An autopsy case of Creutzfeldt‐Jakob disease with a prion protein gene codon 180 mutation presenting with pathological laughing and an exaggerated startle reaction

Abstract

A 78-year-old Japanese woman presented with slow progressive disorientation and memory disturbances. Pathological laughing was observed at an early disease stage and continued for several months. Around the same time, the patient began to exhibit an exaggerated startle reaction and mild myoclonus. The pathological laughing and startle reaction disappeared before the patient reached an akinetic mutism state approximately 16 months after symptom onset. MRI showed extensive hyperintensity of the cerebral cortex and striatum on diffusion-weighted images, and swelling in the cerebral cortex on T2-weighted and fluid attenuated inversion recovery images. A prion protein (PrP) gene analysis revealed a V180I mutation with methionine homozygosity at codon 129. Neuropathological examination showed extensive spongiform changes with characteristic various-sized and non-confluent (VaSNoC) vacuoles in the cerebral neocortex and striatum. Gliosis and hypertrophic astrocytosis were generally mild in character. Neurons were relatively preserved in number. We believe that pathological laughing and an exaggerated startle reaction are possible pathognomonic findings of V180I genetic Creutzfeldt-Jakob disease. Based on the pathological findings of the present case, the presence of the VaSNoC-type spongiform changes with relative preservation of the neurons in the cerebral cortex and a lack of apparent brainstem involvement are associated at least in part with the pathological laughing and startle reaction.

Autopsy case of V180I genetic Creutzfeldt‐Jakob disease presenting with early disease pathology

“…The diagnosis of CJD in the present case was suspected based on MRI findings in the early disease stage. Previous reports have indicated that V180I gCJD cases exhibit a characteristic finding as if the cerebral cortex is swelling in T2‐weighted and FLAIR images, as well as widespread cortical hyperintensity on DWI, except for the medial occipital and cerebellar cortices . We speculate that these typical MRI findings may also provide a rationale for clinically suspecting V180I gCJD prior to performing PrP gene analysis.…”

“…In the present case, diffuse vacuoles in the cerebral cortex were observable macroscopically by loupe on the images of HE‐stained tissue. VaSNoC‐type vacuoles are visually different from the “fine vacuoles” observed in MM1‐type sCJD, as well as from the “large confluent vacuoles” observed in MM2‐cortical type sCJD . The appearance of VaSNoC‐type vacuoles in the cerebral cortex is considered a feature of V180I gCJD .…”

“…Previous reports on V180I gCJD have indicated the presence of extensive spongiform changes in the cerebral cortex and striatum and the absence of apparent cerebellar and brainstem lesions despite prolonged disease duration . Gliosis, hypertrophic astrocytosis, and neuron loss were generally mild compared to those in sCJD cases with prolonged disease duration in the cerebral cortex, despite the presence of innumerable vacuoles . With regard to PrP immunostaining, very weak synaptic‐type PrP deposition was reported .…”

“…Because DWI of V180I gCJD consistently showed hyperintense regions not only in early, but also in later disease stages, we had previously speculated that these hyperintensities result from the characteristic VaSNoC‐type vacuoles in the cerebral cortex. Moreover, the hyperintensity brightness of DWI of the present case was considerably higher than that observed in MM1‐type sCJD cases.…”

“…The appearance of VaSNoC‐type vacuoles in the cerebral cortex is considered a feature of V180I gCJD . The presence of VaSNoC‐type vacuoles in the cerebral cortex of patients with CJD is suggestive of V180I mutation …”