Neuroimagen estructural y funcional en las enfermedades priónicas humanas / Structural and functional neuroimaging in human prion diseases

Introducción: Las prionopatías son un conjunto de enfermedades neurodegenerativas producidas por el acúmulo de una isoforma anormal de la proteína priónica celular (PrPc). Se clasifican en adquiridas, hereditarias y esporádicas. Aunque son muchas las características clí- nicas, evolutivas y anatomopatológicas que las diferencian, todas ellas tienen en común un curso desfavorable y un pronóstico fatal. Desarrollo: Si bien algunos tipos como el kuru, prácticamente han desaparecido, otras formas como la variante de la enfermedad de Creutzfeldt-Jakob (vECJ) o la iatrogénica siguen vigentes y suponen un reto en la medicina actual. El diagnóstico de certeza se realiza postmortem, salvo en el caso de la vECJ en la que la biopsia amigdalar puede detectar el 100% de los casos. Ello ha supuesto que se definan criterios diagnósticos en función de una probabilidad estadística, que precisa la realización de exámenes complementarios tales como el estudio electroencefalográ- fico y la detección de la proteína 14-3-3 en el líquido cefalorraquídeo (LCR). Solamente la vECJ ha llegado a incluir en los criterios diagnósticos de la OMS el «signo del pulvinar» en resonancia magnética cerebral(RM). En este artículo se revisan los hallazgos de neuroimagen que han sido descritos para cada tipo de prionopatía en pacientes con un diagnóstico de certeza. Conclusiones: La finalidad es definir la utilidad de estas pruebas complementarias como una herramienta de apoyo para el diagnóstico de este conjunto de enfermedades neurodegenerativas (AU)

Introduction: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform ofthe cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. Review summary: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) orthe detection of 14-3-3 protein in cerebrospinal fluid (CSF).Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The presentreview discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. Conclusions: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases (AU)

Structural and functional neuroimaging in human prion diseases.

INTRODUCTION: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. REVIEW SUMMARY: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) or the detection of 14-3-3 protein in cerebrospinal fluid (CSF). Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The present review discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. CONCLUSIONS: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases.

Encefalopatia espongiforme e príon inseridos em discussão de caso como decorrência do interrogatório meticuloso consecutivo à anamnese / Spongiform encephalopathy prion and inserted into case discussion as a result of meticulous interrogation subsequent to the interview

Contexto e objetivo: Revelações surpreendentes resultam do interrogatório, consecutivo à anamnese, promovendo considerações que enriquecem o conhecimento de professor e aluno.Estudo e local: Ensino curricular de Doenças Infecciosas e Parasitárias na Enfermaria do Departamento de Medicina da Escola Paulista de Medicina - Universidade Federal de São Paulo.Método: Programa para ensino de doutorandos e residentes sobre possíveis diagnósticos de pacientes recém-admitidos, com participação dos docentes ativos e dos aposentados, em atuação voluntária.Resultado: Exemplificação de como um por menor na história do doente pode ampliar o ensino.Conclusão: É conveniente proceder interrogatório detalhista que direcione a diagnose.

Prionpatías: las encefalopatías por priones / Prion diseases: prion encephalopathies

Las prionpatías o encefalopatías por priones son un grupo de enfermedades poco frecuentes que comparten una fisiopatología similar con distintas características clínicas. La enfermedad de Creutzfeldt-Jakob (ECJ) esporádica es la más conocida. Se manifiesta con una demencia rápidamente progresiva, ataxia y sintomatología extrapiramidal. Aunque el diagnóstico de certeza es anatomopatológico se puede llegar al diagnóstico probable empleando los criterios establecidos por la Organización Mundial de la Salud. Se está discutiendo en la actualidad la posibilidad de integrar la resonancia magnética nuclear en dichos criterios para aumentar la sensibilidad del diagnóstico. Las técnicas moleculares de estudio de proteínas en el líquido cefalorraquídeo tienen un peso creciente y colaboran en el diagnóstico. El diagnóstico de las otras encefalopatías por priones no es tan avanzado como el de la ECJ. El tratamiento de todas estas enfermedades continúa siendo paliativo (AU)

Prion diseases or prion encephalopathies are a group of rare disorders that share a similar pathophysiology with different clinical characteristics. Sporadic Creutzfeldt-Jakob disease (CJD) is best known. It presents as a rapidly progressive dementia, ataxia and extrapyramidal symptoms. Although accurate diagnosis is by histopathological examination, a diagnosis can be probably achieved using the criteria established by the World Health Organization. We are currently discussing the possibility of integrating the nuclear magnetic resonance into this criteria for increasing the sensitivity of diagnosis. Molecular techniques for studying proteins in cerebrospinal fluid have an increasingly significant role in aiding diagnosis. The diagnosis of other prion encephalopathies is not as advanced as that of CJD. The treatment of these diseases remains palliative (AU)

Kuru: its ramifications after fifty years.

