This case was originally published in 2017. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.
A 65-year-old man presented with confusion, memory loss, and ataxia. His family noted that the onset of memory loss had become noticeable over the past three months and had become particularly striking in the past week when he was noted to exhibit abnormal "sudden, jerking movements." There was no history of alcoholism, psychiatric disease, lithium exposure, or heavy metal exposure. A CT scan was normal. A biopsy was obtained.
Whole Slide Image
The whole slide image provided is an H&E stain from a brain biopsy.
The presence of a perivascular inflammatory infiltrate in the biopsy would rule out which of the following?
Acute demyelinating encephalomyelitis
Systemic lupus erythematosus
The presence of vacuolation of the white matter would implicate which of the following?
Cerebral amyloid angiopathy
Chronic traumatic encephalopathy
Progressive supranuclear palsy
In contrast to other dementing diseases, which anatomic site is typically spared in Creutzfeldt-Jakob disease?
Discussion and Diagnosis
The diagnosis is Creutzfeldt-Jakob disease (CJD), a spongiform encephalopathy. The descriptor 'spongiform' is derived from the peculiar vacuolated appearance confined to the cortex (Image A, Image B, and Image C) and deep gray matter. The pathologic abnormality can be distinguished from a processing artifact by the absence of concomitant spongiform change in the white matter, which appears normal on H&E stain (Image B), and the presence of gliosis and neuronal loss in the cortex. In contrast to viral diseases, CJD exhibits no microglial nodules, inclusions, or meningeal/perivascular inflammation. In autopsied cases, the hippocampus is typically spared while the basal ganglia and cerebellum are targeted - a pattern which helps to distinguish CJD from the spongiform change seen occasionally in Dementia with Lewy Bodies. Most commonly presenting as a rapidly progressive dementia leading to death within six months, CJD may also be accompanied by other neurological manifestations including ataxia, visual disturbances, and weakness. While the sporadic form of this disease has been diagnosed in a wide range of ages, it is most often encountered in the seventh decade in both men and women. The overall annual incidence of the disease is one to two cases per million.
Prion protein (PrPc) is a normal protein (the superscripted ‘c’ refers to ‘cellular’) derived from the human prion protein gene (PRNP). The function of PrPc is not precisely known; however, it is heavily expressed in neurons in the CNS. Sporadic CJD is not associated with any genetic mutation of PRNP, but rather with an accumulation of an abnormal isoform of the prion protein (PrPSc) (Image D), which is thought to be neurotoxic (the superscripted ‘Sc’ refers to ‘scrapie,’ a prion disease in sheep). Although the pathogenesis of PrPSc is not well understood, conversion of PrPc to PrPSc has been demonstrated in cell free conditions - implicating a non-genetic pathogenesis. Studies have failed to identify any consistent occupational or dietary risk factors in sporadic CJD. Several instances of acquired/iatrogenic CJD have been reported including those associated with tissue transplantation (cornea and dura mater), neurosurgical instruments, and hormone replacement therapy (human pituitary-derived growth hormone). Variant CJD (vCJD) in humans is acquired following ingestion of animal products contaminated with bovine spongiform encephalopathy (BSE). Familial forms of CJD have also been identified resulting from inherited PRNP mutations. Among other diseases associated with mutations of the PRNP gene are Gerstmann-Straussler-Scheinker disease (GSS, characterized by a progressive ataxia, dysarthria, incoordination of saccadic eye movements, as well as pyramidal and pseudo-bulbar signs) and fatal familial insomnia (FFI, characterized by alteration in sleep-wake cycle, dysautonomia, and motor signs associated with thalamic atrophy).
Electroencephalographic (EEG) studies that exhibit characteristic periodic triphasic complexes at about one per second can be found in the majority of cases, and MRI findings of T2-hyperintensity in basal ganglia and thalami with persistent restricted diffusion on diffusion-weighted imaging (DWI) have been incorporated into the diagnostic criteria for sporadic CJD. Combined with an appropriate clinical examination and cerebrospinal fluid studies demonstrating elevated 14-3-3 protein level, the diagnosis is typically made without a biopsy. However, in certain cases, the disease can be suspected in the absence of typical findings. In such cases, special handling of the brain sample is strongly urged to avoid contamination of laboratory instruments, surfaces, and personnel. The CDC has published guidelines on the proper handling of these samples and familiarity with the guidelines is essential prior to handling a specimen suspicious for CJD. The National Prion Disease Pathology Surveillance Center provides up-to-date information on the handling and submission of tissues to their facility for diagnostic testing.
Take Home Points
- Creutzfeldt-Jakob disease (CJD) is designated as a spongiform encephalopathy by virtue of the pattern of spongy vacuolization observed in gray matter tissue samples under the microscope.
- While prion protein is normally found in the human brain, CJD is related to an abnormal accumulation of a misfolded prion protein isoform.
- Biopsies and autopsies for the diagnosis of CJD should only be undertaken with precautions in place to prevent contamination.
- Biopsy and autopsy tissue should be sent to the National Prion Diseases Pathology Surveillance Center for complete analysis.
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- The presence of a perivascular inflammatory infiltrate in the biopsy would rule out which of the following?
- A. Acute demyelinating encephalomyelitis
- B. Creutzfeldt-Jakob disease
- C. Lyme disease
- D. Multiple sclerosis
- E. Systemic lupus erythematosus
- The presence of vacuolation of the white matter would implicate which of the following?
- A. Cerebral amyloid angiopathy
- B. Chronic traumatic encephalopathy
- C. Parkinson disease
- D. Progressive supranuclear palsy
- E. Processing artifact
- In contrast to other dementing diseases, which anatomic site is typically spared in Creutzfeldt-Jakob disease?
- A. Caudate nucleus
- B. Cerebellum
- C. Frontal Lobe
- D. Hippocampus
- E. Thalamus