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Creutzfeldt-Jakob disease is a prion disease clinically characterised by rapidly progressing dementia, cerebellar and extrapyramidal signs, and myoclonus. Cerebral imaging procedures are considered to be of little value for definite premortem diagnosis, which still depends on brain biopsy. Corresponding to cognitive deficits neuropathological changes mostly affect the cerebral cortex, and less severely other grey matter areas such as the caudate, putamen, and thalamus.1 The following case report suggests that MRI using a fluid attenuated inversion recovery (FLAIR) sequence might detect pathological changes in the cerebral cortex.
A 45 year old man presented with a three month history of progressive memory deficit, listlessness, and loss of speech. He repeatedly lost his orientation in the forest where he had worked as a wood cutter for many years. His history was remarkable for bulbectomy of the right eye at the age of 15 months, probably due to retinoblastoma. On examination he complied with simple requests, only. He spoke very little with multiple perseverations. Severe deficits of memory and orientation were obvious. Pronounced irritability with bursts of aggressiveness made neuroleptic therapy necessary. Deep tendon reflexes were brisk but plantar responses were flexor. Rigidity affecting all limbs and hypomimia indicated involvement of the extrapyramidal system. On walking the right arm did not swing. The gait was broad based and fixation did not suppress the oculocephalic reflex suggesting cerebellar involvement. Serial electric ECG recordings disclosed a progressive general slowing and a left frontotemporal, non-periodic slow wave activity. Cerebrospinal fluid cell count and protein composition were normal. Caeruloplasmin and urinary copper concentrations were within the normal range. In accordance with a negative family history for prion disease a single strand conformation polymorphism analysis did not detect any mutations in the coding sequence of the prion protein (PrP) gene. At residue 129 the patient was homozygous for valine.
Two months after onset of clinical symptoms MRI was performed. T1 weighted images before and after infusion of a contrast agent were normal, whereas on T2 and proton density weighted images the left frontal cortex appeared thicker and returned a higher signal than the other hemisphere (figure). However, when using a FLAIR sequence the patchy hyperintense signal of the cortical layer was more apparent.
An open brain biopsy of the left frontal lobe was performed. Histopathological examination disclosed spongiform changes of the cerebral cortex, loss of neurons and astrogliosis, but no inflammatory infiltrates. A diagnosis of spongiform encephalopathy (Creutzfeldt-Jakob disease) was made based on typical pathological changes. Immunhistochemistry showed no PrP deposits.
On follow up, the patient continued to deteriorate. Eight months after onset of symptoms he was reported to be completely unresponsive. At that time myocloni of the arms were seen. He died 16 months after onset of symptoms.
At necropsy the brain showed pronounced frontal cortical atrophy. The ventricular system was enlarged and atrophy of the caudate nucleus was seen. No cerebellar atrophy was detectable. Histology showed severe spongiform degeneration, severe gliosis, and nerve cell loss in the cerebral cortex. Severe changes were also found in the putamen and to a lesser extent in the thalamus. In the cerebellum only mild spongiform changes in the molecular layer were seen. The granular cell layer seemed unaffected. Immunhistochemistry was performed using the antibodies Gö138 and 3F4. As in the brain biopsy no prion protein deposits were detectable in the neocortex or cerebellum. In western blot analysis, proteinase K resistant prion protein was found.
This patient presented with the clinical features of Creutzfeldt-Jakob disease. Diagnosis of spongiform encephalopathy was confirmed by brain biopsy. Whereas T1 weighted MRI was normal, and T2 and PD weighted images showed only subtle findings, a cortical hyperintensity could be easily seen on FLAIR images. This hyperintensity predominantly affected the left frontal, insular, and parietal cortex; the right frontal cortex was also involved (figure). Findings in MRI have been reported in several cases of pathologically established Creutzfeldt-Jakob disease. Brain MRI might be normal or show either brain atrophy or symmetric, hyperintense signals of the basal ganglia in T2 weighted images.2 3
Occasionally, hyperintense signals of the cerebral cortex have been reported.2 The low incidence of cortical involvement reported on MRI contradicts neuropathological data. In a series of 21 necropsied cases, the cortex was the earliest and most severely involved by spongiform changes.1 The basis of this discrepancy may be that on conventional T2 weighted MRI the high intensity of CSF interferes with a sensitive display of cortical signal.
To our knowledge, application of the FLAIR sequence in Creutzfeldt-Jakob disease has not been reported so far. The FLAIR sequence is a heavily weighted inversion recovery sequence with an inversion time designed to null the CSF signal but allow recovery of most of the brain magnetisation. This sequence reduces the CSF artefact and enhances contrast of pathology at the surface of the brain or adjacent to the ventricles.
There was a left frontotemporal accentuation of the hyperintense changes of the cortex in our patient. A focal involvement of the cortex has been reported as an early neuropathological finding in Creutzfeldt-Jakob disease.4 Experimental data suggest that the infectious process begins focally and spreads via an axonal trans-synaptic pathway.5 Spread of the infectious agent via commissural pathways to the contralateral cortex could explain the partially symmetric distribution of the hyperintense signal seen in our case.
The present case suggests that MRI using FLAIR sequences may be helpful in the diagnosis of Creutzfeldt-Jakob disease antemortem and provides a tool for characterising the pathological process in cases of Creutzfeldt-Jakob disease.
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