Differential Diagnosis Of Creutzfeldt-Jakob Disease Research Articles

Steroid-responsive encephalopathy in autoimmune thyroiditis (SREAT) as a differential diagnosis of Creutzfeldt-Jakob disease.

Steroid-responsive encephalopathy in autoimmune thyroiditis (SREAT) is characterised by a wide range of neuropsychiatric symptoms and elevated thyroid antibodies. SREAT can mimic sporadic Creutzfeldt-Jakob disease (sCJD) and distinguishing between both entities is important because SREAT responds to corticosteroids. Data of patients reported to the National Reference Centre for the Surveillance of CJD in Göttingen, Germany between August 1994 and October 2008 was retrospectively reviewed. In the case and control groups, 49 patients had SREAT and 48 had sCJD with elevated thyroid antibodies. Antibodies against thyroid peroxidase were the most common antibodies in both SREAT (86%) and sCJD (88%), followed by antibodies against thyroglobulin (SREAT, 63.3%; sCJD, 39.6%; p = 0.020) and TSH-receptor-antibodies (SREAT, 14.3%; sCJD, 2.1%; p = 0.059). Epileptic seizures were observed more frequently in the SREAT group (SREAT, 44.9%; sCJD, 12.5%; p < 0.001). Dementia (SREAT, 61.2%; sCJD, 100%; p < 0.001), ataxia (SREAT, 44.9%; sCJD, 89.6%; p < 0.001), visual impairment (SREAT, 22.4%; sCJD, 50%; p = 0.005), extrapyramidal disorder (SREAT, 32.7%; sCJD, 60.4%; p = 0.006), myoclonus (SREAT, 38.8%; sCJD, 81.3%; p < 0.001) and akinetic mutism (SREAT, 6.1%; sCJD, 37.5%; p < 0.001) were observed more frequently in sCJD. Cerebrospinal fluid (CSF) pleocytosis was observed more frequently in SREAT patients (SREAT, 33.3%; sCJD, 6.4%; p = 0.001), as was a pathological increase in protein concentration (SREAT, 68.8%; sCJD, 36.2%; p = 0.001). In a case of encephalopathy, the diagnosis of SREAT should also be considered in suspected cases of CJD so as to be able to start corticosteroid treatment quickly.

Contribution of cerebrospinal fluid Alzheimer biomarkers to the diagnosis of Creutzfeldt‐Jakob disease

AbstractBackgroundThe definite diagnosis of Creutzfeldt‐Jakob disease (CJD) requires a neuropathological examination revealing the presence of the pathogenic prion protein. As a reliable in vivo diagnosis is required for clinical care, without pathological confirmation, diagnostic criteria for CJD have been proposed including neuroimaging, electrophysiology and 14.3.3 protein positivity in cerebrospinal fluid (CSF) but their accuracy remains suboptimal. Tau protein in cerebrospinal fluid was found to be extremely elevated in CJD and the phosphorylated‐Tau to Tau ratio (P‐Tau/Tau) was reported to be decreased for some CJD patients.MethodWe first aimed to evaluate the efficiency of the P‐Tau/Tau ratio to distinguish CJD from other neurodegenerative disorders in a cohort of patients with a rapidly progressive cognitive disorder and high CSF Tau level above 1000 pg/ml. Then, retrospectively gathering 49 CJD patients from 7 French University Hospital, the Alzheimer CSF biomarkers and the P‐Tau/Tau ratio sensitivity were compared to current CJD diagnosis criteria. A P‐Tau/Tau ratio value below 0.075 was considered as indicative of CJD.ResultThe diagnoses in the first cohort of 24 patients were: CJD (n = 11), Alzheimer disease (n = 11), Frontotemporal dementia (n = 1) and a Gayet‐Wernicke’s encephalopathy (GWE) (n = 1). Using the threshold of 0.075, the ratio P‐Tau/Tau correctly categorized all CJD patients and only one patient, with GWE, was wrongly classified (fig. 1). The area under the curve of the P‐Tau/Tau ratio was 95% (IC 95% 0.85‐1.0). In the 49 CJD series, the ratio was abnormal in 100% of the patients, while the clinical criteria were met in 81.6% and 91.7% for neuroimaging, 50% for helectroencephalogram and 55.1% for protein 14‐3‐3.ConclusionAlzheimer CSF biomarkers with Tau level and P‐Tau/Tau ratio may increase diagnosis accuracy for positive and differential diagnosis of CJD with a complementary value to current validated diagnosis criteria. They could be particularly helpful in clinical practice for patients with rapid cognitive decline and Tau &gt; 1000 pg/ml or in atypical cases with unmet diagnosis criteria.

Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and A\u03b242 levels

The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82–96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-β (Aβ) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and Aβ42 as markers of brain tauopathy and β-amyloidosis.

