We evaluated adenine arabinoside (vidarabine) for treatment of herpes simplex encephalitis in a placebo-controlled study. In 28 cases proved by isolation of Type 1 virus from brain biopsy, treatment reduced mortality from 70 to 28 per cent (P = 0.03), and over 50 per cent of treated survivors had no or only moderately debilitating neurologic sequelae. This improvement was achieved without evidence of acute drug toxicity. Thus, adenine arabinoside has a good therapeutic index (efficacy/toxicity) for the treatment of Type 1 herpes simplex encephalitis. However, the drug must be given early in the course of infection before the advent of coma to have a beneficial effect. Moreover, it should be coupled with brain biopsy for specific diagnosis to avoid unnecessary treatment of nonresponsive encephalitides that can mimic herpes simplex. (N Engl J Med 297:289–294, 1977)

Adenine Arabinoside Therapy of Biopsy-Proved Herpes Simplex Encephalitis

Anterograde and retrograde tracing experiments have been used to demonstrate the origin and terminal distribution of commissural fibers in the first somatosensory cortex (SI) of the rat. The commissural fibers originate from pyramidal cells of all layers, but predominantly from layers III and V. The fibers terminate in a series of approximately vertical bands. In each of these there are concentrations of terminals extending from the inner portion of the molecular layer to the deep portion of layer III as well as in the superficial part of layer V, and in layer VI. Discrete vertical bands of cortex are reciprocally connected across the midline to give both the origin and terminal regions of the projection a patchy or “columnar” appearance. The commissural fibers arise from and terminate in areas of the cortex that lie between and alongside the aggregations of granule cells that distinguish SI of the rat. No commissural fibers terminate within the aggregations of layer IV cells themselves but the more superficial terminal ramifications may come to overlie these aggregations. A heterotopic projection to the contralateral second somatosensory cortex has been observed and is similar in form to the homotopic projection to SI.



Many commissural fibers have crossed the midline in the corpus callosum by the day of birth but lie in the underlying white matter and do not enter the cortical plate until at least the third postnatal day. During the first postnatal week these fibers grow somewhat diffusely into the maturing cortex and their topographic and laminar pattern of distribution attains its adult characteristics by the end of the first week. Commissural axons, thus, arise from immature cells but the maturation of cell form seems to precede the ingrowth of these axons and the acquisition of commissural synapses.

The organization and postnatal development of the commissural projection of the rat somatic sensory cortex.

PIP: Herpes-simplex virus 1 (HSV1) and 2 can cause recurrent infection in man and in nonhuman species localized on a specific area of the body, such as face, cornea, or genitals. The origin of the virus responsible for a recurrent infection is not usually apparent. Some possible sources of virus can be exogenous infection, endogenous infection from another site of the body, chronic, continuous viral multiplication around the site of involvement, and persistence of the virus at the site of the recurrent infection. No definite information is yet available regarding the mechanism by which HSV1 or HSV2 persists and it is triggered to multiply, or regarding the cells that harbor the virus. It is possible that frequent or constant antigenic stimulation occurs in at least some cases of recurrent herpetic infections. The role of antibodies and of interferon in host resistance to HSV remains to be elucidated. Several recent studies have shown the association of more than a dozen herpes viruses with cancer in man and various animals; for example with limphoma, and with squamous cell carcinoma of the lip and cancer of the cervix. Genital HSV infections and cervical cancer were first linked when it was noted that women with genital herpes had a high frequency of cervical dysplasia and cancer. The results of new seroepidemiologic studies on this subject are still difficult to evaluate. Inocculation of HSV2 in laboratory animals has resulted in sarcomas, but it has never been possible to prove that the virus caused the tumors, since no HSV antigens could be detected in the tumors. However, herpesvirus antigens have been demonstrated by immunofluorescent technics in exfoliated cervical cells obtained from women with dysplasia, carcinoma in situ, and invasive carcinoma. In the absence of other kinds of data, it is difficult to rule out the possibility that the presence of HSV2 or of antigens is not an independent event unrelated to the cancer.

Infection with herpes-simplex viruses 1 and 2. II.

The localization, mode of action, and roles of complement in the Guillain-Barre syndrome have been controversial. We used high-resolution immunocytochemistry to localize complement activation products in early stages of the acute inflammatory demyelinating polyneuropathy (AIDP) pattern of Guillain-Barre syndrome. Three AIDP subjects who were autopsied had had symptoms for 3 to 9 days at the time of death. Immunocytochemistry was performed on etched, epoxy resin-embedded sections, and the next thin section was compared by electron microscopy (thick/thin sections). Many fibers had a rim of the complement activation marker C3d and the terminal complement complex neoantigen C5b-9 along the outer surface of the Schwann cells. Ultrastructural analysis of these C3d-positive fibers showed mild vesicular changes of the outermost myelin lamellae. Vesicular degeneration was seen before the invasion of macrophages into the myelin, and was the predominant change in the subject with symptoms for 3 days. C3d staining was not found on myelin membranes. The results suggest that at least some forms of AIDP are complement mediated. We speculate that complement is activated by antibody bound to epitopes on the outer surface of the Schwann cell and that the resulting complement activation initiates the vesiculation of myelin.

Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy.

Patterns of lamination during development of the fetal human cerebellar cortex were analyzed in Nissl- and H & E-stained serial sections, rapid Golgi preparations, reduced silver impregnations, electron micrographs, and autoradiograms. The layering pattern changed dramatically with time, as analyzed in detail for the culmen, the earliest region to differentiate. Up to about 10 weeks of gestation, cells proliferated only at or near the ventricular surface and migrated radially outward to occupy the full thickness of the cerebellar primordium except for an outermost cell-sparse marginal layer (2-layer stage). The external granular layer first appeared at 10-11 weeks while another group of cells became concentrated beneath the marginal layer (3-layer stage). At 20–21 weeks the lamina dissecans first became evident as a relatively acellular band in the midst of the zone of compact cells below the marginal (now molecular) layer, and for the next ten weeks the cerebellar cortex displayed this 5-layered form. At about 32 weeks the lamina dissecans disappeared (4-layer stage) and postnatally the external granular layer in turn disappeared as the last of its cells migrated inward (adult 3-layer configuration).

