Probable sCJD Research Articles

Case series of probable sporadic Creutzfeldt-Jakob disease from Eastern India

Background:Creutzfeldt-Jakob disease is a rapidly progressive, fatal, transmissible neurodegenerative disorder caused by prion protein. It is still considered rare in countries like India. This is probably due to nonavailability of autopsy studies in majority of the center. The recent European diagnostic criterion for sporadic CJD (sCJD) is useful for making an early diagnosis.Objective:To report a series of patients of probable sCJD from a neurology institute of eastern India.Materials and Methods:Patients of rapidly developing dementia fulfilling the diagnostic criteria for sCJD were included. All were investigated in detail to find out any possible treatable cause including electroencephalography (EEG), magnetic resonance imaging (MRI) of brain, and cerebrospinal fluid analysis.Results:A total 10 patients of probable sCJD diagnosed using the European diagnostic criterion between December 2011 and January 2013. The clinical features are consistent with other reported series. While 60% of patients had the classical EEG findings, 100% had typical MRI features. Eight patients died within a mean duration of 4.56 months from the disease onset.Conclusions:The clinical features are similar to other reported series. Our observation raises question about the prevalence of this disease in India which needs more elaborate studies.

Sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) comprises approximately 85% of human prion diseases and is considered due to a post-translational modification of the native prion protein. Definitive diagnosis is only possible through neuropathologic examination at postmortem analysis or via an antemortem brain biopsy. Accurate and early clinical diagnosis of sCJD is important for patients and families, and to decrease the risk of iatrogenic transmission. Moreover, the low prevalence rate and rapid course of the illness hamper researchers' ability to perform clinical trials. Probable sCJD is diagnosed after excluding all other possible causes and with the aid of EEGs and assays for detection of the 14-3-3 protein in CSF.1 However, both of these diagnostic tests have limitations, including low …

Comparison of diffusion-weighted MRI with 18F-fluorodeoxyglucose-positron emission tomography/CT and electroencephalography in sporadic Creutzfeldt–Jakob disease

18F-fluorodeoxyglucose-positron emission tomography/CT (18F-FDG PET/CT) scanning may be a useful tool for early diagnosis of sporadic Creutzfeldt–Jakob disease (sCJD), as it may reveal lowered cellular glucose transport and metabolism in the cortex, cerebellum and basal ganglia. The aim of the present study was to compare the findings from PET/CT, MRI and electroencephalography (EEG) for patients with sCJD, to explore whether typical sites or reliable patterns of regional metabolic change could be found and to evaluate the results of diagnostic imaging in the light of clinical symptomatology. Five patients with biopsy-confirmed sCJD and nine with probable sCJD (aged 36–68years) were evaluated using PET/CT, diffusion-weighted (DW)-MRI and EEG. In 13 of the 14 patients (92.86%), PET/CT imaging detected extra regions with abnormalities in addition to the hyperintense areas shown with DW-MRI. Two patients with no abnormal DW-MRI findings in the basal ganglia had bilateral extrapyramidal signs accompanied by basal ganglia hypometabolism on PET. Eight patients (57.14%) had decreased FDG uptake in the thalamic nuclei on PET scans; however, DW-MRI did not identify corresponding hyperintense changes in the thalamic nuclei. In 11 patients (78.57%), DW-MRI revealed more regions with abnormalities than EEG, and 10 patients (71.43%) had DW-MRI abnormalities in the thalamic nuclei and basal ganglia that EEG was unable to detect. There was a high level of correspondence among the PET/CT, DW-MRI and EEG results, with PET revealing more abnormal regions than the other imaging modalities. In the absence of neuropathological findings, FDG-PET could improve the accuracy of sCJD diagnosis when combined with DW-MRI and EEG, particularly for differentiating sCJD from paraneoplastic syndromes. Our results suggest that PET/CT is able to detect sCJD at an earlier stage and with greater sensitivity than DW-MRI.