Diagnostic Accuracy of a Combined Analysis of Cerebrospinal Fluid t-PrP, t-tau, p-tau, and Aβ42 in the Differential Diagnosis of Creutzfeldt-Jakob Disease from Alzheimer's Disease with Emphasis on Atypical Disease Variants.

According to recent studies, the determination of cerebrospinal fluid (CSF) total tau (t-tau)/phosphorylated tau (p-tau) ratio and total prion protein (t-PrP) levels significantly improves the accuracy of the diagnosis of Alzheimer’s disease (AD) in atypical cases with clinical or laboratory features mimicking Creutzfeldt-Jakob disease (CJD). However, this has neither been validated nor tested in series including atypical CJD variants. Furthermore, the added diagnostic value of amyloid-β (Aβ)42 remains unclear. To address these issues, we measured t-PrP, 14-3-3, t-tau, p-tau, and Aβ42 CSF levels in 45 typical and 44 atypical/rapidly progressive AD patients, 54 typical and 54 atypical CJD patients, and 33 controls. CJD patients showed significantly lower CSF t-PrP levels than controls and AD patients. Furthermore, atypical CJD was associated with lower t-PrP levels in comparison to typical CJD. T-tau, 14-3-3, or t-PrP alone yielded, respectively, 80.6, 63.0, and 73.0% sensitivity and 75.3, 92.1, and 75% specificity in distinguishing AD from CJD. On receiver operating characteristic (ROC) curve analyses of biomarker combinations, the (t-tau×Aβ42)/(p-tau×t-PrP) ratio achieved the best accuracy, with 98.1% sensitivity and 97.7% specificity overall, and 96.2% sensitivity and 95.5% specificity for the “atypical” disease groups. Our results show that the combined analysis of CSF t-PrP, t-tau, p-tau, and Aβ42 is clinically useful in the differential diagnosis between CJD and AD. Furthermore, the finding of reduced CSF t-PrP levels in CJD patients suggest that, likewise Aβ42 in AD, CSF t-PrP levels reflect the extent of PrPc conversion into abnormal PrP (PrPSc) and the burden of PrPSc deposition in CJD.

Sjögren syndrome presenting with encephalopathy mimicking Creutzfeldt–Jakob disease

A 61-year-old man developed subacute progressive dementia, general fatigue, a tonic–clonic seizure, and a decreased level of consciousness. He had a past history of chronic hepatitis type C and was diagnosed as having hepatic encephalopathy due to hyperammonemia. His level of consciousness did not improve even though the serum ammonia level improved. In addition, he had repeated general myoclonic seizures. Head MRI (diffusion-weighted imaging) showed high signal intensities in the right thalamus and the cerebral cortices in the frontal, temporal and parietal lobes (predominantly on the right side). An electroencephalogram (EEG) showed periodic lateralized epileptic discharges (PLEDs). Cerebrospinal fluid analysis revealed high total tau protein and 14-3-3 protein levels. This case was diagnosed as Creutzfeldt–Jakob disease (CJD) based on these clinical data. However, the patient gradually improved without specific treatment. The differential diagnosis was reconsidered, and an increased erythrocyte sedimentation rate and positive serum anti-SS-A and anti-SS-B antibodies were noted. A diagnosis of Sjögren syndrome (SjS) was finally made based on a biopsy of a minor salivary gland showing infiltration of lymphocytes around the gland ducts. Steroid therapy (prednisolone 40mg/day orally) was given, and his clinical condition improved. The lesions on the head MRI decreased, and the EEG findings normalized. This case suggests that SjS has a wide spectrum, including neurological disorders, and that SjS should be considered in the differential diagnosis of CJD.

Movement disturbances in the differential diagnosis of Creutzfeldt‐Jakob disease

Movement disturbances are common in dementia disorders and are a central feature of the clinical classification criteria of Creutzfeldt-Jakob disease (CJD). Polymorphism at codon 129 of the prion protein gene is known to determine the clinical picture of CJD. The frequency and characteristics of movement disturbances in other dementing disorders, such as Alzheimer's disease (AD), is barely known and leads to misdiagnoses. We investigated the occurrence and characteristics of movement disturbances in 143 patients neuropathologically confirmed with CJD (n = 100), AD (n = 29), dementia with Lewy bodies (DLB) (n = 7), or other diagnoses (n = 7). All patients had been referred with the differential diagnosis of prion disease. Ataxia and dysmetria were significantly more frequent in CJD than in AD or DLB patients, whereas hypokinesia was up to five times more frequent in AD or DLB (P < 0.05). Using an ordered logistic regression to identify constellations of movement disturbances, the diagnosis of CJD was likely in patients presenting ataxia but not hypokinesia. The reverse situation was statistically associated with AD. Ataxia and cogwheel rigidity were associated with valine-homozygosity and akinesia with methionine-homozygosity in the CJD patients. Our results indicate that the careful assessment of movement disturbances may be helpful in the differential diagnosis of Creutzfeldt-Jakob disease.

CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease

To analyze the diagnostic sensitivity and specificity of various brain-derived proteins (14-3-3, Tau, neuron specific enolase [NSE], and S100b) in the CSF of patients with Creutzfeldt-Jakob disease (CJD) and to analyze biologic factors that modify these parameters. CSF was tested for 14-3-3, Tau, NSE, and S100b in 1,859 patients with sporadic, genetic, iatrogenic, and variant CJD, and in 1,117 controls. The highest sensitivity was achieved for 14-3-3 and Tau in sporadic CJD (85% and 86%), and a combined determination of 14-3-3 and Tau, S100b, or NSE increased the sensitivity to over 93%. A multivariate analysis showed that the sensitivity of all tests was highest in patients with the shortest disease duration, age at onset >40 years, and homozygosity at codon 129 of the prion protein gene. In a group of patients with repeated lumbar punctures, a second test also increased the diagnostic sensitivity. The detection of elevated levels of brain-derived proteins in the CSF in patients with suspected Creutzfeldt-Jakob disease is a valuable diagnostic test. A second lumbar puncture may be of value in patients with atypical clinical course in whom the first test was negative.

Hashimoto Encephalopathy: a do–not–miss in the differential diagnosis of dementia

Sirs: Hashimoto-encephalopathy (HE) is a steroid-sensitive, relapsing or steadily progressive encephalopathy that is far more common than generally thought. It can be treated if recognized in good time and thus ought to be considered in the differentials of dementia. Interestingly, it has been shown to represent an important differential diagnosis of Creutzfeldt-Jakob disease (CJD) [9]. We describe a patient who presented with a rapidly progressive dementia-like syndrome that improved remarkably on steroid treatment. MRI showed diffuse white matter lesions in the parietal and occipital lobes. Antithyroid antibodies were positive, providing the diagnosis of Hashimoto encephalopathy. The pathophysiology of HE is not entirely clear. It is closely associated with Hashimoto thyroiditis (HT) and is similarly thought to be caused by disorders of immune mechanisms. Most recent reports argue in favor of an inflammatory response to antineuronal antibodies [2, 7, 11]. This 79-year-old lady complained of malaise, dizziness and difficulty in concentration progressing over the past 3 weeks. Her past medical history was unremarkable. Examination revealed a friendly elderly lady who was disoriented in time and place and said she felt “funny in my head”. Vital signs were normal (BP 120/75), physical examination showed head tremor, extensor plantar response, and on MMSE she achieved 10/28. The same evening, she had a generalized tonic-clonic seizure. Over the following weeks, her condition slowly deteriorated, she became somnolent, perseverated and hallucinated. Physical examination showed no new focal neurological deficits, myoclonus or oculomotor abnormalities. EEG initially showed continuous focal epileptiform activity over the left temporal lobe. Later EEGs showed an increasingly generalized picture with diffuse background slowing and intermittent periodic sharp-slow waves (Fig. 1a). MRI revealed hyperintense signals on T2-weighted and FLAIR-images over the left temporal and both parieto-occipital lobes in the subcortical white matter (Fig. 2). The CSF showed elevated protein, no pleocytosis and negative oligoclonal bands. In spite of intensive serological screening for infectious, toxic, (para-)neoplastic and metabolic etiologies, none could be determined. PML was excluded by negative PCR for JC-Virus in CSF and negative HIV-Serology. The absence of hypertension, renal insufficiency or immunosuppression ruled out the suspicion of reversible posterior leukencephalopathy [4]. Intriguingly, the CSF was positive for protein 14-3-3 which is considered a relatively sensitive and specific marker for CJD [13]. However, false positives can be obtained after neuronal injury caused by infection, inflammation, ischemia or after an epileptic seizure. The detection of protein 14-3-3 in the CSF has been described in HE [12]. Considering ADEM as a possible diagnosis, we started high-dose corticosteroids. 3 days later, she was walking and responding adequately, she was still disoriented and knew that “something in my head isn’t right”. In parallel to these clinical findings, there was a marked improvement in her EEGfindings (Fig. 1b). Only then, anti-thyroglobulin and anti-microsomal antibodylevels were measured and found to be increased (thyroglobulinautoantibodies 195 kU/l (ref. 85 % of reported cases were female, aged 12–86). Clinically, both focal-neurological and signs of more diffuse brain dysfunction can be found [6]. Characteristic symptoms are dementia, focal or generalized epileptic seizures, psychotic phenomena and impaired level of consciousness [3, 5]. Ataxia and myoclonus have commonly been described, relating to CJD as a possible differential [9]. Physical examination may show pyramidal tract signs. Anti-thyroglobulin and antimicrosomal-antibodies comprise the mainstay of diagnosis. CSF shows elevated protein and in some cases mild pleocytosis, oligoclonal bands may be positive. EEGfindings consist mainly of slowwave abnormalities reflecting the degree of severity of the underlying encephalopathy and often paralleling the course of the disease LETTER TO THE EDITORS

