context. The predictive relationship between surveillance intensity and disease incidence should facilitate more rapid delineation of aberrations in disease occurrence and assessment of the adequacy of disease monitoring by national registries.

Iatrogenic Creutzfeldt-Jakob disease, final assessment.

The era of iatrogenic Creutzfeldt-Jakob disease (CJD) has nearly closed; only occasional cases with exceptionally long incubation periods are still appearing. The principal sources of these outbreaks are contaminated growth hormone (226 cases) and dura mater grafts (228 cases) derived from human cadavers with undiagnosed CJD infections; a small number of additional cases are caused by neurosurgical instrument contamination, corneal grafts, gonadotrophic hormone, and secondary infection with variant CJD transmitted by transfusion of blood products. No new sources of disease have been identified, and current practices, which combine improved recognition of potentially infected persons with new disinfection methods for fragile surgical instruments and biological products, should continue to minimize the risk for iatrogenic disease until a blood screening test for the detection of preclinical infection is validated for human use.

Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease.

OBJECTIVE: Variant Creutzfeldt-Jakob disease (vCJD), a novel form of human prion disease, was recognized in 1996. The disease affected a younger cohort than sporadic CJD, and the early clinical course was dominated by psychiatric and sensory symptoms. In an attempt to aid diagnosis and establish standardization between surveillance networks, diagnostic criteria were established. These were devised from the features of a small number of cases and modified in 2000 as the clinical phenotype was established. Since then, only minor changes have been introduced; revalidation of the criteria in the current format is overdue. METHODS: Included in this study are autopsy/cerebral biopsy-proven cases of vCJD referred to the National CJD Surveillance Unit (NCJDSU) between 1995 and 2004 and suspect cases in which an alternative diagnosis was identified following autopsy/cerebral biopsy. RESULTS: Over the 10-year period, 106 definite cases of vCJD and 45 pathologically confirmed "noncases" were identified from the archives of the NCJDSU. The median age at onset of the cases was significantly younger than that of the noncases (27 years [range, 12-74 years] vs 43 years [range, 10-64 years]), and the median duration of illness was significantly shorter (14 months [range, 6-39 months] vs 22 months [range, 2-139 months]). The most commonly identified core clinical feature in cases was dementia; persistent painful sensory symptoms were the least frequent. Eighty-eight of 106 (83%) vCJD cases were retrospectively classified as probable in life, 6 cases were classified as possible. Most cases were classified as probable on the basis of core clinical features and brain magnetic resonance imaging. To date, the diagnostic criteria remain 100% specific, with no autopsy/cerebral biopsy-proven noncases classified as probable in life. INTERPRETATION: This study confirms that the diagnostic criteria for vCJD are sensitive and specific and provide a useful standard framework for case classification in a surveillance setting.

Non-white cases of sporadic Creutzfeldt-Jakob disease: A 28 year review of United Kingdom National Surveillance Data.

AIMS: Descriptions of sporadic Creutzfeldt-Jakob disease (sCJD) in non-White populations are limited. Improved understanding may aid diagnoses and case ascertainment within surveillance programmes. We aimed to: 1) Ascertain the proportion of sCJD cases with non-White ethnicity in the United Kingdom (UK); 2) Compare clinical and investigation findings between non-White and White cases. METHODS: We analysed records of probable and definite sCJD cases assessed by the UK National CJD Research and Surveillance Unit over 28 years (1990-2017). Cases were stratified into White and non-White groups. Demographics, clinical features, investigation findings, and post-mortem numbers were compared. RESULTS: 1697 sCJD cases were included: 1642 (97%) White, 55 (3%) non-White (Asian/Asian British, Black/African/Caribbean). The proportion of non-Whites among sCJD cases is 7% lower than the proportion the non-White population make up in the UK (p < 0.001). This was not statistically significant when age-matched by ≥60 years (p = 0.071). Age at symptom onset was 4 years lower in the non-White population (p = 0.007). Clinical and investigation characteristics were otherwise similar between ethnic groupings. The proportion of non-Whites undergoing autopsy and classification as definite was 30% and 24% lower (p < 0.001) respectively in comparison to those for White cases. CONCLUSIONS: Approximately 3% of sCJD cases in the UK are non-White, despite non-Whites representing approximately 10% of the UK population. This difference was not statistically significant when age-matched at ≥60 years. Non-White cases tend to be younger and likelihood of autopsy is lower; relevant considerations for surveillance programmes. Reasons for these differences in non-White populations are unclear and merit further evaluation.

