Retrograde perfusion of the spinal cord during aortic crossclamping: initial observations in the swine model.

BACKGROUND: Retrograde perfusion has emerged as a useful technique for the preservation of the heart and brain when arterial circulation is interrupted. Herein, this study was designed to test the hypothesis that retrograde perfusion of the azygos vein is sufficient to maintain viability of the spinal cord during aortic occlusion in the swine model. METHODS: Female swine, 17 to 22 kg, underwent left thoracotomy, creation of a shunt between the aortic arch and the azygos vein, and aortic crossclamping for 60 minutes: the shunt was open in the retrograde perfusion group (n = 5) and closed in the control group (n = 4). The animals were evaluated for neurologic function for 8 days and killed. Spinal cords were processed for histologic examination. Additional animals underwent left thoracotomy and injection of a casting solution in the azygos vein (n = 2), left thoracotomy and angiography of the azygos vein (n = 2), and a compartmentalization procedure to separate the azygos vein from the caval system followed by angiography (n = 2). RESULTS: Differences in the neurologic (2-sample t test, P =.11) and histologic (2-sample t test, P =.65) scores of retrograde perfusion and control groups were likely due to chance. Casting and angiography groups showed extensive collaterals between azygos and caval systems, only partially interrupted by compartmentalization. CONCLUSIONS: Retrograde perfusion does not protect the spinal cord from ischemic injury. The collateral network between the azygos and caval systems prevents the oxygenated blood from reaching the cord. Surgical separation between the 2 systems was only partially successful in this study.

Selective protection of gray and white matter during spinal cord ischemic injury.

BACKGROUND: Ischemic injury in the gray matter is associated with excitatory amino acid neurotransmitters (EAA) release, and in the white matter is associated with intracellular sodium accumulation. We investigated the protective effect during spinal ischemia of the EAA antagonist, 2-carboxypiperazinyl-propylphosphonic acid (CPP), and the sodium channel blocker (2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX). METHODS: Sprague-Dawley rats were randomized in four groups, received intrathecally 10 microL of saline, CPP, QX, or QX/CPP, and underwent balloon occlusion of the aorta. Proximal pressure was lowered by exsanguination. In the acute protocol, 28 rats were used to calculate the length of occlusion, resulting in paraplegia in 50% of animals (P50). In the chronic study, 60 rats underwent 11' occlusion. The chronic animals were scored daily for 28 days and submitted to cord histology. RESULTS: The P50 of QX (11'22") and QX/CPP (11'54") were longer than saline (10'39"), suggesting a beneficial effect. Neurologic scores of all treatment groups (p = 0.0001) and histologic scores of CPP (p = 0.003) and QX/CPP (p = 0.002) were better than saline. CONCLUSIONS: Protection of spinal cord during ischemia can be achieved with intrathecal administration of selective agents directed to the gray and white matter.

Primary T-cell lymphoma of the brain in acquired immunodeficiency syndrome: case report.

In patients with acquired immunodeficiency syndrome (AIDS), primary central nervous system lymphoma (PCNSL) is now the most common noninfectious intracranial mass lesion and the fourth leading cause of death. Most cases of PCNSL are B-cell in origin and are only rarely of T-cell origin. We report the first complete clinical description of T-cell PCNSL in a patient with AIDS. This patient underwent stereotactic biopsy of a cerebellar lesion that demonstrated T-cell lymphoma by immunohistochemical staining. The patient died from opportunistic infection after partial radiation therapy. Complete autopsy revealed no evidence of residual T-cell lymphoma. The authors compare T-cell PCNSL in patients with and without AIDS, and discuss differences between T-cell and B-cell PCNSL. In conclusion, T-cell PCNSL can occur in patients with AIDS. The tumor is often located infratentorially and appears to be radiosensitive. However, the patient's survival is short because death is usually caused by opportunistic infection rather than mass effect from lymphoma.

Histopathologic changes in primate spinal cord after single and repeated epidural phenol administration.