Follow-Up Investigations of Tau Protein and S-100B Levels in Cerebrospinal Fluid of Patients with Creutzfeldt-Jakob Disease

Background: S-100B and tau protein have a high differential diagnostic potential for the diagnosis of Creutzfeldt-Jakob disease (CJD). So far there has been only limited information available about the dynamics of these parameters in the cerebrospinal fluid (CSF). However, there is a special interest in finding biochemical markers to monitor disease progression for differential diagnosis and treatment. Patients and Methods: We analyzed CSF of 45 patients with CJD and of 45 patients with other neurological diseases for tau protein and S-100B in a follow-up setting. All diagnoses of CJD were later neuropathologically verified. A ratio between tau protein differences and the time between lumbar puncture was calculated. The same was done for S-100B. Results: Tau protein levels of 34 cases were above the cut-off level for CJD (>1,300 pg/ml) in the first CSF sample. In 7 of 11 patients with lower tau levels in the first CSF sample, tau levels rose. The above-mentioned ratio was significantly higher in the CJD group than in the group with other neurological diseases. Similar results were obtained for S-100B. Conclusion: We conclude that follow-up investigations and calculation of ratios is a useful tool in the differential diagnosis of CJD. Variations in this pattern were observed in single cases.

Clinical and differential diagnosis of Creutzfeldt-Jakob disease.

Until recently, the clinical diagnosis of CJD relied mainly on three criteria. These include patient history (rapidly progressive dementia), neurological findings (ataxia, pyramidal/extrapyramidal signs, myoclonus, akinetic mutism) and typical electroencephalographic (EEG) findings. These criteria are fulfilled in typical cases. The occurrence or increase of certain proteins in cerebrospinal fluid (CSF; 14-3-3, neuron-specific enolase) now provide important adjuncts in recognizing variant forms. Although these proteins can be detected in other neurological diseases accompanied with substantial brain damage such as encephalitis, they are also characterized by their high sensitivity and specificity with regard to other dementing processes (Alzheimer and vascular dementia). The increase in the number of positive cases during the last years in Germany reflects an improved case ascertainment rather than the appearance of the variant CJD (vCJD). Although several recent cases with a long duration of the disease were actually recognized, they did not reveal the typical florid plaques at autopsy. They were revealed as a rare variant of sporadic CJD, which is characterized by homocygosity for valine at codon 129 and PrP(Sc) type 1. This variant is positive for the 14-3-3 protein in CSF. Further subtypes described by Parchi et al. can also be characterized by a certain pattern of clinical symptomatology, EEG- and 14-3-3-findings. In addition, differential diagnosis revealed some treatable dementias among the most common diseases (Alzheimer and vascular dementia) such as herpes encephalitis, multiple sclerosis and Hashimoto encephalitis, particularly in the younger age group.

Hashimoto’s encephalitis as a differential diagnosis of Creutzfeldt-Jakob disease

OBJECTIVESDuring an epidemiological study of Creutzfeldt-Jakob disease in Germany, Hashimoto’s encephalitis was encountered as a differential diagnosis, which has not yet been described in this context.METHODSThe symptoms and findings of...

Diagnosis of Creutzfeldt-Jakob disease by measurement of S100 protein in serum: prospective case-control study

Objective: To analyse serum concentrations of brain specific S100 protein in patients with Creutzfeldt-Jakob disease and in controls.Design: Prospective case-control study.Setting: National Creutzfeldt-Jakob disease surveillance unit.Subjects: 224 patients referred to...

Cerebrospinal fluid concentration of neuron-specific enolase in diagnosis of Creutzfeldt-Jakob disease

Neuron-specific enolase (NSE) is among the biochemical markers in cerebrospinal fluid reported to be useful in the differential diagnosis of Creutzfeldt-Jakob disease from other dementing illnesses. In a group of 58 patients with definite and probable Creutzfeldt-Jakob disease, NSE concentrations (median 94·0, interquartile range 256 ng/mL) were significantly higher (p<0·001) than in 26 control patients (9·5, 15·5 ng/mL). At a cut-off of 35 ng/mL an optimum sensitivity of 80% with a specificity of 92% for the diagnosis of Creutzfeldt-Jakob disease by NSE in cerebrospinal fluid was obtained.