Status Spongiosus Research Articles

Cycloleucine encephalopathy.

Cycloleucine, a non-metabolizable amino acid analogue produces status spongiosus in cerebral white matter of rats and mice as well as a distinctive lesion of astrocytes. Its mechanisms of action include competition with natural amino acids from transport across the blood-brain barrier leading to inhibition of entry of circulating amino acids into brain, interference with ribosomal RNA maturation, and blockage of transmethylation reactions, including the conversion of homocystine to methionine. Cycloleucine also affects the kidney, producing aminoaciduria. Electron microscopy of cerebral white matter reveals spongiform changes of myelin sheaths caused by separation of myelin lamellae along intraperiod lines and accumulation of whorls of filaments in astrocytes. The myelinopathy is dose related and its toxicity is cumulative due to its long half-life in animals. The findings are discussed with reference to other spongiform myelinopathies, including status spongiosus observed in homocystinuria and other aminoacidurias.

Neutral involvement in kawasaki disease.

Neurological findings and histopathology of the nervous system were studied in 30 patients with Kawasaki disease. As neurological manifestations, irritability, lethargy, meningeal signs such as nuchal rigidity, Kernig's sign, and opisthotonus, and facial nerve paralysis were present in 8 patients. In 9 out of 11 patients who had examination of cerebrospinal fluid, pleocytosis mainly consisting of lymphocytes and mononuclear cells was seen. Protein and glucose concentrations were within normal range. On histopathological investigation, aseptic chorio and/or leptomeningitis were present in 7 out of 14 patients. Severe edema, edema necrosis and localized status spongiosus were frequently observed. Atrophy, nonspecific degeneration and loss of neurons were detected, but pathognomonic changes were not evident. Marginal gliosis in the subpendimal region and superficial cerebral cortex and glial nodule formation surrounding the degenerated neurons were occasionally seen. Vascular changes such as endoarteritis, periarteritis and perivascular cuffing were present in 5 out 14 patients, though such lesions were geneally mild. Ganglionitis and neuritis in the various areas were seen in 13 patients.

ULTRASTRUCTURAL CHANGES OF OLIGODENDROGLIA AND MYELIN SHEATHS INDUCED BY ETHIDIUM BROMIDE

Intracisternal injection of ethidium bromide, an inhibitor of mitochondria associated RNA, DNA and protein synthesis, produced status spongiosus in the subpial surface of the CNS of rats. Ultrastructurally, numerous intra-myelinic vacuoles and prominent degenerative changes of oligodendroglia were observed. The vacuoles were formed between the myelin lamellae by splitting of the intraperiod lines, between the axolemma and the innermost myelin lamellae, and/or between the inner tongue of oligodendroglia and myelin lamellae. In the degenerating oligodendroglia, proliferation and alteration of the endoplasmic reticulum were prominent. In places, altered membranes of the endoplasmic reticulum formed concentrical scroll-like structures. These ultrastructural changes in ethidium bromide treated rats were compared with other similar previously described changes in animals treated with TET, cuprizone, hexachlorophene, hypocholesterolaemic drugs and actinomycin D.

Moléstia de Creutzfeldt-Jakob: estudo clínico, histopatológico e eletromicroscópico de um caso

É apresentado o caso de paciente de 53 anos de idade com quadro de rebaixamento mental e comprometimento piramidal, com evolução progressiva até mutismo acinético em 6 meses de evolução. Um pneumencefalograma mostrou aumento simétrico do sistema ventricular. Uma biópsia cerebral permitiu encontrar alterações neuronais, gliose e estado espongioso que permitiram classificar o caso como de moléstia de Creutzfeldt-Jakob. São discutidos os achados eletromicroscópicos.