The Purkinje cell population was established by 13 weeks, though the cerebellum was destined subsequently to increase several orders of magnitude in surface area and volume. The increase was achieved in part by cell growth, but mainly by extensive cell proliferation in the external granular layer. At 22 weeks, about 30% of the external granular cells incorporated thymidine-H3 upon a single supravital exposure; the external granular layer attained maximum cell number at some stage after birth.

At the 5-layer stage from about 21 to 32 weeks, the interrelationships between various classes of young neurons in the cerebellar cortex became very complex. The Purkinje cells developed ascending branched dendritic processes with growth cones and displayed transient short cytoplasmic processes that extended from the soma in all derections. Basket cell neurons had formed but their axons appeared not to envelop the Purkinje somas as yet. Less mature, smaller cells were beginning to migrate from the external granular layer inward past the Purkinje somas. Their cell bodies in the newly forming granular were separated from the Purkinje cell bodies by a dense tangle of axons in the lamina dissecans. Many of these axons terminated in swellings interpreted tentatively as immature mossy endings, while others passed outward to enclose the cell bodies and proximal dendrites of the Purkinje cells.

Some general points emerged from a comparison of cerebellar development in man and animals. The time of cell origin cannot be inferred necessarily from the time of overt differentiation; deep cerebellar neurons and Purkinje neurons arise in the first trimester, but the former cells differentiate much earlier. Purkinje cells acquired characteristic shapes by the middle of gestation, when very few granule cell neurons had yet formed, and thus appear to develop relatively independently of the granule cells. Although the adult cerebellum appears to be organized similarly among mammals, a developmental component, the lamina dissecans, has been illustrated only in man and whale; its appearance may reflect the combination of early Purkinje cell and late granule cell differentiation in species with a prolonged period of development. One of the most intriguing features of the lamina dissecans is that it appears to contain axon terminals at a time prior to the arrival of the postsynaptic cells.

Histogenesis of cortical layers in human cerebellum, particularly the lamina dissecans

The development of granule cells and their connections was reinvestigated in organotypic cultures of cerebellum. Modified Golgi‐Cox preparations showed numerous maturing granule cells, some with fully mature claw‐shaped dendritic endings, within presumptive cortex. Large cortical neurons often had dendrites richly encrusted with synaptic spines. Sometimes bundles of thin parallel processes were oriented orthogonally to the spiny dendrites. Semithin sections and electron micrographs showed granule cell somas distributed in closely packed clusters, with directly apposed cell membranes. Several types of glio‐glial membrane apposition were observed, including extensive desmosome‐like junctions. The neuropil contained closely packed bundles of thin parallel processes and numerous synaptic complexes, often within the parallel bundles. The postsynaptic elements, when identifiable, often proved to be dendritic spines; axodendritic and axosomatic synapses were less common than axospinous. A few synaptic complexes resembled glomeruli, with linked granule cell dendrites surrounding a presynaptic element. The concurrence of several lines of evidence proves the identity of granule cells in presumptive cortex, but the existence of basket and Golgi Type II neurons and the source of presynaptic element in the glomerulus cannot be demonstrated. The criteria and importance of rigorous cell identification in cultures are discussed. Copyright © 1970 The Wistar Institute of Anatomy and Biology

Anatomy of cultured mouse cerebellum. I. Golgi and electron microscopic demonstrations of granule cells, their afferent and efferent synapses.

The action of Guillain-Barré syndrome serum on myelin ☆: A tissue culture and electron microscopic analysis

Diagnosis and treatment of herpes encephalitis. A multidisciplinary approach.

Des techniques histochimiques modernes des mucopolysaccharides et des glycoproteines ont ete appliquees, a l'etude des corps de Lafora, observees dans l'epilepsie-myoclonie. Les resultats obtenus ne plaident pas en faveur de la presence dans les corps de Lafora de glycogene ou de mucopolysaccharides acides, mais permettent d'etablir l'existence au sain de ces inclusions, de molecules complexes comprenant
 Ces observations ne permettent pas d'etablir s'il existe au sein des corps de Lafora un seul corps complexe aux proprietes chimiques diverses ou deux ou plusieurs composes chimiques differents.

Etude histochimique des corps de Lafora

Mature explants of mouse spinal cord and ganglia have been infected with Herpes virus hominis type 2. After 48 h, a high titer of virus was detected in the explant and typical herpes-like particles were seen by electron microscopy. They were more numerous in sensory neurons and Schwann cells than in the CNS possibly because of a more rapid propagation through the extracellular space in spinal ganglia. In the infected nuclei, besides the naked particles, numerous tubular formations were found, apparently resulting from virus infection and specific for herpes type 2. Their dimensions and fine structure are illustrated and compared to other microtubular formations.

M. Dubois-Dalcq

Papers

Anatomy of cultured mouse cerebellum. I. Golgi and electron microscopic demonstrations of granule cells, their afferent and efferent synapses.

The action of Guillain-Barré syndrome serum on myelin ☆: A tissue culture and electron microscopic analysis

Diagnosis and treatment of herpes encephalitis. A multidisciplinary approach.

Etude histochimique des corps de Lafora

Herpes virus hominis type 2 and intranuclear tubular structures in organized nervous tissue cultures