Racial and Ethnic Differences in Individuals with Sporadic Creutzfeldt-Jakob Disease in the United States of America

BackgroundLittle is known about racial and ethnic differences in individuals with sporadic Creutzfeldt-Jakob disease (sCJD). The authors sought to examine potential clinical, diagnostic, genetic, and neuropathological differences in sCJD patients of different races/ethnicities.Methodology/Principal FindingsA retrospective study of 116 definite and probable sCJD cases from Johns Hopkins and the Department of Veterans Affairs Healthcare Systems was conducted that examined differences in demographic, clinical, diagnostic, genetic, and neuropathological characteristics among racial/ethnic groups. Age at disease onset differed among racial/ethnic groups. Non-Hispanic Whites had a significantly older age at disease onset compared to the other groups (65 vs. 60, p = 0.036). Non-Whites were accurately diagnosed more rapidly than Whites (p = 0.008) and non-Hispanic Whites were more likely to have normal appearing basal ganglia on brain magnetic resonance imaging (MRI) compared to minorities (p = 0.02). Whites were also more likely to undergo post-mortem evaluation compared to non-Whites (p = 0.02).Conclusions/SignificanceRacial/ethnic groups affected by sCJD demonstrated differences in age at disease onset, time to correct diagnosis, clinical presentation, and diagnostic test results. Whites were more likely to undergo autopsy compared to non-Whites. These results have implications in regards to case ascertainment, diagnosis, and surveillance of sCJD and possibly other human prion diseases.

Comparative peptidome analyses of the profiles of the peptides ranging from 1­–10 KD in CSF samples pooled from probable sporadic CJD and non-CJD patients

The shotgun strategy applying tandem mass spectrometry has been widely used to identify the proteins that are differentially distributed among diseases for its high reliability and efficiency. To find out the potential difference of protein profiles in cerebrospinal fluids (CSF) between Creutzfeldt-Jakob disease (CJD) and non-CJD patients, especially in the fraction ranging from 1–10 KD, the CSF samples of 40 probable sporadic CJD (sCJD) patients, 32 non-CJD cases with dementia and 17 non-CJD cases without dementia were separately pooled and enriched by the magnetic beads based weak cation exchange chromatography (MB-WCX). After trypsin digestion, each enriched CSF was separated and identified by RP-HPLC-ESI-QTOF MS/MS. In total, 42, 53 and 47 signals of proteins were identified in the pooled CSF fraction less than 10 KD of probable sCJD, non-CJD with dementia and non-CJD without dementia, respectively. Compared with that of probable sCJD, the similarity of CSF protein profiles of non-CJD with dementia (76.2%) were higher than that of non-CJD without dementia (57.1%). Nine CSF proteins were found to be specially observed in probable sCJD group. Those data may help to select the potential biomarkers for diagnosis of CJD. Additionally, further studies of the small segments of cellular proteins in CSF of CJD patients may also provide scientific clues for understanding the neuropathogenesis of TSEs.

Detection of anti-glutamate receptor ε2 and anti-N-methyl-d-aspartate receptor antibodies in a patient with sporadic Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) is the most common type of human prion disease. CJD, particularly sporadic CJD (sCJD), is not completely related to immunological responses. However, immune abnormalities such as elevated proand anti-inflammatory cytokines have been reported in patients with sCJD [1, 2], warranting investigation of the immunological aspects of this disease. Here we present an sCJD case with autoantibodies against the Nmethyl-D-aspartate (NMDA)-type glutamate receptor. A 70-year-old right-handed woman developed a hand tremor, right-predominant rigidity in the upper limbs, and Myerson’s sign. Two months later, she developed left hemineglect. Her memory, insight, and judgment were normal at that time, but dressing apraxia, acalculia, and Balint’s syndrome were observed. She developed idiopathic hyponatremia, but her cognitive impairment progressed even after treatment of the hyponatremia. She underwent tracheostomy (without mechanical ventilation) 6 months after onset. Subsequently, she developed myoclonus of the left upper limb. About 2 years after onset, she developed akinetic mutism. Her disease duration was more than 8 years. Serum anti-thyroid peroxidase, anti-thyroglobulin, and anti-voltage-gated potassium channel complex antibodies were found to be negative. The cell count was 1/mm, protein level was 63 mg/dl, 14-3-3 protein was strongly positive, and total tau protein was 8,860 pg/mL (cut-off value 1,300 pg/mL) in the cerebrospinal fluid (CSF) collected 6 months after onset. Diffusion-weighted imaging performed 7 months after onset showed widespread cortical hyperintensity (Fig. 1a), but the signal changes were less evident on fluid-attenuated inversion recovery (Fig. 1b). An electroencephalogram showed diffuse slow waves at early stages, and periodic sharp wave complexes (PSWCs) were evident about two and a half years after onset. She was homozygous for methionine at prion protein gene codon 129, and no mutations were identified. Probable sCJD was diagnosed as per the World Health Organization criteria [3]. Accordingly, she did not receive any immunotherapy. Real-time quaking-induced conversion (RT-QUIC) [4] of CSF performed later was positive for PrP, validating the diagnosis of CJD. This study has been approved by the Ethics Committee of the Tokushima University Hospital and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. Immunoblot analysis, as described previously [5], detected IgG antibody to the entire NMDA-type glutamate receptor e2 molecule (GluRe2, also called NR2B) in CSF. K. Fujita (&) Y. Izumi R. Kaji Department of Clinical Neuroscience, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan e-mail: kof@clin.med.tokushima-u.ac.jp

