Accuracy of a history of blood donation from surrogate witnesses: data from the UK TMER study.

Look-back studies of blood transfusion in Creutzfeldt-Jakob disease commonly rely on reported history from surrogate witnesses. Data from the UK Transfusion Medicine Epidemiology Review have been analysed to determine the accuracy of the blood donation history provided by the relatives of cases. Our results show that only a small percentage of cases were found to be registered as donors on UK Blood Service (UKBS) databases when there was no family report of blood donation. In contrast, a history of reported donation was less accurate.

Isolated language impairment as the primary presentation of sporadic Creutzfeldt Jakob Disease.

OBJECTIVES: Sporadic Creutzfeldt Jakob Disease (sCJD) is a neurodegenerative disorder that typically presents as a rapidly progressive encephalopathy associated with various neurological features, culminating in akinetic mutism and death. Atypical cases, presenting with an isolated focal may cause diagnostic confusion. We described a series of patients with sCJD presenting with isolated language impairment. MATERIALS & METHODS: We report a patient with sCJD referred to the NCJDRSU, who presented with isolated language impairment and subsequently identified all cases of sporadic CJD on the NCJDRSU database (covering the years 1990-2012) with an isolated language impairment presentation. RESULTS: Nineteen patients (11 females) with sCJD (1.19% of all patients) had an isolated language disorder of at least 2 weeks duration as the first neurological symptom pattern. Mean age at onset was 68.28 years. No specific pattern of language affection was seen in these patients. Further progression usually affected more than one neurological domain, with all patients eventually developing cognitive decline and myoclonic jerks. The median duration of illness was 4 months. CSF 14.3.3 was positive and S100b level was elevated in all patients in whom it was performed. EEG and MRI showed typical features of sCJD in six patients each. Most patients showed MM genotype of PRNP codon 129. CONCLUSION: This study highlights the fact that isolated aphasia can be the first neurological symptom approximately in 1% of patients with sCJD. The diagnosis is usually made with appearance of other clinical features and investigation results, but in a small minority, these may not be apparent for relatively long periods.

Ten-year follow-up of two cohorts with an increased risk of variant CJD: donors to individuals who later developed variant CJD and other recipients of these at-risk donors.

BACKGROUND: Transmission of variant Creutzfeldt-Jakob disease (vCJD) through blood transfusion is implicated in three deaths and one asymptomatic infection. Based on this evidence, individuals assessed to be at increased risk of vCJD through donating blood transfused to individuals who later developed vCJD, or through being other recipients of such donors, are followed up to further understand the risks of vCJD transmission through blood. OBJECTIVES: To provide a ten-year follow-up of these at-risk cohorts. METHODS: Blood donors to patients who later died from vCJD were identified by the Transfusion Medicine Epidemiological Review (TMER) study. A reverse risk probability assessment quantified the risk of blood transfusion or exposure through diet as the source of vCJD in the recipients. Donors to these recipients, and these donors' other recipients, with a probability risk above 1%, are classified as at increased risk of vCJD for public health purposes. These cohorts are monitored for any vCJD occurrences. RESULTS: A total of 112 donors and 33 other recipients of their donated blood have been classified as at increased risk. After 2397 and 492 vCJD-free years of follow-up, respectively, no deaths in either at-risk cohort were of vCJD-related causes. CONCLUSIONS: The at-risk cohorts have survived disease-free far longer than the estimated incubation time for dietary-acquired vCJD (donors) and transfusion-acquired disease (other recipients). However, due to our still limited understanding of, and a lack of a reliable test for, asymptomatic vCJD infection, public health follow-up is necessary for continued monitoring of at-risk cohorts.

Creutzfeldt-Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study.

BACKGROUND AND OBJECTIVES: This paper reports the results to 31 May 2015 of an ongoing UK study to look for additional cases of variant Creutzfeldt-Jakob disease (vCJD) transmission by blood transfusion, and to seek evidence whether other subtypes of Creutzfeldt-Jakob disease (CJD) may be transmissible via blood components. MATERIALS AND METHODS: All vCJD cases of appropriate age and any sporadic CJD (sCJD) or familial CJD (fCJD) cases with a history of blood donation or transfusion are notified to the UKBS. Donation records are sought and the usage of all donations is determined by look back. Death certificates are obtained for all donors to patients with CJD and recipients of transfused components from patients with CJD who are deceased. RESULTS: The study identified 29 sCJD blood donors, of 370 reported, with transfusion to 211 recipients. Five of these recipients were reported to have died with or of dementia, but were not believed to be cases of CJD. The vCJD arm found 18 vCJD blood donors who had donated blood which was issued for clinical usage, of 24 traced donors from 177 UK vCJD cases. To date, 3 cases of vCJD have occurred in 67 recipients identified in this recipient group, and one recipient had post-mortem confirmation of abnormal prion protein deposition in the spleen (all previously reported). CONCLUSION: The results of the ongoing TMER study show no new cases of transfusion-associated vCJD since 2007 and no evidence of transfusion transmission of sCJD.