Leukoencephalopathy in childhood leukemia

A 14-year-old boy survived for 7 years after the initial diagnosis and treatment of acute lymphocytic leukemia. Neurologic deterioration occured repeatedly throughout his complicated clinical course but it was most severe and only partially reversible following orally administered pyrimethamine. The neuropathologic lesions were distinctive and included a diffuse reactive astrocytosis, axonal degeneration, status spongiosis, circumscribed foci of demyelination and coagulative necrosis, and mural thickening with luminal narrowing of microcirculatory vessels. This collection of findings represents the leukoencephalopathy of childhood leukemia that we and others believe results in large part from the combined effects of cranial irradiation and chemotherapy. The role of folic acid antagonists, namely methotrexate and pyrimethamine, are particularly noteworthy in this regard.

AN AUTOPSY CASE OF CREUTZFELDT‐JAKOB DISEASE WITH KURU‐LIKE NEUROPATHOLOGICAL CHANGES

An autopsy case of Creutzfeldt-Jakob disease with Kuru-like neuropathological changes which revealed clinically extrapyramidal, pyramidal and psychic symptoms is presented in this report. On microscopic examination, status spongiosus, neuronal degeneration, proliferation of hypertrophic astrocytes and numerous plaques were observed in the cerebrum and cerebellum accompanied with widespread demyelinization. These plaques which suggested Kuru plaques measuring 10 to 60 micron were strongly PAS positive and had a dense central core surrounded by a halo of fine radially arranged fibrils. As for the relationship between Creutzfeldt-Jakob disease and Kuru, the significance of these morphological changes is discussed.

“WOOLLY EVERLASTING DAISY” (HELICHRYSUM BLANDOSKIANUM) TOXICITY IN CATTLE AND SHEEP

Investigations into cattle mortalities suspected of being caused by the Woolly Everlasting Daisy (Helichrysum blandowskianum) revealed lesions of marked periacinar liver necrosis, vascular degeneration, widespread haemorrhages and oedema. Brains showed status spongiosus. These lesions were reproduced in cattle and sheep fed Helichrysum and in cattle given an intravenous injection of an extract of the plant.

Observations on hexachlorophene-induced paralysis in the cat and its antagonism by hypertonic urea.

Cats given HCP (20 mg/kg) orally each day developed hindlimb paralysis and greatly elevated CSFP (174 mm saline; 19 mm in controls) in 3 to 5 days. "Status spongiosis" was seen in white matter only in sections of brain and cord. There was no dilation of cerebral ventricles, or damage to their ependymal linings or to the arachnoid villi. The neurological picture excluded any but a terminal effect upon cranial nerve function. There appeared to be no damage to neurons, and recovery of survivors was complete within 6 weeks after cessation of HCP administration. Elevated CSFP in paralyzed anesthetized cats was quickly lowered by an average of 256 mm by slow iv administration of 30% urea (2 g/kg in 10% invert sugar). Unanesthetized cats similarly paralyzed were able to stand and walk for up to 4 hr after this treatment. Neither acetazolamide nor prednisolone alone had any effect, nor did coadministration with urea enhance the effect of urea. The HCP lesion does not appear to be inflammatory in origin, nor does it seem to involve ventricular obstruction or overproduction of cerebrospinal fluid. The reappearance of paralysis about 4 hr after osmotic diuresis, which corresponds with the elimination of urea, suggests that prolonged iv infusion with urea or a similar osmotically active substance may have significant clinical value in the management of HCP poisoning.

HEXACHLOROPHENE‐INDUCED LESIONS IN THE DEVELOPING PERIPHERAL NERVOUS SYSTEM OF MICE

Hexachlorophene‐induced lesions in the developing peripheral nervous system of miceHexachlorophene (HCP) locally applied to the sciatic nerve of mice less than 2 weeks old caused a marked sponginess of the myelin. Ultrastructurally, this was due to a splitting of the minor dense lines of the myelin lamellae with the formation of vacuoles. The changes were reversed after discontinuing the treatment. Unexpectedly, this sponginess in the peripheral nerves was much less and failed almost completely to occur when the HCP application was continued after the second week of life. HCP treatment given to mice older than two weeks caused no sponginess of peripheral nerves, but status spongiosus instead developed in the white matter of the central nervous system. The only change in the peripheral nervous system (PNS) in the older mice was a Wallerian type of degeneration of nerve fibres at and distal to the site of HCP injection. It is therefore concluded that the response of the myelin of mouse PNS to HCP is age dependent and differs from the responses of CNS myelin.