Kuru was the first human neurodegenerative disease in the group of transmissible spongiform encephalopathies, prion diseases or, in the past, slow unconventional virus diseases. It was reported to Western medicine in 1957 by Gajdusek and Zigas. Kuru was spread by endocannibalism and because of this the ratio of affected women and children to men was excessive. The hallmark of kuru neuropathology is the amyloid plaque. We may speculate what would happen if kuru had not been discovered or did not exist. The infectious nature of Creutzfeldt-Jakob disease (CJD) would probably not have been suspected until the beginning of the variant CJD (vCJD) outbreak in the UK. Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease would have remained for decades as obscure neurodegenerations of merely academic interest. The familial forms of CJD would not have benefited from PRNP gene (a gene encoding for prion protein) analysis, but only later would have been studied by linkage analysis and reverse genetics probably. The study of kuru would have probably been of minimal interest to veterinarians and anthropologists until the bovine spongiform encephalopathy (BSE) epidemic began to exert its devastating effect. The discovery of vCJD would have been delayed, as no surveillance would have been initiated for CJD. And perhaps most importantly, the realization of 'protein-misfolding diseases', including not only the neurodegenerative but also an increasing number of non-neurological disorders, would have been delayed by decades.

A history of kuru.

Kuru is placed in its geographic and linguistic setting in the Eastern Highlands of Papua New Guinea. The epidemic of kuru has declined over the period 1957 to 2005 from more than 200 deaths a year to 1 or none. Since transmission of the kuru prion agent through the mortuary practice of transumption ceased by the early 1960s, the continuation of the epidemic into the present century demonstrates the long incubation periods that are possible in human prion diseases. Several histories of kuru are portrayed, from the different perspectives of the Fore people, of the scientists striving to elucidate the disease, of those engaged in research on prions, and of humans confronting the implications of kuru-like epidemics in the remote past. Kuru has connections to bovine spongiform encephalopathy through intraspecies recycling. The influence of host genetics on the incubation period in kuru may help to predict the shape of the still ongoing epidemic of variant Creutzfeldt-Jakob disease.

[Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Part I]. / Choroba Creutzfeldta-Jakoba i inne pasazowalne encefalopatie gabczaste czlowieka. Czesc I.

In the first part of this work the main problems of prion diseases--also called transmissible cerebral amyloidoses (TCA) or subacute (transmissible) encephalopathies (SSE, TSE)--and clinical symptoms of Creutzfeldt-Jakob disease are presented. Some problems of neuropathology of Creutzfeldt-Jakob disease and basic informations about other human prion diseases will be presented in the second part. The growth of the interest in prion diseases during last years is caused by the problem of bovine spongiform encephalopathy (BSE or "mad cow disease") and its transmission into a human. The new variant of Creutzfeldt-Jakob disease (nvCJD) has appeared. Prion diseases: Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI) and particularly the most frequent of them--Creutzfeldt-Jakob disease (CJD)--have nonspecific, sometimes variable clinical (psychopathological and neurological) symptoms. The imaging, EEG, cerebrospinal fluid tests and other laboratory tests are not specific either and their diagnostic value is limited. Neuropathological studies are needed but their interpretation is often difficult. The only certain diagnostic marker for TSE is the presence of PrP(Sc), the prion protein, which is presently believed to be a direct cause for all transmissible cerebral amyloidoses (TCA).

Notes on the history of the prion diseases. Part I.

The astute observation by William Hadlow, an American veterinary neuropathologist of the similarity between the histopathology of kuru, an obscure disease of the primitive tribe in New Guinea, and scrapie of sheep, was the first clue to the etiology of the transmissible spongiform encephalopathies (TSE). The knowledge that scrapie was transmissible but only after an unusually long incubation period, that the causative agent was highly resistant to heat and formalin, and that it seemed to be able to replicate in the absence of nucleic acid, eventually led to the discovery of the prion by Stanley Pruisner and the still controversial protein-only hypothesis of etiology of the TSE.

[Prions, infections and confusions in the "transmissible" spongiform encephalopathies. The other evidence-based science. III. Review]. / Priones, infecciones y confusiones en las encefalopatías espongiformes "trasmisibles". Ciencia basada en la otra evidencia III. Revisión.

