Treatable neurological disorders misdiagnosed as Creutzfeldt‐Jakob disease

Abstract

Objective Heightened awareness of Creutzfeldt-Jakob disease (CJD) among physicians and the lay public has led to its frequent consideration in the differential diagnosis of patients with rapidly progressive dementia (RPD). Our goal was to determine which treatable disorders are most commonly mistaken for CJD. Methods We performed a retrospective clinical and neuropathological review of prion-negative brain autopsy cases referred to the US National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University from January 2006 through December 2009. Results Of 1,106 brain autopsies, 352 (32%) were negative for prion disease, 304 of which had adequate tissue for histopathological analysis. Alzheimer disease (154) and vascular dementia (36) were the two most frequent diagnoses. Seventy one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (20), cerebellar (14), or extrapyramidal (12) signs, myoclonus (12), visual disturbance (9) and akinetic mutism (5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (26), neoplasia (25, most often lymphoma), infections (14), and metabolic disorders (6). Interpretation In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill WHO criteria. RPD with positive 14-3-3 CSF protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive MRI features of prion disease, is likely to improve diagnostic accuracy.

14-3-3 and enolase abundances in the CSF of Prion diseased rats

“…These findings are similar to findings by Torres et al (2012) where 14-3-3 protein levels were inconsistent in longitudinal samples and did not track with advancing disease in CJD patients [43]. Furthermore, use of 14-3-3 detection in the diagnosis of CJD has led to an increase in over diagnosis of sporadic CJD and misdiagnosis of potentially treatable diseases [46,47]. Our data indicates a lack of prognostic utility for 14-3-3 and NSE for prion infection and questions the utility of these biomarkers for clinical diagnosis in the context of improved imaging and development of direct detection of PrP CJD by RT QuIC.…”

Neuropathology of Dementia Disorders

“…The differential diagnosis shows a wide range, and in addition to frequent prion diseases includes rapidly progressing neurodegenerative tauopathies and synucleinopathies, autoimmune condition infections, toxic-metabolic and neoplastic diseases [204][205][206]. According to the US National Prion Disease Pathology Surveillance Center (NPDPSC) in patients with RPD, treatable disorders are frequently mistaken for CJD [207]. A rapidly progressive dementia with thalamic degeneration and cortical prion immunoreactivity but absence of resistent PrP has been reported recently [208].…”

“…A rapidly progressive dementia with thalamic degeneration and cortical prion immunoreactivity but absence of resistent PrP has been reported recently [208]. Among 1,106 brain autopsies of RPD, 32% were negative for prion disease; most frequent were AD (50%) and VaD (12%), while 23% were potentially treatable diseases, eg., immune-mediated, infectious disorders or tumors [207]. In a rapidly progressing form of AD that clinically may mimic CJD, the genetic profile (absence of ApoE ε4 homozygenity and biomarkers) differs from classical AD, suggesting that it might represent a distinct subtype of AD [209].…”

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases

“…63 Recently, the Prion Surveillance Centers in the US and Europe independently described a novel subgroup of patients who have rapidly progressive dementia that clinically imitates prion diseases, and which, after exhausting neuropathological investigation and prion protein gene sequencing, is concluded to be rapidly progressive late-onset AD (rpAD). 64,[71][72][73][74] The data collected from multiple Prion Centers uniformly demonstrate the absence of positive family history or comorbidity, the presence of distinctive clinical characteristics, and a frequency of e4 alleles in the APOE gene that corresponds to the general population. A systematic investigation of the genetics and molecular pathology of Aβ and tau in those patients should lead to the identification of biological factors responsible for the variable progression rates of AD.…”