Variant CJD and blood transfusion: are there additional cases?

BACKGROUND AND OBJECTIVES: In this study, we compare variant Creutzfeldt-Jakob disease (vCJD) cases definitely linked to blood transfusion, those with a history of blood transfusion in which no donor has developed vCJD and primary cases with no history of blood transfusion. The aim is to determine whether there are any differences in the demographics or clinical phenotype in these groups that might suggest additional cases of transfusion transmission of vCJD. MATERIALS AND METHODS: All cases of vCJD who are old enough to donate blood (i.e. >17 years old) are notified to the UKBTS at diagnosis, regardless of whether they are known to have a blood donation history. A search is then made for donor records and, if found, all components produced and issued to hospitals are identified and their fate determined. Recipient details are then checked against the NCJDRSU register to establish whether there is a match between these individuals and patients who have been diagnosed with vCJD. In the reverse study, attempts are made to trace the donors to all cases reported to have received a blood transfusion and donors' details are checked against the register to determine if any have developed vCJD. RESULTS: Of the 177 cases of vCJD diagnosed in the UK as of 1 February 2014, the TMER study identified 15 cases reported to have received a blood transfusion. Transfusion records were unavailable for 4 of these cases, all pre-1980, and in one other case there was no transfusion recorded in the medical notes. Transfusion records were found for 10 cases. One case transfused at symptom onset was excluded from this analysis. The mean age at onset of symptoms of the remaining nine transfusion recipients (four female and five male) was 42·9 years; 57·6 years in the three known transfusion-transmitted cases and 35·5 years in the six not linked cases. In one of these cases, details of components transfused were unavailable, and the remaining five cases received a total of 116 donor exposures with 112 donors identified, none of whom is known to have developed clinical vCJD. To date, five of the 112 identified donors have died and none was certified as dying of vCJD or any other neurological disorder. Two of the transfusion-transmitted cases did not fulfil diagnostic criteria for probable vCJD during life but were confirmed at post-mortem. Both cases were in the older age range (68 and 74 years, respectively), and neither had a positive MRI brain scan. The remaining cases all fulfilled the criteria for the diagnosis of vCJD in life, but two of these had atypical features and were older than the expected age at onset for vCJD. CONCLUSION: In conclusion, it is possible that one or more of the vCJD cases that received a blood transfusion derived from an individual not known to have vCJD were infected by the blood transfusion. However, the evidence for this is weak, and the absence of a past history of transfusion in most cases of vCJD excludes a large number of unrecognised transfusion-transmitted cases.

Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate.

BACKGROUND: A small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there have been no reports on the findings of postmortem examination of the brain in treated patients and the reasons for the extended survival are uncertain. We report on the neuropathological findings in a case of vCJD treated with PPS. METHODS: Data on survival in vCJD is available from information held at the National CJD Research and Surveillance Unit and includes the duration of illness in 176 cases of vCJD, five of which were treated with iPPS. One of these individuals, who received iPPS for 8 years and lived for 105 months, underwent postmortem examination, including neuropathological examination of the brain. RESULTS: The mean survival in vCJD is 17 months, with 40 months the maximum survival in patients not treated with PPS. In the 5 patients treated with PPS survival was 16 months, 45 months, 84 months, 105 months and 114 months. The patient who survived 105 months underwent postmortem examination which confirmed the diagnosis of vCJD and showed severe, but typical, changes, including neuronal loss, astrocytic gliosis and extensive prion protein (PrP) deposition in the brain. The patient was also given PPS for a short period by peripheral infusion and there was limited PrP immunostaining in lymphoreticular tissues such as spleen and appendix. CONCLUSIONS: Treatment with iPPS did not reduce the overall neuropathological changes in the brain. The reduced peripheral immunostaining for PrP may reflect atrophy of these tissues in relation to chronic illness rather than a treatment effect. The reason for the long survival in patients treated with iPPS is unclear, but a treatment effect on the disease process cannot be excluded.

Risk factors for variant Creutzfeldt-Jakob disease in dental practice: a case-control study.