The Epidemiological, Clinical, and Laboratory Features of Sporadic Creutzfeldt-Jakob Disease Patients in China: Surveillance Data from 2006 to 2010

BackgroundCreutzfeldt-Jakob disease (CJD) is a rare, rapidly progressive fatal central nervous system disorder, which consists of three main catalogues: sporadic, familial, and iatrogenic CJD.Methodology/Principal FindingsIn China, the surveillance for CJD started in 2006, covering 12 provincial Centers for Disease Control and Prevention (CDCs) and 15 hospitals. From 2006 to 2010, 624 suspected patients were referred to China CJD surveillance. The epidemiological, clinical and laboratory features of sporadic CJD (sCJD) were analysed. Both groups of probable and possible sCJD showed highest incidences in the population of 60 to 69 year-olds. The most common presenting symptoms were progressive dementia and mental-related symptoms (neurological symptoms including sleeping turbulence, depression, anxiety and stress). Among the four main clinical manifestations, myoclonus was more frequently observed in the probable sCJD patients. About 2/3 of probable sCJD cases showed positive 14-3-3 in CSF and/or periodic sharp wave complexes (PSWC) in electroencephalography (EEG). The presence of myoclonus was significantly closely related with the appearance of PSWC in EEG. Polymorphisms of codon 129 in PRNP of the notified cases revealed a highly predominant M129M genotype in Han Chinese. Among 23 genetic human prion diseases, ten were D178N/M129M Fatal familial insomnia (FFI) and five were T188K genetic CJD (gCJD), possibly indicating a special distribution of gCJD-related mutations in Han Chinese.ConclusionFrom the period of 2006 to 2010, 261 patients were diagnosed as sCJD and 23 patients were diagnosed as genetic human prion diseases in China. The epidemiological, clinical and laboratory analysis data were consistent with the characteristics of sporadic CJD, which provide insight into the features of CJD in China.

Temporal evolution of sporadic Creutzfeldt–Jakob disease monitored by 3-Tesla MR spectroscopy