Toxicity and Health Effects of Selected Organotin Compounds: A Review

The toxicity of selected tin compounds is reviewed. Over the years, a variety of uses has been found for organic and inorganic tin compounds, as fungicides, as stablizers in plastics, moluscicides, and miticides; they have also been suggested as insect chemosterilants and for other industrial uses. Many of these products are unpalatable when mixed into diets and have been suggested as rodent repellents. Inhaling tin as dust or fumes may cause a benign pneumoconiosis in exposed workers. The organotin compounds can be divided into alkyltin and aryltin compounds. The trimethyl and triethyltin compounds are well absorbed from the gastrointestinal tract and are the most toxic in this group. Triethyltin particularly produces status spongiosus of the white matter of the central nervous system. Most of the other alkyl and aryl tin compounds are poorly absorbed from the gastrointestinal tract, and are less toxic when given orally than when given parentally. Only one compound, tricyclohexyltin hydroxide, is now registered by the Environmental Protection Agency as a miticide. This product produces skin irritation in rabbits. Studies should be conducted to determine whether it causes contact dermatitis in humans.

Toxicity and health effects of selected organotin compounds: a review.

The toxicity of selected tin compounds is reviewed. Over the years, a variety of uses has been found for organic and inorganic tin compounds, as fungicides, as stablizers in plastics, moluscicides, and miticides; they have also been suggested as insect chemosterilants and for other industrial uses. Many of these products are unpalatable when mixed into diets and have been suggested as rodent repellents. Inhaling tin as dust or fumes may cause a benign pneumoconiosis in exposed workers. The organotin compounds can be divided into alkyltin and aryltin compounds. The trimethyl and triethyltin compounds are well absorbed from the gastrointestinal tract and are the most toxic in this group. Triethyltin particularly produces status spongiosus of the white matter of the central nervous system. Most of the other alkyl and aryl tin compounds are poorly absorbed from the gastrointestinal tract, and are less toxic when given orally than when given parentally. Only one compound, tricyclohexyltin hydroxide, is now registered by the Environmental Protection Agency as a miticide. This product produces skin irritation in rabbits. Studies should be conducted to determine whether it causes contact dermatitis in humans.

FURTHER OBSERVATIONS ON THE EXPERIMENTAL TRANSMISSION OF CREUTZFELDT‐JAKOB DISEASE FROM MAN TO SQUIRREL AND SPIDER MONKEYS

Inoculation of brain material from three female patients with Creutzfeldt‐Jakob disease into squirrel and spider monkeys produced an experimental neurological disease similar to Creutzfeldt‐Jakob disease in all the inoculated animals. The incubation period in squirrel monkeys varied from 17 to 29 months, but in the spider monkeys all the animals developed the disease between 19 and 22 months following inoculation. The early clinical signs were more readily recognized in squirrel monkeys than in spider monkeys. Itch and rubbing was a characteristic feature in all but one squirrel monkey, but it was absent in spider monkeys. The pathological change, in the form of widespread status spongiosus in the brain, as a rule was of greater severity in spider than in squirrel monkeys.

Status spongiosus of rat central nervous system induced by actinomycin D.

The effect on central myelin of Actinomycin D, an RNA--and, secondarily, a protein-synthesis inhibitor, has been studied by light and electron microscopy. The intracranial injection of this drug produced an extensive status spongiosus of the white matter in the cerebrum, cerebellum, brain stem and optic nerve within 48 h. The status spongiosus was due to vacuole formation within the myelin sheath and to enlargement of the extracellular space. Three types of vacuoles were observed: (a) the most common varieties formed between the inner tongue and the remainder of the myelin sheath; (b) a second variety formed by enlargement of the periaxonal space with separation of the axon from its myelin sheath, and (c) a less common type of vacuolization was due to splitting of the myelin lamellae at the interperiod line to form large intramyelinic vacuoles. Myelinic vacuoles were preceded by nuclear and cytoplasmic changes in oligodendrocytes, which included nucleolar segregation, disaggregation, and diminution in number of ribosomes. These changes were similar to those previously reported in a variety of cells exposed to Actinomycin D. It is suggested that myelin vacuoles result secondarily from the Actinomycin D inhibitory effect on oligodendroglial RNA--and protein-synthesis, rather than from a direct effect of this drug on the myelin sheath.

