Martin Zeidler

Diagnosis of new variant Creutzfeldt-Jakob disease

As of December 31, 1998, 35 deaths had been attributed to new variant Creutzfeldt‐Jakob disease (nvCJD) in the United Kingdom, of which 33 cases had been neuropathologically confirmed and 2 classified as probable nvCJD. Fifteen cases were male and 20 female. The median illness duration was 14 months (range, 8–38 months) and the median age at death was 29 years (range, 18–53 years). The clinical features were consistent with previous descriptions. In nearly all cases, there were early psychiatric symptoms after a median period of 6 months ataxia developed, followed by involuntary movements and cognitive impairment. Electroencephalograms did not show the “typical” appearances found in sporadic CJD, about half the cases tested had a positive 14‐3‐3 immunoassay, and over 70% of cases had bilateral pulvinar high signal on magnetic resonance brain scanning. Prion protein gene analysis showed that all cases were homozygous for methionine at codon 129. Diagnostic criteria for nvCJD have been formulated, which have a high sensitivity and specificity. Ann Neurol 2000;47:575–582

The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease.

BACKGROUND There is a need for an accurate non-invasive diagnostic test for variant Creutzfeldt-Jakob disease (vCJD). We investigated the sensitivity and specificity of bilateral pulvinar high signal on magnetic resonance imaging (MRI) for the diagnosis of vCJD. METHODS MRI from patients with vCJD and controls (patients with suspected CJD) were analysed. Scans were reviewed on two separate occasions by two neuroradiologists and scored for the distribution of changes, and likely final diagnosis. Scans from vCJD cases were reassessed to reach a consensus on all abnormalities. FINDINGS We analysed 36 patients and 57 controls. vCJD patients were correctly identified based on bilateral pulvinar high signal in 29 of 36 and 32 of 36 cases on the first assessment by the two radiologists, and 32 of 36 and 31 of 36 on their second assessment. Bilateral increased pulvinar signal was identified in one of 57 and one of 57 controls on the first assessment and two of 57 and three of 57 controls on the second assessment. These reported changes in controls were graded as minimal/equivocal in six of seven patients and moderate in one (<0.5% of all control assessments). 80% of the assessments in vCJD cases were graded as moderate or substantial. On consensus review, 28 of 36 cases and none of 57 controls had prominent bilateral pulvinar signal-sensitivity 78% (95% CI 60-90%) and specificity 100% (95% CI 94-100%). Other common MRI features of vCJD were medial thalamic and periaqueductal grey matter high signal, and the notable absence of cerebral atrophy. Pulvinar high signal correlated with histological gliosis. INTERPRETATION In the appropriate clinical context the MRI identification of bilaterally increased pulvinar signal is a useful non-invasive test for the diagnosis of vCJD.

Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95

BACKGROUND Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy. Genetic and iatrogenic forms have been recognised but most are sporadic and of unknown cause. We have studied risk factors for CJD as part of the 1993-95 European Union collaborative studies of CJD in Europe. METHODS The 405 patients with definite or probable CJD who took part in our study had taken part in population-based studies done between 1993 and 1995 in Belgium, France, Germany, Italy, the Netherlands, and the UK. Data on putative risk factors from these patients were compared with data from 405 controls. FINDINGS We found evidence for familial aggregation of CJD with dementia due to causes other than CJD (relative risk [RR] 2.26, 95% CI 1.31-3.90). No significant increased risk of CJD in relation to a history of surgery and blood transfusion was shown. There was no evidence for an association between the risk of CJD and the consumption of beef, veal, lamb, cheese, or milk. No association was found with occupational exposure to animals or leather. The few positive findings of the study include increased risk in relation to consumption of raw meat (RR 1.63 [95% CI 1.18-2.23]) and brain (1.68 [1.18-2.39]), frequent exposure to leather products (1.94 [1.13-3.33]), and exposure to fertiliser consisting of hoofs and horns (2.32 [1.38-2.91]). Additional analyses, for example stratification by country and of exposures pre-1985 and post-1985, suggest that these results should be interpreted with great caution. INTERPRETATION Within the limits of the retrospective design of the study, our findings suggest that genetic factors other than the known CJD mutations may play an important part in CJD. Iatrogenic transmission of disease seems rare in this large population-based sample of patients with CJD. There is little evidence for an association between the risk of CJD and either animal exposure, or consumption of processed bovine meat or milk products for the period studied.