Creutzfeldt–Jakob disease (CJD) is a progressive neurodegenerative disease. How the lesions of CJD initiate and propagate in the brain remains largely unknown. Magnetic resonance (MR) techniques including proton MR spectroscopy (MRS) are useful for diagnosing CJD [1–3]. MRS allows for noninvasive and spatially resolved measurement of several brain compounds, including N-acetyl aspartate (NAA), a neuronal marker, and choline-containing compounds (Cho), a marker of membrane density and integrity [4]. However, the use of MRS to investigate the temporal evolution of CJD has been limited. We analyzed serial 3-Tesla MRS findings in patients with sporadic CJD (sCJD). Two patients with diagnoses of probable (case 1) and definite (case 2) sCJD [5] were enrolled. The profiles of patients are summarized in Table 1. MRS examinations were performed using a 3-Tesla MR unit (Signa 3T HDx; GE Medical Systems, Milwaukee, WI, USA). Each patient underwent the sessions twice at intervals of 4 (case 1) and 6 (case 2) weeks. MR spectra were obtained using the multivoxel method performed with chemical shift imaging (repetition time/echo time = 1,500/144 ms). The MRS values from voxels of interest in the left cerebrum were analyzed (Fig. 1a). The comparison was made between the two MRS studies in each patient. The values of NAA, Cho, lactate, and the Cho to NAA ratio (Cho/NAA) were compared using Student’s t tests. Statistical significance was accepted for p \ 0.05. This study was approved by the Ethics Committee and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. In case 1, the MRS analysis showed a significant decrease in NAA (p \ 0.05, Fig. 1b), a trend toward increased Cho (mean values, 1,100 vs. 1,314, p = 0.07), and a significant increase in the Cho/NAA (p \ 0.005, Fig. 1c) over time. In case 2, although a decrease in NAA was found, it was not significant (mean values, 238 vs. 163, p = 0.29), there were no significant temporal changes in Cho (mean values, 428 vs. 470, p = 0.78), and the Cho/ NAA was significantly increased (p \ 0.005, Fig. 1d). Interestingly, lactate peaks were noted in all sessions of both cases. The lactate values were not significantly different in the serial studies of each case (mean values: case 1, 146 vs. 163, p = 0.52; case 2, 105 vs. 145, p = 0.25). In case 2, a necropsy of the left frontotemporal lobe confirmed the diagnosis of definite sCJD (Fig. 1e–f). Our study revealed that the Cho/NAA increased over time and lactate peaks were present in the 3-Tesla MRS studies of patients with sCJD. A reduced NAA to Cho ratio (or elevated Cho/NAA) has been reported in familial CJD [6]. Increases in Cho/NAA have also been reported in malignant tumors, cerebral infarctions, inflammation, and K. Fujita (&) Y. Izumi R. Kaji Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan e-mail: kof@clin.med.tokushima-u.ac.jp

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

BackgroundIt 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...

MRI sequence findings in sporadic Creutzfeldt–Jakob disease

MRI has had an important role in the diagnosis of Creutzfeldt–Jakob disease (CJD). The aim of our study was to compare the efficacy of different MRI sequences among six biopsy-proven patients with sporadic CJD (sCJD) and seven patients with probable sCJD. These 13 patients with CJD aged from 36 years to 75 years (mean age: 55.5 years) were evaluated with T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) MRI and diffusion-weighted imaging (DWI). The characteristic MRI lesion pattern was found to be bilateral, symmetric and hyperintense signal changes in the basal ganglia and cortical regions. Two major lesion patterns were identified in all patients involving the cortex and basal ganglia. No signal abnormality was found in the thalamus. We found lesions in the cortex and basal ganglia in 7/13 patients (54%), isolated cortical involvement in 2/13 patients (15%), and isolated basal ganglia lesions in 4/13 patients (31%). The cortical involvement was widespread (in at least two regions) and usually included the frontal or occipital lobes (9/13, 69%) on DWI. Only one patient showed moderate high-signal intensity in the basal ganglia on T2-weighted MRI. T1-weighted MRI revealed no signal intensity abnormalities. We conclude that high signal changes in the basal ganglia and cerebral cortex on FLAIR and DWI are useful in the diagnosis of sCJD. Isolated cortical involvement on DWI and FLAIR should lead to a suspicion of CJD. DWI is the most sensitive MRI technique in the diagnosis of CJD, which supports an amendment to the clinical diagnostic criteria for sCJD to include findings from MRI.

Nosocomial transmission of sporadic Creutzfeldt–Jakob disease: results from a risk-based assessment of surgical interventions

ObjectivesEvidence of surgical transmission of sporadic Creutzfeldt–Jakob disease (sCJD) remains debatable in part due to misclassification of exposure levels. In a registry-based case–control study, the authors applied a risk-based classification...