OBJECTIVE: To assess the risk of variant Creutzfeldt-Jakob Disease (vCJD) associated with dental treatment. DESIGN: Case-control study, investigation of links between cases. SETTING: National CJD surveillance, general dental practice and practice boards in Great Britain, 2008-2009. METHODS: Variant CJD cases were recruited from all those referred between May 1995 and August 2009 (n = 160); controls were recruited from the general population in 2003 using randomly selected geographic clusters and age-weighted sampling of individuals (n = 584). Risk factors were ascertained from dental records, with consent, using a structured questionnaire. RESULTS: Dental records were available for fewer cases (49%, 78 out of 160) than control subjects (78%, 457 out of 584). Variant CJD cases were no more or less likely than control subjects to have undergone dental treatment (p ≥0.05). Two cases had attended the same dental practice, but the type and timing of treatments did not provide strong evidence that this was linked to the route of transmission. CONCLUSION: There is no evidence of a vCJD risk associated with dental treatment, but because dental information is limited we cannot exclude this possibility. Improved methods for dental record keeping are recommended to aid future investigations of associations between infectious diseases and dental treatment.

Health professions and risk of sporadic Creutzfeldt-Jakob disease, 1965 to 2010.

In 2009, a pathologist with sporadic Creutzfeldt-Jakob Disease (sCJD) was reported to the Spanish registry. This case prompted a request for information on health-related occupation in sCJD cases from countries participating in the European Creutzfeldt Jakob Disease Surveillance network (EuroCJD). Responses from registries in 21 countries revealed that of 8,321 registered cases, 65 physicians or dentists, two of whom were pathologists, and another 137 healthcare workers had been identified with sCJD. Five countries reported 15 physicians and 68 other health professionals among 2,968 controls or non-cases, suggesting no relative excess of sCJD among healthcare professionals. A literature review revealed: (i) 12 case or small case-series reports of 66 health professionals with sCJD, and (ii) five analytical studies on health-related occupation and sCJD, where statistically significant findings were solely observed for persons working at physicians' offices (odds ratio: 4.6 (95 CI: 1.2-17.6)). We conclude that a wide spectrum of medical specialities and health professions are represented in sCJD cases and that the data analysed do not support any overall increased occupational risk for health professionals. Nevertheless, there may be a specific risk in some professions associated with direct contact with high human-infectivity tissue.

Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK.

INTRODUCTION: Establishing an early clinical diagnosis in variant Creutzfeldt-Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD. METHODS: Retrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system. RESULTS: There is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset. CONCLUSIONS: Early clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt-Jakob disease in the UK: a 10-year review.

BACKGROUND: It is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt-Jakob disease (sCJD) by the WHO. Since that time, other CSF proteins, such as S100b and tau protein, have been proposed as surrogate markers for sCJD. The authors aimed to investigate the diagnostic value of each of these three proteins. METHODS: CSF samples collected from patients who were referred to the National CJD Surveillance Unit as suspected cases of sCJD during the period 1997-2007 were analysed for 14-3-3, S100b and tau protein. The sensitivity, specificity, positive predictive value and negative predictive value of each of these markers, either alone or in combination for the diagnosis of sCJD, were assessed. The impact of CSF 14-3-3 analysis on the case classification of sCJD was investigated. RESULTS AND DISCUSSION: CSF 14-3-3 had the greatest sensitivity (86%) when compared with tau protein (81%) and S100b (65%). The combination of a positive CSF 14-3-3 or an elevated tau protein with a raised S100b had the highest positive predictive power for sCJD. During the study period, 100 patients were classified as probable sCJD solely on the basis of the clinical features and a positive CSF 14-3-3. The most sensitive marker for sCJD was a positive CSF 14-3-3. The analysis of CSF 14-3-3 plays a crucial role in the case classification of sCJD.

Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease.

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.

A retrospective case note review of deceased recipients of vCJD-implicated blood transfusions.

BACKGROUND: To date, four instances of probable transfusion-transmission of variant Creutzfeldt-Jakob disease (vCJD) infection have been described, and surviving recipients of vCJD-implicated blood components have been informed that they may be 'at risk' of vCJD. Nearly two-thirds of all recipients of vCJD-implicated blood components are deceased, and many died before the vCJD risk was known. The primary aim of this study was to determine retrospectively whether there was evidence that any of the other deceased recipients of vCJD-implicated blood components had any clinical signs or symptoms suggestive of vCJD in life. In addition, pathological material from recipients, stored at the time of surgery or autopsy, was sought to allow testing for evidence of vCJD infection. A secondary aim of the study was to obtain information on invasive healthcare procedures undertaken on recipients following the transfusion to identify the potential for onward transmission of infection. METHODS: A retrospective review of medical case notes of deceased recipients of vCJD-implicated blood components was carried out, and relevant information was extracted. In cases undergoing post-mortem, details of the findings were obtained. RESULTS: The medical case notes of 33 (83%) deceased recipients of vCJD-implicated blood components, not already known to be infected with vCJD, were reviewed. The median age of recipients was 68 years (interquartile range 57-79 years). Almost half (16) were male. The median time from transfusion to death was 175 days (interquartile range 43-701 days). Most (66%) recipients died in hospital. None of the recipients had documented evidence of clinical signs or symptoms suggestive of vCJD. Only two recipients, both of whom died within a year of transfusion, underwent autopsy examination. Neither brain nor peripheral lymphoreticular tissue was available from either recipient, and pathological material was unavailable from any of the other deceased recipients. Almost half of all recipients underwent at least one invasive healthcare procedure post-transfusion. CONCLUSIONS: A retrospective review of the medical case notes of the deceased recipients of vCJD-implicated blood components found no evidence that any further cases expressed clinical signs or symptoms suggestive of vCJD during life, but only four of the recipients survived for more than 5 years post-transfusion.