Use of 14–3–3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease

OBJECTIVES The detection of the protein 14–3–3 in the CSF has been shown to be a reliable and sensitive marker for sporadic Creutzfeldt-Jakob disease (CJD). Other brain-specific proteins such as neuron specific enolase (NSE), S-100b, and tau protein have also been reported to be increased in the CSF of patients with sporadic CJD. In 1996 a variant of CJD (vCJD) was described which is likely to be causally linked to the bovine spongiform encephalopathy agent. This study reports and compares the findings of CSF brain specific protein analysis in 45 patients with vCJD and in 34 control patients. METHODS The CSF from 45 patients with vCJD and 34 controls were investigated for the presence of 14–3–3 by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting with chemiluminescent detection. Tau protein, S-100b, and NSE concentrations in CSF were measured using enzyme immunoassays. RESULTS Protein 14–3–3 was detected in the CSF of 22/45 patients with vCJD and in 3/34 controls. The mean concentrations of NSE, S-100b, and tau protein in CSF were significantly raised in patients with vCJD compared with controls. The positive predictive value of CSF 14–3–3 was 86% and the negative predictive value was 63%. These values are lower than those reported for sporadic CJD. An increased CSF tau had a positive predictive value of 93% and a negative predictive value of 81%. The combination of CSF 14–3–3 and/or increased CSF tau had a positive predictive value of 91% and a negative predictive value of 84%. CONCLUSIONS CSF protein 14–3–3 is not as useful a marker for vCJD as it is for sporadic CJD. Increased concentration of CSF tau was found to be a sensitive marker of vCJD but as concentrations may be increased in many forms of non-CJD dementia, this may limit its usefulness as a diagnostic test.

Sporadic Creutzfeldt-Jakob disease in the United Kingdom: analysis of epidemiological surveillance data for 1970-96

Abstract Objective: To identify changes in the occurrence of Creutzfeldt-Jakob disease that might be related to the epidemic of bovine spongiform encephalopathy. Design: Epidemiological surveillance of the United Kingdom population for Creutzfeldt-Jakob disease based on (a) referral of suspected cases by neurologists, neuropathologists, and neurophysiologists and (b) death certificates. Setting: England and Wales during 1970-84, and whole of the United Kingdom during 1985-96. Subjects: All 662 patients identified as sporadic cases of Creutzfeldt-Jakob disease. Main outcome measures: Age distribution of patients, age specific time trends of disease, occupational exposure to cattle, potential exposure to causative agent of bovine spongiform encephalopathy. Results: During 1970-96 there was an increase in the number of sporadic cases of Creutzfeldt-Jakob disease recorded yearly in England and Wales. The greatest increase was among people aged over 70. There was a statistically significant excess of cases among dairy farm workers and their spouses and among people at increased risk of contact with live cattle infected with bovine spongiform encephalopathy. During 1994-6 there were six deaths from sporadic Creutzfeldt-Jakob disease in the United Kingdom in patients aged under 30. Conclusions: The increase in the incidence of sporadic Creutzfeldt-Jakob disease and the high incidence in dairy farmers in the United Kingdom may be unrelated to bovine spongiform encephalopathy. The most striking change in the pattern of Creutzfeldt-Jakob disease in the United Kingdom after the epidemic of bovine spongiform encephalopathy is provided by the incidence in a group of exceptionally young patients with a consistent and unusual neuropathological profile. The outcome of mouse transmission studies and the future incidence of the disease in the United Kingdom and elsewhere, will be important in judging whether the agent causing bovine spongiform encephalopathy has infected humans. Key messages The overall incidence of Creutzfeldt-Jakob disease in the United Kingdom has increased in recent years The largest increases have been in the oldest age groups and probably represent improved case ascertainment rather than a real change in incidence The comparatively high incidence of Creutzfeldt-Jakob disease in dairy farmers in the United Kingdom is comparable to that observed in dairy farmers in countries where bovine spongiform encephalopathy is rare or absent The observation of a group of comparatively young patients with Creutzfeldt-Jakob disease characterised by unusual neuropathological features during 1994-6 remains unexplained The results of mouse transmission studies and the future incidence of Creutzfeldt-Jakob disease in the United Kingdom and elsewhere will be important in judging whether the causative agent of bovine spongiform encephalopathy has infected humans

European surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors

Medical risk factors for Creutzfeldt-Jakob disease (CJD) were analyzed in a prospective ongoing case-control study based on European CJD surveillance. Detailed data on past and recent medical history were analyzed in 405 cases and controls matched by sex, age, and hospital. Data were correlated with polymorphism at codon 129 of the prion protein gene. Our analysis did not support a number of previously reported associations and failed to identify any common medical risk factor for CJD. Although not statistically significant, brain surgery was associated with an increased risk of CJD. A detailed medical history should be obtained in every suspected CJD case in order to identify iatrogenic sources of CJD.

Original articlesEuropean surveillance on Creutzfeldt-Jakob disease: a case-control study for medical risk factors

Medical risk factors for Creutzfeldt-Jakob disease (CJD) were analyzed in a prospective ongoing case-control study based on European CJD surveillance. Detailed data on past and recent medical history were analyzed in 405 cases and controls matched by sex, age, and hospital. Data were correlated with polymorphism at codon 129 of the prion protein gene. Our analysis did not support a number of previously reported associations and failed to identify any common medical risk factor for CJD. Although not statistically significant, brain surgery was associated with an increased risk of CJD. A detailed medical history should be obtained in every suspected CJD case in order to identify iatrogenic sources of CJD.

Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease.

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.