Variant Creutzfeldt-Jakob disease in France and the United Kingdom: Evidence for the same agent strain.

OBJECTIVE: Variant Creutzfeldt-Jakob disease (vCJD) was first reported in the United Kingdom in 1996. Since then, the majority of cases have been observed in the United Kingdom where there was a major epidemic of bovine spongiform encephalopathy. France was the second country affected. To address the hypothesis of the involvement of a common strain of agent, we have compared clinical, neuropathological, and biochemical data on vCJD patients from both countries. METHODS: In France and the United Kingdom, epidemiological and clinical data were obtained from analysis of medical records and direct interview of the family of the patients using the same standardized questionnaire in both countries. When brain material was available, we performed with similar methods a comparative study of brain lesions and PrP(res) glycoform ratios in both vCJD populations. RESULTS: Clinical data, genetic background, neuropathological finding, and biochemical findings in the 185 patients observed in France (n = 23) and the United Kingdom (n = 162) were similar except for age at death. Currently, blood transfusion is a risk factor identified only in the United Kingdom. INTERPRETATION: The close similarity between the cases of vCJD in France and the United Kingdom supports the hypothesis that a common strain of infectious agent is involved in both countries. The 5-year delay in the peak that we observed in France compared with the United Kingdom fits well with the increase in the importation of beef products to France from the United Kingdom between 1985 and 1995.

Variant Creutzfeldt-Jakob disease in a transfusion recipient: coincidence or cause?

BACKGROUND: To date there have been four instances of infection transmitted through blood transfusions derived from individuals who later developed variant Creutzfeldt-Jakob disease (vCJD). The identification of further transmission of vCJD through this route would have important implications for risk assessment and public health. STUDY DESIGN AND METHODS: Through the UK Transfusion Medicine Epidemiology Review (TMER) the fate of blood donations from individuals who develop vCJD is traced and recipients of labile components are identified. The details of recipients are cross-checked with the register of vCJD cases held at the National CJD Surveillance Unit (NCJDSU) to identify any linkage between donors and recipients. In the reverse study, when individuals with vCJD are found to have a history of blood transfusion the donors of the transfused blood components are traced and their details cross-checked with the vCJD register to identify any missed or unrecognized linkage between donors and recipients. CASE REPORT: A case of vCJD has been identified with a history of blood transfusion in infancy. The donors who provided the components transfused cannot be identified, but a blood donor known to have donated blood to another individual who subsequently developed vCJD could have been a donor to the index case. RESULTS: The at-risk donor is alive 20 years after the relevant donation and continued to donate for some years, until identified as at risk, with 27 other blood components issued for use in patients, none of whom are known to have developed vCJD. CONCLUSION: Circumstantial evidence has raised the possibility that the case in this report represents a further instance of transfusion transmission of vCJD. However, detailed investigation indicates that the pattern of events may have occurred by chance and disease in this individual may have been caused by transmission of bovine spongiform encephalopathy infection, as is the presumed cause in other primary cases of vCJD.

Investigation of variant Creutzfeldt-Jakob disease implicated organ or tissue transplantation in the United Kingdom.