MRI lesion profiles in sporadic Creutzfeldt-Jakob disease.

BACKGROUND: With respect to sporadic Creutzfeldt-Jakob disease (sCJD), six molecular subtypes (MM1, MM2, MV1, MV2, VV1, and VV2) have been described, which vary with respect to age at disease onset, disease duration, early symptoms, and neuropathology. MRI signal alterations were reported to correlate with distinct Creutzfeldt-Jakob disease (CJD) subtypes. This multicenter, international study aimed to describe the brain MRI findings associated with each of the sCJD molecular subtypes. METHODS: Pathologically confirmed sCJD cases with codon 129 genotype (MM, MV, and VV), PrP(Sc) type, and fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted imaging (DWI) were collected in seven countries. All MRI scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus, and cerebellum. RESULTS: MRI scans were evaluated in 211 CJD patients (98 MM1, 23 MM2, 19 MV1, 30 MV2, 9 VV1, and 32 VV2). Basal ganglia hyperintensities occurred most frequently in MV2, VV2, and MM1 subtypes (79, 77, and 70%). Wide cerebral cortical signal increase was most common in VV1, MM2, and MV1 subtypes (86, 77, and 77%). Thalamic hyperintensities occurred most often in VV2 (45%) and MV2 (43%). The most consistent finding across most subtypes was high signal in basal ganglia, with these abnormalities found in 63% (FLAIR) and 71% (DWI). CONCLUSION: Cortical signal increase and hyperintensities in the basal ganglia and thalamus are detected by MRI across all molecular sporadic Creutzfeldt-Jakob disease subtypes. Our findings argue that characteristic MRI lesion patterns may occur for each molecular subtype.

Variant Creutzfeldt-Jakob disease and exposure to fractionated plasma products.

BACKGROUND: The risk to public health of onward transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion and plasma product administration is of on-going concern, particularly with the recent reported detection of abnormal prion protein in a person with haemophilia. OBJECTIVES: To describe the history of fractionated plasma product exposure in clinical cases of vCJD in the UK. METHODS: Through examination of records held at the National CJD Surveillance Unit (from relatives, general practices and hospitals). RESULTS: Nine out of 168 UK vCJD cases had a history of receipt of fractionated plasma products on 12 different occasions (1 pre-vCJD risk in 1970, the remaining between 1989-1998). According to the UK CJD Incident Panel risk assessment criteria, 11 were low-risk products and one was low or medium risk. CONCLUSION: It is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. However, the possibility that such transmission may result in vCJD cases in the future cannot be excluded.

Cold comfort pharm.

In Wilson's disease copper accumulates within the basal ganglia resulting in a movement disorder. Treatment is with copper chelation. In the case described here treatment with trientene failed because the medication was stored at the incorrect temperature.

MRI in the classical MM1 and the atypical MV2 subtypes of sporadic CJD: an inter-observer agreement study.

BACKGROUND AND PURPOSE: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. METHODS: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. RESULTS: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). DISCUSSION: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.

Cold comfort pharm.

In a difficult case when either the diagnosis remains elusive, or the treatment does not seem to work, sit down and carefully review all the records-a lesson from Wilson's disease. Practical issues to do with drug treatment may be just as important as its efficacy.

Sporadic Creutzfeldt-Jakob disease in two adolescents.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (CJD) is a condition predominantly affecting older age groups, with cases aged less than 45 years rare and an age at onset or death of less than 20 years exceptional. METHODS: Data from the systematic study of sporadic CJD in the UK are available from 1970 onwards. Clinical and pathological data are reviewed in order to identify atypical cases, including those at the extremes of the age range of sporadic CJD. Detailed analysis of atypical cases is undertaken, and in selected cases laboratory transmission studies are carried out in order to provide information on the characteristics of the infectious agent. RESULTS: In the UK, two cases of sporadic CJD in adolescents have been identified, dying at ages 16 and 20 years. The first case predated the epidemic of bovine spongiform encephalopathy and the characteristics of the second case, including laboratory transmission studies, are consistent with a diagnosis of sporadic rather than variant CJD. CONCLUSION: The cases in this report indicate that sporadic CJD can develop at a very young age, that variant CJD is not the only form of CJD occurring in this age group and that neuropathological examination is essential for accurate diagnosis of human prion disease.