There are some neurological disorders with a pathological hallmark called spongiosis which include Creutzfeld-Jakob disease and its new variant, the Gertsmann-Straussler-Scheinker Syndrome and the Fatal Familial Insomnia in humans; and Scrapie and Bovine Spongiform Encephalopathy, among others, in animals. The etiological agent has been considered either transmissible or hereditary or both. Curiously, this agent has no nucleic acids, is impossible to filter, is resistant to inactivation by chemical means, has not been cultured and is unobservable at electron microscopy. All of these facts have led to some researches to claim that these agents are similar to viruses appearing in computers. However, after almost fifty years of research, is still not possible to explain why and how such elements produce the diseases commented about. On the contrary, during these years have been possible to know that these entities called slow viral infections, transmissible amyloidosis, transmissible dementia, transmissible spongiform encephalopathies or prion diseases appear in individuals with genetical predispositions exposed to several worldwide immunological stressors. The possibility that prions are the consequence and not the cause of these diseases in animals and man is day by day more reliable, and supports the suggestion that a systematic intoxication due to pesticides as well as mycotoxin ingestion, produced mainly by different molds such as Aspergillus, Penicillium or Fusarium, seem to be the true etiology of these neurodegenerative disorders.

The diagnosis of human prion diseases.

Prion diseases present a wide spectrum of clinical and neuropathological features. In this review, clinical and neuropathological findings are summarized along with criteria for the diagnosis of the molecular-phenotypic subtypes of sporadic Creutzfeldt-Jakob disease (CJD), familial CJD, new variant CJD, iatrogenic CJD, Gerstmann-Straussler-Scheinker disease, fatal familial insomnia and kuru.

[Human prion diseases]. / Prionkrankheiten beim Menschen.

The interest in prion diseases, particularly the Creutzfeldt-Jakob type (CJD), rose dramatically in the last years for two reasons. 1) The general public wants to know whether eating beef may cause CJD. Discovering the new variant Creutzfeldt-Jakob disease (nvCJD) and experimental evidence that nvCJD and bovine spongiforme encephalopathy (BSE) are caused by the same prion strain make this idea probable. 2) Infectiologists and Neuroscientists recognise a model disease for a new infectious principle in that the same disease may occur as being inherited as well as transmitted. Additionally, it might allow new insights into the possible aetiologies of neurodegenerative disease.

Gerstmann-Sträussler-Scheinker disease with A117V mutation in a second French-Alsatian family.

We report a kindred of French/Alsatian origin with symptoms of Gerstmann-Sträussler-Scheinker disease over 3 generations. In the propositus, cerebellar signs and memory disturbance were the presenting features, followed by other neurological manifestations. Biopsy of the cerebral cortex showed numerous multicentric and "kuru"-type amyloid plaques that on immuno-light and electron microscopy stained with antibody to prion protein. Molecular genetic analysis revealed an A117V mutation in the open reading frame of the prion protein gene. Questions as to pathology and spread of this mutation are discussed.

[Neuropathology of non conventional infectious agents or prions]. / Neuropathologie des agents infectieux non conventionnels ou prions.

The neuropathological diagnosis of infections by non conventional agents relies on four lesions: astrocytic gliosis (cell hypertrophy and proliferation) usually contrasting with absent mononuclear cell infiltrates (lymphocytes, monocytes-macrophages, and/or microglia) revealed by conventional techniques, and neuronal loss in the most affected areas are little specific findings. Amyloid plaques that are inconstantly found, and spongiosis of gray matter, a characteristic and very frequent finding, are most specific. PrP immunohistochemistry brings additional data. The main diagnostic difficulties are emphasized, and guidelines for Pathological studies are recalled.

[Gerstmann-Sträussler-Scheinker disease. Pathologal and genetic study]. / Maladie de Gerstmann-Sträussler-Scheinker. Etude pathologique et généalogique.

Gerstmann-Sträussler-Scheinker's disease is a familial spongiform encephalopathy whose pathological hallmark is the existence--especially in the cerebellum--of numerous amyloid plaques. We report here the third clinicopathological case in a French family. Brain tissue from one of its members--initially described as familial Creutzfeldt-Jakob's disease--has been reported as successfully inoculated to monkeys. We present the currently accumulating data favouring the hypothesis of a common etiology for familial Creutzfeldt-Jakob's disease and Gerstmann-Sträussler-Scheinker's disease. The familial characteristics, resulting in different durations of incubation and evolution, could lead to different clinical and histological expressions.