Sporadic Creutzfeldt-Jakob disease mimicking nonconvulsive status epilepticus

Nonconvulsive status epilepticus (NCSE) in patients with confusion may be difficult to distinguish from nonepileptic (metabolic/toxic, postanoxic, and spongiform) encephalopathies. This study aimed to describe the misleading presentation of patients with sporadic Creutzfeldt-Jakob disease (sCJD) who were initially diagnosed with a refractory NCSE (rNCSE). We retrospectively reviewed the clinical characteristics, EEG records, brain MRI scans, 14-3-3 protein detection in CSF, genotype of the prion protein gene, and neuropathologic data of patients referred to our neurologic intensive care unit (NICU) with this presentation. Ten patients with a final diagnosis of definite (n = 7) or probable (n = 3) sCJD were referred to our NICU with an initial diagnosis of rNCSE. Reanalysis of the EEG ruled out ictal rhythmic activities, but showed diffuse, periodic, or semiperiodic sharp-wave complexes (PSWC) with short period. PSWC were briefly attenuated by auditory (n = 5) or painful (n = 3) stimuli and by IV injection of antiepileptic drugs (n = 5) but without clinical improvement. In addition, PSWC showed fluctuations according to the vigilance level (n = 5). Brain MRI showed hyperintensities in basal ganglia (n = 9/10) and in cortical areas (n = 7/10). 14-3-3 Protein was detected in CSF (n = 10). Only 2 sCJD subtypes were found (MM1 5/7, MV1 2/7). This series of patients suggests that sporadic Creutzfeldt-Jakob disease should be considered as a differential diagnosis, rather than as a cause, of apparent refractory nonconvulsive status epilepticus. Criteria for nonconvulsive status epilepticus diagnosis should rely on careful examination of both EEG parameters and clinical state so that aggressive, unnecessary treatments can be avoided.

Surveillance for Creutzfeldt-Jakob disease in China from 2006 to 2007

BackgroundHuman transmissible spongiform encephalopathies (HTSE), or Creutzfeldt-Jakob disease (CJD), is a group of rare and fatal diseases in central nervous system. Since outbreak of bovine spongiform encephalopathy (BSE) and variant CJD, a worldwide CJD surveillance network has been established under the proposition of WHO. In China, a national CJD surveillance system has started since 2002. The data of CJD surveillance from 2006 to 2007 was analyzed.MethodsTotal 12 provinces are included in CJD surveillance system. The surveillance unit in each province consists of one or two sentinel hospitals and the provincial CDC. All suspected CJD cases reported from CJD surveillance were diagnosed and subtyped based on the diagnostic criteria for CJD issued by WHO.ResultsTotal 192 suspected CJD cases were reported and 5 genetic CJD, 51 probable and 30 possible sporadic CJD (sCJD) cases were diagnosed. The collected sCJD cases distribute sporadically without geographical clustering and seasonal relativity and the highest incidences in both probable and possible sCJD cases appeared in the group of 60–69 year. The most common three foremost symptoms were progressive dementia, cerebellum and mental-related symptoms. The probable sCJD patients owning both typical EEG alteration and CSF protein 14-3-3 positive have more characteristic clinical syndromes than the ones having only one positive. The polymorphisms of codon 129 of all tested reported cases shows typical patterns of Han Chinese as previous reports, that M129M are predominant whereas M129V are seldom.ConclusionChinese CJD patients possessed similar epidemiological and clinical characteristics as worldwide.

Surgery and Risk of Sporadic Creutzfeldt-Jakob Disease in Denmark and Sweden: Registry-Based Case-Control Studies

Background: Epidemiologic evidence of surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD) remains controversial. Methods: From Danish and Swedish registries we selected 167 definite and probable sCJD cases (with onset between 1987 and 2003) and 3,059 controls (835 age-, sex-, and residence-matched, and 2,224 unmatched). Independent of case/control status, surgical histories were obtained from National Hospital Discharge Registries. Surgical procedures were categorized by body system group and lag time to onset of sCJD. Exposure frequencies were compared using logistic regression. Results: A history of any major surgery, conducted ≧20 years before sCJD onset, was more common in cases than both matched (OR = 2.44, 95% CI = 1.46–4.07) and unmatched controls (OR = 2.25, 95% CI = 1.48–3.44). This observation was corroborated by a linear increase in risk per surgical discharge (OR = 1.57, 95% CI = 1.13–2.18; OR = 1.50, 95% CI = 1.18–1.91). Surgery of various body systems, including peripheral vessels, digestive system and spleen, and female genital organs, was significantly associated with increased sCJD risk. Conclusions: A variety of major surgical procedures constitute a risk factor for sCJD following an incubation period of many years. A considerable number of sCJD cases may originate from health care-related accidental transmission.

