Enfermedades por virus lentos del sistema nervioso central: ¿un nexo fisiopatogénico común? Vías hacia nuevos enfoques terapéuticos / Slow virus diseases of the central nervous system: a common physiopathogenic nexus? Paths towards new therapeutic approaches

Las enfermedades por virus lentos del sistema nervioso central (SNC) son aquellas en las que el periodo de incubación previo a las manifestaciones clínicas es muy prolongado y se mide en meses e incluso en años. Nos proponemos revisar la concepción actual existente sobre la fisiopatogénesis de estas enfermedades, con el fin de abrir el debate sobre nuevos enfoques terapéuticos, dado el oscuro pronóstico y el escaso éxito de los tratamientos actuales para ellas. El enfoque clásico ante cualquier enfermedad infecciosa es el de actuar frente al patógeno. En este artículo expondremos el importante papel que puede desempeñar el sistema inmune en estas afecciones y, por tanto, la posibilidad de un enfoque terapéutico desde el punto de vista de la inmunomodulación. Nuestra opinión es que los pacientes quizá se beneficien de combinar la estrategia clásica antiviral (inosiplex, ribavirina, IFN-alfa) con el uso de inmunomoduladores del tipo de la pentoxifilina, o de los nuevos que se describen (hormona estimulante de los melanocitos alfa [MSH-alfa], dexanabinol). Mientras, no existan fármacos antivirales específicos de cada uno de estos patógenos, los inmunomoduladores podrían aportar un beneficio clínico como fármacos adyuvantes o paliativos. Esto supondría, no sólo una innovación en el tratamiento de estas enfermedades, sino también un cambio en la concepción del enfoque terapéutico, poniendo al sistema inmune en el mismo plano de importancia que el propio virus (AU)

Auditory brain-stem response in zitter rats with genetic spongiform encephalopathy.

Zitter rats with genetic spongiform encephalopathy and hypomyelination developed an abnormal auditory brain-stem response (ABR) before the appearance of spongy lesions in the central nervous system (CNS). The ABR abnormalities were characterized by a dual peak of wave I, with a longer latency than in normal rats, and decreased or absent waves III and IV. Hypomyelination in both peripheral and central nerves may have been responsible for these abnormalities. The slow negative wave became wide and obscure with aging. These changes accompanied age-dependent progression of spongy changes in the CNS. These findings suggest that at least two mechanisms, one involving hypomyelination and the other causing spongy lesions, are responsible for the brain-stem auditory pathway dysfunction in zitter rats.

[Annotation to the mitochondrial genome]. / Anmerkungen zum mitochondrialen Genom.

After a brief explanation of the mitochondrial function, especially in the relation to the inner-cell coordination, the study analyzed the mitochondrial hypertroph-dilatative cardiomyopathy, myopathy and scrapie which were recently tied to the "D-loop fragment" of the mtDNA. Any primary connection between viral unconventional slow infections and the mitochondrial genome seems unlikely. It is argued in the study that this category of diseases can be much better explained through the transfer of the so-called mobile retroelements.

Slow virus diseases of the central nervous system.

Slow virus diseases are characterized by a long asymptomatic period, often months or years in duration, between the introduction of the infectious agent and the appearance of clinical illness. Two distinct groups cause serious degenerative diseases of the brain and spinal cord. The first to be identified are those caused by "unconventional agents," kuru and Creutzfeldt-Jakob disease. The second category, "conventional virus diseases," include SSPE (subacute sclerosing panencephalitis), PML (progressive multifocal leukoencephalopathy), progressive rubella encephalitis, and HIV encephalopathy. The universal focus on acquired immune deficiency syndrome (AIDS) has stimulated new research on slow viruses. The extreme neurological deficits, the chronic nature of these diseases, and the possible concern with infection control make patients with these diseases a challenge to nursing.

Subacute spongiform encephalopathy with periodic paroxysmal activities: clinical evolution and serial EEG findings in 20 cases.

Evolution of both clinical and EEG abnormalities was analyzed in 20 (16 pathologically confirmed) patients suffering from subacute spongiform encephalopathy with periodic paroxysmal activities (PPA) on the EEG. Illness duration was less than 4 and greater than 17 months in 65% and 10% of cases, respectively. All data but EEG were utilized to assess 3 conventional clinical stages in 20 patients. The early clinical stage was characterized by gradual presentation of gait disturbances, mental deterioration, sensory or autonomic disorders. In contrast with other reports, no PPA were observed in 10 EEG recordings from 7 patients examined at the early clinical stage. Both clinical and EEG findings were not in contrast with a hypothetic subcortical onset of disease. Similar to recent data in the literature, early PPA appeared within 12 weeks of disease evolution in 88% of patients who underwent EEG recordings in the first 3 months of disease. Nonetheless, these early PPA always occurred at an intermediary stage, when our patients showed a marked worsening of the clinical picture. Focal, segmental and/or generalized myoclonic jerks were observed in 15%, 53% and 100% of cases at prodromal, intermediary and terminal stages respectively. Different kinds of PPA were observed: bi-tri-phasic periodic complexes (PC), periodic complexes with multiphasic configuration (PPC) and periodic polyspiking discharges (PPD). Abnormal "pacing" of PC by slowly repeated flashes was found in 4 patients presenting visual hallucinations or cortical blindness. Burst-suppression activity was frequently found at the terminal stage in decorticate patients.

General features of persistent virus infections.

Persistent virus infections are discussed from the virus point of view in terms of the bodily sites in which the infection persists. Glands and body surfaces are thought to be significant because they give the virus protection at the topographical level from immune forces, and because they are appropriate sites for the shedding of virus to the exterior. Germ cells are relevant sites because infection can thus be transmitted vertically from generation to generation in the host. The central nervous system, however, is generally a 'dead end' from which there is no shedding to the exterior. Persistance in blood may be relevant when continued arthropod transmission becomes possible. Most persistent viruses infect lymphoreticular tissues, and this is interpreted by suggesting that it results in an impaired immune response to the infecting virus, which in turn favours persistence. It is suggested that the biological function of virus transformation and the integration of viral into host cell DNA is that it enables the infection to persist in the host and undergo reactivation. Papovaviruses, adenoviruses and oncornaviruses are considered from this point of view.

A transmissible subacute spongiform encephalopathy in a visitor to the eastern highlands of New Guinea.

A Caucasian male, clinically ill with a respiratory disease, visited the Eastern Highlands of New Guinea (endemic for kuru in the Fore people) and developed subacute spongiform encephalopathy (Jakob-Creutzfeldt disease) ten weeks later, from which he subsequently died. Brain material was inoculated intracranially into squirrel monkeys, and several of them developed a spongiform encephalopathy. Monkeys that received control material (normal brain) were normal. Electronmicroscopic features in affected brain tissue are described, and the question of a relationship between Jakob-Creutzfeldt disease and kuru is considered.