Hyman Donnenfeld

Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis

Twenty-two of 32 sporadic cases of amyotrophic lateral sclerosis had argyrophilic spheroids, 20 micrometers or larger, in the anterior horns of the spinal cords. The fine structure of these spherical bodies was characterized by interwoven, small bundles of 10 nm neurofilaments. Scattered mitochondria, vesicles and fragments of smooth endoplasmic reticulum were commonly found among the bundles of neurofilaments. The spheroids were present not only in the myelinated axons, but also in the perikarya of the anterior horn cells. In anterior horn neurons occasional fragments of rough endoplasmic reticulum, lipofuscin and even nuclei were found among the neurofilaments, in addition to the other components. Rarely, some filamentous accumulations contained unusual features such as paracrystalline arrays, polyglucosan bodies and honeycomb-like structures. Linear densities, associated with ribosome-like particles, were found scattered within focal collections of randomly arranged neurofilaments in some perikarya of two cases. Occasional mitochondria with regularly arranged short protrusions on the outer membrane were observed in the myelinated axons in one case.

Cell death and birth in multiple sclerosis brain

The hallmark of the brain pathology in multiple sclerosis is the white matter plaque, characterized by myelin destruction and oligodendrocyte loss. To examine the role that cell death plays in the development of MS lesions, we used the in situ TUNEL technique, a method that sensitively detects DNA fragmentation associated with death at the single cell level. We found that patchy areas within acute MS lesions have massive numbers of inflammatory and glial cells undergoing cell death. The punched out areas of some long-standing chronic lesions also had labeled glial cells showing that the attack was not a single event. Immunocytochemical identification of the dying cells with glial specific marker co-labeling showed that 14-40% were the myelin-sustaining oligodendroglial cell. Confocal microscopic evaluation of fluorescein-labeled TUNEL positive cells revealed nuclei with morphologic characteristics of apoptosis, and electrophoresed MS brain DNA produced a ladder characteristic of apoptotic DNA cleavage confirming that substantial numbers of labeled cells, but not necessarily all, were dying by apoptotic mechanisms rather than cell necrosis. Companion studies using a marker for cell proliferation on MS lesions revealed that unexpectedly large populations of perivascular inflammatory cells and parenchymal glial cells had entered the cell proliferation cycle. These findings establish that two opposing glial cell responses - relentless cell death and coincident brisk cellular proliferation - are important features of MS pathology. In the end, however, glial cell loss prevails, and we suspect apoptosis may be the critical death mechanism responsible for the depletion of myelin observed in this condition.

Acute myelopathy secondary to spinal venous thrombosis

A 66-year-old female presented with the acute onset of paraplegia progressing rapidly to quadriplegia and terminating fatally in less than a month. At autopsy extensive hemorrhagic infarction of the spinal cord was noted associated with widespread venous thrombosis. Other similar cases are reviewed and the pathophysiology is discussed.

Hydrocephalus in Down’s Syndrome

An infant with hydrocephalus, aqueductal stenosis and partial agenesis of the corpus callosum in association with Downs syndrome is reported. Review of the literature reveals that hydrocephalus is infrequent in Downs syndrome. Of special interest is the occurrence of agenesis of the corpus callosum in our patient, a lesion often reported with other chromosomal abnormalities, but not previously observed in Downs syndrome.

Immunoregulatory and activated T cells in amyotrophic lateral sclerosis patients

Circulatory immune complexes are increased in amyotrophic lateral sclerosis (ALS) and an autoimmune mechanism has been inferred. Autoimmune diseases may have changes in the percentages of immunoregulatory T cells and increased activated T cells (Ia+ T) in peripheral blood. The latter are also increased with active viral and bacterial infection and immunization. We found no significant changes of the percentages of immunoregulatory T cells and no relation of the individual values to the clinical state. Ia+ T cells were not increased over the normal range but within that range there was significant negative correlation with the ALS clinical score.

Kinetics of Replication of Lactate Dehydrogenase-Elevating Virus in Age-Dependent Polioencephalomyelitis

The kinetics of replication of lactate dehydrogenase-elevating virus (LDV) in age-dependent polioencephalomyelitis was studied in genetically susceptible (C58/J) and resistant (C57BL/6J) mice. The peripheral replication pattern (plasma concentration) for LDV was similar in both strains. However, the concentration of virus within the central nervous system was strikingly different. In nonsusceptible C57BL/6J mice, little or no virus was found within the central nervous system. In the lumbar cord of susceptible C58/J mice, an increase in the concentration of LDV began 5 days postinfection and continued during the preclinical stages of disease. A direct correlation was shown between the concentration of LDV in spinal cord and the appearance of motor neuron disease but not the degree of inflammatory reaction.

Enteroviral-Related Antigen in Circulating Immune Complexes of Amyotrophic Lateral Sclerosis Patients

Circulating immune complexes were isolated by polyethylene glycol precipitation from the sera of patients with amyotrophic lateral sclerosis. Rabbits immunized with circulating immune complexes from 3 of 5 amyotrophic lateral sclerosis patients induced antisera that specifically reacted with enterovirus-infected cells by immunofluorescence and enzyme-linked immunosorbent assay. These antisera were nonneutralizing and did not react with purified virus. In addition, peripheral lymphocytes of amyotrophic lateral sclerosis patients produced lymphokine in response to extracts from enterovirus (Coxsackie B4) infected cells. These results suggest both a humoral (circulating immune complex) and a cellular immune response in some patients with amyotrophic lateral sclerosis to enterovirus-coded or -induced antigen.