Effects of hexachlorophene in the rat and their reversibility

Treatment of albino rats once daily for 6 weeks with graded doses of hexachlorophene led to pathologic changes in the white tracts of the central nervous system. These changes were dose related with respect to both incidence and severity and consisted of focal vacuolization (status spongiosus) which was most severe in the cerebellum, less severe in the spinal cord, and least severe in the cerebrum. The effect was graded as severe for cerebellar tissue at dose levels of 40 mg/kg and higher, and a lower incidence of less severe changes was observed at 20 mg/kg. Dietary administration of hexachlorophene for 90 days at levels up to 200 ppm led to a moderate degree of vacuolization in only 2 of 20 rats at the highest level and no signs of central nervous system disorders were observed. Hexachlorophene blood concentrations were dose related but did not increase with duration of exposure beyond 30 days. These concentrations ranged from 1.5 to 3 μg/ml at the highest feeding level. Sequential sacrifice of rats following daily treatment for 42 days with 40 mg/kg by gavage produced evidence that the effects are reversible. Gross effects disappeared within 1 week, and histopathologic changes gradually and regularly diminished from severe changes for animals sacrificed 6 hr after the last dose to barely detectable changes after a recovery period of 84 days. No effect was detectable after 168 days. Examination of tissues stained with solochrome cyanine yielded no evidence of demyelination, and electron micrographs suggest that the changes consist of edema together with axonal swelling in instances of severe effects.

Transmission of Creutzfeldt-Jakob Disease from Man to the Guinea Pig

Intracerebral and intraperitoneal inoculation of two guinea pigs with biopsy material from a patient with Creutzfeldt-Jakob disease produced a similar fatal encephalopathy characterized by status spongiosus 422 and 512 days after inoculation. Serial transmission of this disease from guinea pig to guinea pig was achieved in subsequent passages.

Disseminated necrotizing leukoencephalopathy: a complication of treated central nervous system leukemia and lymphoma.

This report describes a form of disseminated necrotizing leukoencephalopathy that has been observed in four children with acute lymphoblastic leukemia, and one child with Burkitt's lymphoma terminating in a leukemic phase. In addition to systemic vincristine, cytosine arabinoside, cyclophosphamide, and steroids, these patients received courses of intrathecal methotrexate, cytosine arabinoside, and hydrocortisone, because of meningeal tumor cell infiltration. Whole brain radiation was also given either before or during intrathecal therapy. Three of the children had a progressive irreversible neurologic illness, which developed either at or shortly after the completion of combined triple intrathecal therapy, death ensuing approximately 2 months later. The neuropathologic lesions consisted of discrete multifocal necroses of coagulative type, apparently extending by confluence, and disseminated in the cerebral white matter in a random manner. In one case, extensive symmetrical demyelinating and necrotizing lesions involved the centrum ovale bilaterally. There was a remarkable absence of inflammatory cellular response and a relative paucity of macrophage reaction, with usually little or no tissue breakdown. In addition to demyelination and glial cell loss, there was striking axonal damage, with conspicuous axonal swelling both within and around the necrotizing lesions. The surrounding white matter showed focal status spongiosus and a moderate astrocytic response. Vascular fibrinoid necrosis was inconstant and, except in one case, rarely observed. The possible causal relationship of these lesions to combined triple intrathecal antimetabolite therapy and brain radiation is discussed.

Experimental kuru in the spider monkey. Histopathological and ultrastructural studies of the brain during early stages of incubation.