BACKGROUND: Person-to-person transmission of variant Creutzfeldt-Jakob disease (vCJD) has occurred through blood transfusion and could also theoretically occur as a result of the transplantation of organs or tissues. This study aimed to investigate whether there were transplant-associated vCJD cases in the United Kingdom (UK). METHODS: Medical histories were reviewed for 177 UK vCJD cases to identify situations where the transplantation of organs or tissues might have occurred. A "look-back" was then performed to trace the respective donors or recipients of the implicated organ or tissue. RESULTS: A single patient had undergone an organ (liver) transplant before vCJD onset, from a donor who had died of causes unrelated to vCJD. The look-back was able to trace six other organ or tissue donations made by the same donor. No other situations were identified where the receipt or donation of organs or tissues had occurred in people who went on to develop vCJD. There was considered no need, on this particular occasion, to implement public health measures associated with the organ transplantation, beyond those already in place. CONCLUSIONS: This study provides no evidence of transplant-associated vCJD in the UK. It is, however, important to continue to seek to identify individuals who might be at risk of vCJD by this route so that appropriate public health measures can be implemented.

The role of cerebrospinal fluid proteins as early diagnostic markers for sporadic Creutzfeldt-Jakob disease.

The utility of cerebrospinal fluid (CSF) proteins such as 14-3-3, tau protein and S-100b as diagnostic markers in the early stages of sporadic Creutzfeldt-Jakob disease (sCJD) is unclear. We examined the diagnostic value of these CSF proteins in the early stages of sCJD (within 6 weeks of onset of symptoms). Four groups of patients were compared: patients with probable or neuropathologically confirmed sCJD with CSF taken within 6 weeks of onset ('sCJD<6-week group', n=47); patients with CSF taken within 6 weeks of disease onset but with a diagnosis other than CJD ('non-sCJD<6-week group', n=21); patients with neuropathologically proven sCJD where CSF was taken later than 6 weeks after onset ('sCJD>6-week group', n=206); patients with CSF taken later than 6 weeks after onset of symptoms but with a diagnosis other than CJD ('non-sCJD>6-week group', n=166). The sensitivity and specificity of different combinations of neuronal proteins were ascertained. The sensitivities of all three markers were similar and ranged from 96% to 98%. The sensitivity of these markers was greater in the 'sCJD<6-week group' than in the 'sCJD>6-week group'. This may be due to differences in the PRNP codon 129 and PrP isotype distribution between these groups. CSF tau protein had the greatest specificity (82%). We found all three CSF protein markers to be highly sensitive in the early stages of sCJD, with CSF tau protein having the greatest specificity and efficiency. Our findings indicate that CSF protein markers are effective tests in the early stages of sCJD.

Prion protein heterogeneity in sporadic but not variant Creutzfeldt-Jakob disease: UK cases 1991-2002.

Human prion diseases can occur as an idiopathic disorder (sporadic Creutzfeldt-Jakob disease) or can be acquired, as is the case for variant Creutzfeldt-Jakob disease. These disorders are characterized by the accumulation of a protease-resistant form of the host-encoded prion protein termed PrP(Sc) in the brains of affected individuals. PrP(Sc) has been proposed to be the principal, if not sole, component of the infectious agent, with its accumulation in the central nervous system the primary event leading to neurodegeneration. A major question remains as to whether self-propagating structural differences in PrP(Sc) might account for the clinicopathological diversity evident in Creutzfeldt-Jakob disease and whether different prion protein types underlie the existence of different strains of causative agent. Here, we describe the results of a large-scale biochemical study of PrP(Sc) from autopsy-proved cases of variant Creutzfeldt-Jakob disease (n = 59) and compare these with cases of sporadic Creutzfeldt-Jakob disease (n = 170) in the United Kingdom over the period 1991 to 2002. The results show PrP(Sc) in variant Creutzfeldt-Jakob disease to be remarkably stereotyped. In contrast, considerable heterogeneity in PrP(Sc) exists both between and within cases of sporadic Creutzfeldt-Jakob disease.