A case of protease sensitive prionopathy in a patient in the UK

In 2008 the USA National Prion Disease Pathology Surveillance Centre reported a novel human prion disease, which they termed protease sensitive prionopathy (PSPr), based on a cohort of 11 patients [1]. The clinical features included behavioural and psychiatric presenting symptoms in addition to dementia and ataxia. The patients had a mean age at onset of 62 years and a mean duration of illness of 20 months. Neuropathological assessment showed minimal spongiform change, minimal gliosis, microplaques in the cerebellum and abnormal prion protein accumulation in the form of coarse aggregates, granules and microplaques. The patients had no known risk factors for prion exposure; no mutations in the prion protein gene (PRNP) coding sequence were found, but each patient was homozygous for valine (VV) at codon 129 of PRNP, and a family history of dementia was reported in the majority of the patients. The most striking and perhaps defining feature of the PSPr phenotype was the presence of abnormal prion protein (PrP) in a form that was markedly less protease-resistant than that found in other known human prion diseases, thus making it difficult to detect using conventional Western blot analysis for PrP, and resulting in a faint ladder of prion protein fragments extending from the low molecular weight range to the size of the N-terminally truncated PrP, characteristic of most forms of Creutzfeldt–Jakob disease (CJD) [2]. Although the family history of dementia might be taken to suggest a genetic aetiology, an acquired or a sporadic/ spontaneous aetiology could not be ruled out. An international epidemiological evidence base is lacking for PSPr. In particular, it is important to determine the true prevalence of PSPr, whether it is a new disease or a newly described entity, and whether such cases have been referred to surveillance systems outside the USA [3]. Here we report a case of human prion disease referred to the UK National CJD Surveillance Unit that shares many features with PSPr. A 56-year woman presented with forgetfulness and unusual behaviour in January 2005. Four months later she became tearful, with odd speech patterns and difficulty finding her way around. She developed increasing difficulties in recognizing and using common objects and started to confuse fictional with real life. These difficulties progressed very rapidly, plateaued for a few weeks and then progressed again. Eight months after onset, she had features of a rapidly progressing dementia with frontal lobe features (Mini Mental State Examination 8, Addenbrooke’s Cognitive Examination 29), but without any other specific neurological features. At 12 months she was significantly cognitively impaired. At 16 months, she was unable to name objects, was doubly incontinent, but mobile. Myoclonus was noted on two occasions. At 25 months, she was nearly mute, but still able to eat; by 27 months, she was in an akinetic mute state, dying in June 2008, after a total illness duration of 42 months. In the early stages of the illness, she was tearful at times, prone to become agitated and exhibited some obsessional behaviour, but these were in the context of significant cognitive decline and no specifically psychiatric features were noted. Routine blood tests were normal (save for a positive anti-thyroid peroxidase). EEGs were undertaken on five occasions between 8 and 13 months and were normal, with nonspecific generalized slowing present at 23 months. Cerebral MRI was performed on three occasions showing generalized cerebral atrophy (8 and 10 months) and increased atrophy and periventricular white matter signal change (23 months). No basal ganglia or cortical changes typical of CJD were seen. A lumbar puncture performed at 10 months yielded acellular CSF with a weak positive 14-3-3 and an S100b of 0.65 ng/ml. A weak positive 14-3-3 result is not considered to be of diagnostic significance and as such is not included in our diagnostic criteria for sporadic CJD. Analysis of the PRNP gene showed no pathogenic mutations with valine homozygosity at codon 129. In life, she did not fulfil the current clinical diagnostic criteria for either probable or possible sporadic CJD. A diagnosis of probable sporadic CJD would require typical EEG abnormalities or a definitively positive

Geographical distribution of variant CJD in the UK (excluding Northern Ireland)

BACKGROUND The agent that causes variant Creutzfeldt-Jakob disease (variant CJD) is indistinguishable from the causative agent of bovine spongiform encephalopathy (BSE). The transmission route by which human beings are infected has not been established. One hypothesis is that cases of variant CJD have resulted from exposure to the BSE agent via rendering plants involved in the production of meat and bone meal, the main vehicle of the BSE epidemic. METHODS We identified cases of variant CJD through the National CJD Surveillance Unit, and obtained lifetime residential histories of cases by interviewing a relative. The addresses of all rendering plants in the UK (excluding Northern Ireland) in production in 1988 were available from a survey done in that year. We calculated the distance between each cases place of residence on Jan 1, 1988, and the nearest rendering plant from postcode data, and used data from the 1991 UK census to estimate the population living within various distances of rendering plants. We compared the observed number of cases of variant CJD within a particular distance of a rendering plant with the number expected if there is no association between residential proximity to a rendering plant and the risk of developing variant CJD. FINDINGS Up to Aug 31, 1998, 26 cases of variant CJD with onset in the UK (Northern Ireland not included) had been identified. The observed and expected numbers of variant CJD cases living within a specified distance of any rendering plant up to 50 km were almost the same. Two plants in the county of Kent each had four cases within 50 km in 1988, significantly more cases than expected (plant A, 1.04 expected; plant B, 0.74 expected). Multiple significance tests were done, so some tests would be expected to appear significant by chance alone. Computer simulations suggested that the observation of four cases of variant CJD living in an area with a population of 1.5 million (the size of Kent) is not unexpected. INTERPRETATION There is no evidence that people with variant CJD tended to live closer than the population as a whole to rendering plants in the 1980s. The reported cluster of variant CJD cases in Kent is most probably a chance finding.