Relationship between clinical course and Diffusion-weighted MRI findings in sporadic Creutzfeldt-Jakob Disease

The aim of this study was to investigate the relationship between clinical course and diffusion-weighted MRI (DWI) findings in sporadic Creutzfeldt-Jakob Disease (sCJD). We reviewed clinical records and MRI examination in nine probable sCJD. According to hyperintense signal distribution on DWI, the patients were classified into two groups with cortical ribbon plus basal ganglia hyperintensity (6/9) and with only increased cortical signals (3/9). Clinical features including quadriparesis (3/6), akinetic mutism (2/6), and dysphasia (2/6), which were usually observed in the more advanced stage of CJD, were noted only in patients with cortical ribbon plus basal ganglia hyperintensity at the time of initial DWI examination. The patients with the cortical plus basal ganglia hyperintensity (6.4+/-1.7 weeks) had a shorter interval from symptom onset to akinetic mutism than those with only cortical ribbon hyperintensity (26.0+/-22.5 weeks) (p=0.02). These findings suggest that DWI may predict the clinical course of CJD.

Striatal [123I] FP-CIT SPECT demonstrates dopaminergic deficit in a sporadic case of Creutzfeldt-Jakob disease

The frequent occurrence of movement disorders such as myoclonus, parkinsonism and dystonia, strongly suggests an involvement of the dopaminergic system in sporadic Creutzfeldt-Jakob disease (sCJD), but this issue has not been specifically addressed yet. We report a patient who after a sub-acute focal clinical onset, developed the full clinical picture of probable sCJD. Given the early unilateral right extrapyramidal rigidity, the patient was assessed by single-photon emission computed tomography of the dopamine transporter (DAT) using [123I] FP-CIT. DAT-scan demonstrated reduced values of presynaptic receptorial trace in the putamen, particularly on the left side, consistent with functional putaminal dopaminergic presynaptic alteration. The present observation emphasizes the possible role of DAT imaging studies in the investigation of the pathogenesis of movement disorders in CJD.

Prion diseases are undercompulsory notification in Brazil: Surveillance of cases evaluated by biochemicaland/or genetic markers from 2005 to 2007.

The emergence of the new variant of Creutzfeldt-Jakob disease (vCJD) in the United Kingdom has raised concerns over the risks of this prion disease in other parts of the world. Since 2005, human prion diseases have been under compulsory notification in Brazil. It is well known that some polymorphisms within the cellular prion gene (PRNP) have been associated to a higher susceptibility to sporadic CJD (sCJD) and vCJD.ObjectivesTo describe the first notified cases and to evaluate the presence of mutations and polymorphisms of the PRNP in these cases.MethodsThirty-five notified cases were evaluated by clinical, auxiliary exams and biochemical and/or genetic tests and classified according to the World Health Organization criteria for CJD. A control group (N=202) was included for the purpose of comparing the genetic analyses.ResultsTwenty seven cases (74%) were classified as possible sCJD while 51% fulfilled the criteria for probable sCJD. Brain tissue analysis was available in three cases, where two were classified as definite sCJD and one as unconfirmed sCJD. Mutation of the PRNP was not found, and regarding the codon 129 polymorphism, valine in both alleles (Val129Val) was more frequent in patients than in the control group (OR=4.98; 1.55-15.96; p=0.007) when all possible cases were included, but not when only probable cases were considered.ConclusionsOur data did not show correlation of PRNP polymorphisms with probable sCJD cases. It is necessary to work toward notification of all cases of possible CJD in Brazil and to increase the rate of definitive diagnoses.

MRI in the diagnosis of sporadic Creutzfeldt–Jakob disease: a study on inter-observer agreement