The brains of 10 spider monkeys inoculated intracerebrally with brain suspension from kuru patients have been studied histologically and ultrastructurally. The animals were killed by perfusion of fixative from four to forty-one weeks after inoculation, when healthy and free of neurological signs. Definite histopathological changes had occurred as early as four weeks after inoculation, when moderate numbers of bi-nucleated neurons were found within the limbic cortex, striatum, the hypothalamus and amongst the Purkinje cells of the cerebellum. At later stages of incubation a moderate loss of neurons in the cerebral and cerebellar cortex and a mild to moderate proliferation of fibrous astrocytes here and also in the hypothalamus were the most striking features. None of our cases showed either status spongiosus or the generalized astrocytic proliferation and hypertrophy, characteristic of fully developed experimental kuru, in any region of the brain. The principal ultrastructural abnormalities consisted of the formation of membrane-bound intracytoplasmic vacuoles, predominantly within dendrites, and of concentric laminar arrays derived from the endoplasmic reticulum. The former were seen in all regions of the brain examined and at all stages of incubation. Concentric laminar arrays were confined to the cerebellar nodulus, where they were most numerous in dendrites and neuronal perikarya four weeks after inoculation. Both changes are interpreted as an indication that the kuru agent acts upon the plasma membrane from an early stage onwards and, by stimulating its growth, leads to the formation of complex, membrane-bounded vacuoles and to hyperplasia of the endoplasmic reticulum. The formation of vacuoles is further regarded as the first sign of status spongiosus on an ultrastructural level. Attention is drawn to the great similarities between the changes observed in the present material and those described in the brains of patients dying from kuru and of primates with fully developed experimental kuru. The significance of the relatively rapid spread of the kuru agent throughout the brain is discussed in relation to the concept of "slow virus" diseases.

Spongy degeneration in the central nervous system of domestic animals. Part I: Morphology.

Spongy degeneration or status spongiosus of the central nervous system (CNS) was described in a number of domestic animal species, notably sheep, cattle, pigs and in one goat. The condition was characterized by diffuse or focal vacuolation, or polymicrocavitation of the CNS, particularly the white matter. The vacuolation showed a well defined pattern of distribution following a number of myelinated tracts in CNS white matter, in isolated fibres crossing grey matter in the brain stem, and along grey and white matter borders in the cerebrum and spinal cord. The vacuoles were not altered by a variety of methods of rapid brain fixation, processing and staining. The appearance of the vacuolation repeatedly favouring the same areas in the CNS in a large number of animals studied, its common origin either by hepatocerebral disease or hyperammonaemia, strongly suggests that CNS spongy degeneration of domestic animals is a distinct disease entity.

Licht- und elektronenmikroskopische Untersuchung am Kleinhirn 12 Tage alter Ratten nach Behandlung mit 6-Aminonikotinamid (6-AN)

Light- and electron-microscopie studies were performed in glia cells and neurons of the cerebellum of 12-day-old rats until 48 following intraperitoneal application of 8 mg/kg 6-aminonicotinamide (6-AN), an antimetabolite of nicotinamide that inhibits the oxidative pentose-phosphate pathway. Particularly sensitive were the neuroblasts of the external granular layer. The migration of the neuroblasts was clearly reduced. Parts of the internal granular layer were damaged, while the Purkinje cells and astrocytes remained unchanged. Oligodendrocytes and astrocytes showed vacuolar degeneration. Swelling of the myelin sheath occurred in the form of a status spongiosus. 48 h after 6-AN injection some mitoses and phagocytic cells were found in the internal granular layer.

Transmission of Creutzfeldt-Jakob disease to the patas monkey (Erythrocebus patas) with cytopathological changes in in vitro cultivated brain cells.

The transmission of Creutzfeldt-Jakob disease (CJD) to the patas monkey, Erythrocebus patas, has been accomplished. Clinical neurological disease was first noticed 47 months and 23 days after intracerebral inoculation of infected squirrel monkey brain. The disease progressed slowly and lasted 8 months. Microscopic examination of the brain and spinal cord revealed lesions of status spongiosus and astrogliosis in the cortical gray matter consistent with a diagnosis of experimental CJD. A vacuolating 'spongiform' cytopathological effect was seen in many of the in vitro cultivated brain cells in the outgrowth from explanted brain tissue of this monkey.