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 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 (n = 154) and vascular dementia (n = 36) were the 2 most frequent diagnoses. Seventy-one patients had potentially treatable diseases. Clinical findings included dementia (42 cases), pyramidal (n = 20), cerebellar (n = 14), or extrapyramidal (n = 12) signs, myoclonus (n = 12), visual disturbance (n = 9), and akinetic mutism (n = 5); a typical electroencephalogram occurred only once. Neuropathological diagnoses included immune-mediated disorders (n = 26), neoplasia (n = 25, most often lymphoma), infections (n = 14), and metabolic disorders (n = 6).

Interpretation: In patients with RPD, treatable disorders should be considered and excluded before diagnosing CJD. Misdiagnosed patients often did not fulfill World Health Organization criteria. RPD with positive 14-3-3 cerebrospinal fluid protein should not be regarded as sufficient for the diagnosis of CJD. Adherence to revised criteria for CJD, which include distinctive magnetic resonance imaging features of prion disease, is likely to improve diagnostic accuracy.

Figure 1

Summary of autopsy results.

Figure 2

Representative cases from each clinicopathologic category. a Histopathological section through the thalamus of an 85-year-old woman who presented with cognitive decline, lower limb weakness, myoclonic jerks, and EEG with diffuse generalized slowing, showing granulomatous arteriolar inflammation consistent with primary angiitis of the CNS. bPrimary central nervous system lymphoma in a section of thalamus from a 68-year-old woman with progressive memory decline, personality change, limb and gait ataxia. Her MRI showed periventricular white matter changes; CSF cytology and flow cytometry were negative. c A 54-year-old man presenting with rapid cognitive decline and spastic paraparesis underwent cervical decompression without improvement. His MRI showed bilateral thalamic and frontal hyperintensities. His brain revealed necrotizing eosinophilic meningoencephalitis containing roundworms with lateral spines consistent with Baylisascaris infection. d A section of mammillary body from a 58-year-old woman who had undergone gastric bypass surgery, followed by abdominal pain, nausea, vomiting, weight loss and cognitive decline, dying within 3 months. Her brain showed spongioform degeneration with neuronal sparing in the mammillary body, typical of Wernicke encephalopathy.