According to the current WHO criteria, technical investigations included in the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) are electroencephalogram (EEG) and CSF-analysis for 14-3-3 proteins. MRI is not a criterion for the diagnosis of sCJD, although typical changes have been described. We investigated the reliability of MRI in the sCJD diagnosis, evaluated MRI sequences and compared MRI with EEG and 14-3-3. This study includes 193 consecutive suspected sCJD patients who had been referred to the German CJD Surveillance Unit from 2001 to 2003. Three observers independently analysed MRI scans, blinded to clinical data. MRI was rated as 'typical for sCJD' if increased signal intensity was detected in the caudate nucleus and putamen. We analysed 442 MRI scans [184 T2-weighted sequences, 132 fluid attenuated inversion recovery (FLAIR) sequences, 75 diffusion-weighted sequences and 51 proton-density weighted sequences]. Inter-observer agreement was 123 of 193 patients or 63.7% (overall kappa = 0.53). Sensitivity of MRI in clinically probable or autopsy-proven sCJD was 59.7% for Observer 1, 58.3% for Observer 2 and 70.8% for Observer 3; specificity was high (84.2, 89.5 and 81.6%, respectively). Diffusion-weighted sequences best showed the pathologic changes, followed by FLAIR. Periodic sharp and slow wave complexes were detected in the EEG in 32% (sensitivity), the 14-3-3 proteins in CSF were elevated in 91%. We conclude that the detection of hyperintense basal ganglia in MRI helps to improve the clinical diagnosis, and therefore, we propose to incorporate MRI in the diagnostic criteria for sCJD.

Creutzfeldt-Jakob disease associated with an R148H mutation of the prion protein gene

Sirs, Prion diseases are transmissible diseases that include sporadic, acquired and familial disorders. More than 30 point mutations and insert mutations of the prion protein gene (PRNP) are thought to cause familial prion diseases, i.e. familial Creutzfeldt-Jakob disease (fCJD), GerstmannStraussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Clinical and pathological changes may be similar or indistinguishable from sporadic CJD (sCJD) as in fCJD associated with the E200K mutation, or may be quite different from sCJD as in the P102L mutation that is associated with GSS [1]. The clinical and pathological appearance of sCJD is linked to a methionine–valine polymorphism at codon 129 of PRNP and the biochemical isoform of PrP [2]. The influence of the codon 129 polymorphism in familial prion diseases depends on the particular pathogenic mutation and can be significant. Here we report on a CJD case with an R148H mutation. This patient underwent surgery for hysterectomy when she was 82 years old. After surgery she recovered, but was found somewhat fearful. Five months later she developed a rapidly progressive depressive, anxious disorder, and her state of awareness deteriorated within two weeks. She was admitted to a psychiatric ward. On admission she was disoriented, apprehensive, mistrustful and mute; Babinski’s sign on the right was positive. Within days the patient became somnolent and reacted with a defence reaction to painful stimuli. An evident ‘gegenhalten’ of all extremities was found, and the patient developed myoclonic jerks. She had to be fed by tube. The first EEG showed generalized pathologic alterations, but later periodic sharp wave complexes appeared. In the CT mild cortical atrophy was seen. T2-weighted MRI images revealed symmetric multiple hyperintense lesions in subcortical and periventricular locations. Examinations of the CSF was positive for the 143-3 protein and showed an increased tau protein level (>1,500 pg/ml). The patient was diagnosed with probable sCJD [3]. There was only limited information on her family, but no disease similar to CJD was known in the family. She succumbed six months after the onset of disease and an autopsy was performed. Genomic DNAwas extracted from peripheral blood and was investigated as described [4]. For Western blotting the brain was kept frozen at −80°C until use. Tissue from the frontal cortex and cerebellum was homogenised in 9 volumes (wt./vol) of lysis buffer (0.5% Nonidet P-40, 0.5% DOC, 10 mM EDTA, 100 mM NaCl, 100 mM Tris, pH 7.4) and further processed as described [2]. After PK digestion (50 μg/ml, 1 h at 37°C) cleared homogenates were subjected to SDS-PAGE and blotted on PVDF membranes. Monoclonal antibodies 6H4, 3F4 and L42 were used for immunodetection [5–7]. Blots were developed using NBT-BCIP according to standard protocols. Quantification of band intensities was performed with software TotalLab 1D Gel Analysis, version 2.0. For microscopic investigation the right half of the brain was fixed in formalin and processed for histology, immunohistochemistry and paraffin-embedded tissue (PET) blotting [8]. The monoclonal antibodies L42 and 12F10 were used for immunohistochemistry and PET blotting respectively. B. Krebs . R.-M. Lederer . O. Windl . E.-M. Grasbon-Frodl . H. A. Kretzschmar (*) Institut fur Neuropathologie, LMU Munchen, Feodor-Lynen-Strasse 23, 81377 Munich, Germany e-mail: Hans.Kretzschmar@med.uni-muenchen.de