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Hsich et al recently described the 14–3–3 protein marker for Creutzfeldt-Jakob disease in which they noted a high number of positive assays (11 of 12) for the 14–3–3 protein in the CSF of patients with herpes simplex virus (HSV) encephalitis.1 We report the case of a previously healthy 71 year old woman admitted to hospital with subacute changes in mental status who developed a rapidly progressive dementia characterised by personality change, insomnia, ataxia, and myoclonus. Brain MRI was unremarkable. Serial EEG was markedly abnormal due to the presence of diffuse slowing and continuous bilateral sharp waves with regular or irregular periodicity. Analysis of CSF at LCNSS, NIH showed strong immunoreactivity for the 14–3–3 family of proteins. Analysis of CSF additionally showed a herpes simplex virus-1 IgG titre of 1:10 (normal<1:10). The patient was diagnosed with probable Creutzfeldt-Jakob disease, but was treated with acyclovir for the possibility of herpes simplex virus encephalitis. Transient improvement in her mental status lasting several days was noted, but her symptoms subsequently worsened and she died five months after presentation.
Postmortem examination of the brain showed focal spongiform degeneration, neuronal loss, and gliosis limited almost exclusively to the striatum; most of the cerebral cortex showed no evidence of abnormality. Prion protein extraction from frozen brain tissue showed strong immunoreactivity for the abnormal isoform of prion protein as seen in Creutzfeldt-Jakob disease. Unlike classic Creutzfeldt-Jakob disease, there was also evidence of an encephalitis characterised by diffuse perivascular and leptomeningeal lymphocytic infiltrates and microglial nodule formation. Immunocytochemical stains were positive for herpes simplex virus. Although circumstantial, the presence of parenchymal inflammatory infiltrates with cells positive for herpes simplex virus immunocytochemistry was considered strongly suggestive of herpes simplex virus encephalitis.
Review of the literature disclosed no prior reports of the concurrence of neuropathologically verified Creutzfeldt-Jakob disease and herpes simplex virus encephalitis. Alhough this concurrence may be coincidental, the relation between Creutzfeldt-Jakob disease and herpes simplex virus has been speculated on in the literature, in particular whether Creutzfeldt-Jakob disease may stimulate recrudescence of latent herpes simplex virus harboured asymptomatically in the CNS.2 In retrospect, this patient’s clinical course was typical of the subacute variety of Creutzfeldt-Jakob disease in which altered personality, sleep disturbance, ataxia, and myoclonus occur in the context of normal brain imaging and CSF studies.3 The presence of herpes simplex virus encephalitis in this patient was a secondary diagnostic consideration during her stay in hospital and its presence at necroopsy was considered most consistent with stimulation by Creutzfeldt-Jakob disease of herpes simplex virus harboured latently in the CNS.
Concurrent Creutzfeldt-Jakob disease and herpes simplex virus encephalitis raise diagnostic as well as speculative issues. Traditionally, the diagnosis of Creutzfeldt-Jakob disease has been made on the basis of spongiform change, neuronal loss, gliosis, and the absence of an inflammatory reaction.4 However, as the present case shows, the presence of a virus associated inflammatory response on brain biopsy does not rule out the diagnosis of Creutzfeldt-Jakob disease. Conversely, a positive CSF assay for the 14–3–3 protein for Creutzfeldt-Jakob disease does not rule out the diagnosis of herpes simplex virus encephalitis.
This case illustrates the difficulty which may be encountered in the diagnosis of Creutzfeldt-Jakob disease on the basis of brain biopsy or CSF specimen. Definitive diagnosis of Creutzfeldt-Jakob disease is best accomplished by careful consideration of the results from various diagnostic tests including thorough postmortem examination.