Rapidly progressive dementias and the treatment of human prion diseases

Abstract

Importance of the field Rapidly progressive dementia (RPD) has many possible etiologies and definitive treatment is reliant upon an accurate diagnosis from an appropriate diagnostic work-up. A large portion of the neurodegenerative causes of RPD are due to prion diseases (e.g., Creutzfeldt–Jakob disease). The study of prion diseases, for which there is no currently available treatment, has public health implications and is becoming increasingly more relevant to our understanding of other protein misfolding disorders including Alzheimer’s disease, frontotemporal degeneration, and Parkinson’s disease. Areas covered in this review This article begins with an overview of the etiologies and diagnostic work-up of RPD followed by a detailed review of the literature concerning the treatment of human prion diseases (1971 to present). What the reader will gain The reader will understand the differential diagnosis and work-up of RPD as it pertains to its treatment, as well as an in-depth understanding of treatments of human prion diseases. Take home message An accurate diagnosis of the cause of RPD is of paramount importance when determining appropriate treatment. Most studies of the treatment for human prion diseases are case reports or case series, and results from only one randomized, placebo-controlled study have been reported in the literature (flupirtine). Studies have been hindered by disease heterogeneity and lack of standardized outcome measures. Although no effective prion disease treatment has been revealed through these studies, they provide important considerations for future studies.

Polythiophenes Inhibit Prion Propagation by Stabilizing Prion Protein (PrP) Aggregates

“…No efficient treatments against prion diseases are available (10). The central role played by PrP Sc in prion diseases has inspired searches for compounds influencing PrP Sc stability and/or clearance.…”

Lymphomatosis cerebri mimicking iatrogenic Creutzfeldt-Jakob disease

“…Derivatives of acridine and phenothiazine, similar to chlorpromazine, have been shown to be effective in crossing the blood–brain barrier and to have antiprion properties, and have been seen to inhibit the formation of disease causing isoform PrP (Sc) in animal studies 3 11. A repeat EEG was performed 2 months after the patient's initial EEG, which showed similar findings, and chlorpromazine was changed to phenytoin to control repetitive seizures (figure 2B).…”

“…Periodic spike wave complexes seen in middle and late stages of CJD can also be present in toxic encephalopathy, such as lithium, subacute sclerosing panencephalitis and Hashimoto’s encephalitis. sCJD can be classified as possible, probable or definite cases according to clinical, electrophysiological and neuropathological findings 3 8. Possible sCJD cases are usually characterised as having a rapidly progressive dementia with at least two of the following: myoclonus, pyramidal or extrapyramidal signs, cerebellar or visual symptoms, or akinetic mutism, and a disease course of less than 2 years.…”

“…The most fatal diagnosis is Creutzfeldt-Jakob disease (CJD), a neurodegenerative disorder resulting from the accumulation of a pathological isoform of the prion protein, of which there are sporadic (sCJD), familial (fCJD), variant (vCJD) and iatrogenic (iCJD) types. sCJD is characterised by a plaeomorphic rapidly progressive dementia accompanied by hallucinations, delusions, changes in personality and myoclonic jerks 3 4. Primary central nervous system lymphomas (PCNSL) account for 3–5% of all primary brain tumours5 but are an increasing prevalent group of tumours that can share clinical features of sporadic CJD and should therefore be included in the differential diagnosis of a rapidly progressive dementia.…”

Prionic diseases

“…Care for patients with prion disease is therefore mainly supportive. Isolated case reports of stabilization or improvement following treatment with amantadine, acyclovir, interferons, polyanions, vidarabine, and methisoprinol have not been replicated [32][33][34] . Quinacrine and chlorpromazine, which were found to inhibit PrPSc formation in a cultured neuroblastoma cell line (ScN2a) chronically infected with prions, also failed to show any benefit when used in humans.…”