BACKGROUND AND OBJECTIVES: Epidural phenol for control of pain and spasticity has been advocated for clinical use. This study determined the histopathologic changes that follow single and repeated epidural administration of phenol in saline in nonhuman primates. METHODS: Nine primates received 0.5 mL of either 3% phenol in saline (n = 4) or 6% phenol in saline (n = 5) via lumbar epidural injection. Two additional primates received three consecutive daily epidural doses of 0.5 mL of 3% phenol in saline. Finally, 5 unoperated primates and 5 primates that received only 2 mL of radiographic contrast material served as control subjects. Two weeks after the epidural injection, spinal cords were removed and processed for histopathologic study by a neuropathologist blinded to the solution administered. RESULTS: None of the control animals demonstrated histopathologic changes. One animal that received 6% phenol died 3 days after injection. All phenol-treated animals demonstrated predominantly posterior root damage. Spinal cord damage was seen in all animals receiving 6% phenol, in 2 animals receiving 3% phenol single doses, and in neither animal receiving 3% phenol multiple doses. Anterior root damage occurred in all phenol-treated animals except the 4 that received single 3% phenol injections. Animals that received 6% phenol demonstrated greater lower extremity motor weakness than those in the other groups, but no clear correlation existed between extent of histopathologic changes and motor weakness. CONCLUSIONS: Motor weakness, anterior root damage, and direct cord injury were noted in primates following epidural administration of phenol in concentrations below what has been reported for clinical use in humans. Since it is more difficult to control the spread of epidural versus subarachnoid phenol, the risks of epidural phenol may outweigh the benefits relative to subarachnoid administration.

Degeneration of axons in the corticospinal tract secondary to spinal cord ischemia in rats.

Occlusion of the thoracic aorta and both subclavian arteries (XC) in the rat model produces spastic paraplegia. In order to characterize the lesion of white matter, 14 male Sprague-Dawley rats underwent XC for 10.5 to 12 min, were observed for 32 days and assessed with a lesion score. A sham group of eight underwent surgical manipulations without XC. The spinal cords were studied by optical microscopy and electron microscopy. An additional group of normal animals (n = 8) underwent spinal cord blood flow measurement with the autoradiographic technique. Optical microscopy showed normal histology in sham operated rats and rats with aortic cross-clamp and lesion score = 2-4 (n = 5), rare changes in the white matter of rats with lesion score = 8 (n = 2), and demyelination of the anterior and lateral tracts of the white matter and motor neuron loss in the gray matter of rats with lesion score = 13-15 (n = 7) and spastic paraplegia. In this last group, electron microscopy disclosed severe axonal degeneration of corticospinal tracts. In the same region spinal cord blood flow was higher than the remaining white matter. This study confirms that spastic paraplegia observed in the rat model after XC is due to degeneration of the pyramidal tracts, perhaps more susceptible to injury due to the high spinal cord blood flow.

Morphologic variations of the external arcuate nucleus in infants dying of SIDS: a preliminary report.

The external arcuate nucleus (EAN), located in the ventral medulla, is studied in 24 infants dying of sudden infant death syndrome (SIDS) and 15 age-matched controls to identify differences in morphology in this region, thought to be involved in respiratory regulation. Significant differences are noted in EAN neuronal density, percentage of back-to-back neurons and volume of the EAN relative to the adjacent pyramids. These changes may be useful in evaluating sudden infant death.

Experimental seizures in the frog (Rana pipiens).

We investigated the effects of chemical convulsants in the leopard frog. Systemic kainic acid (5-20 mg/kg) caused limbic-like seizures, with staring, catatonia, fasciculations, and severe motor seizures, which were almost always lethal. Intracerebral electroencephalographic (EEG) recordings showed spike or spike-and-wave patterns at 6-8 Hz that decreased in frequency and increased in amplitude, maximal at an electrode in the midline olfactory/telencephalic (OLF-M) region. With time, an interictal pattern of 100-200 microV periodic spikes developed, followed by diffuse suppression of all brain activity. Seizures induced by pentylenetetrazole (150-450 mg/kg) and bicuculline (5-10 mg/kg) were characterized by the abrupt onset of motor activity, which continued intermittently for several hours, followed by recovery. EEG recordings in animals treated with pentylenetetrazole showed rhythmic spike-and-wave bursts at 1.5-3 Hz that were maximal at OLF-M. Recordings from frogs treated with bicuculline showed repetitive 3-6 Hz spike-and-wave discharges maximal at OLF-M that were nearly constant in amplitude and at times became continuous. Strychnine (1-5 mg/kg) caused reversible seizures characterized by tonic extensions of the extremities, that seemed to originate in the spinal cord. Frogs with recurrent seizures from systemic cis-diamminedichloroplatinum II showed 4-8 Hz rhythmic spike-and-wave activity that gradually slowed in frequency and increased in amplitude. Thus, the frog's reactivity to convulsive agents is similar to that of mammals.

The influenza B virus mouse model of Reye's syndrome: pathogenesis of the hypoglycaemia.

Up to 40% of children with Reye's syndrome have hypoglycaemia that could contribute to the patient's encephalopathy. We developed a mouse model in which intravenous inoculation of influenza B/Lee virus produced a non-permissive infection of hepatocytes and cerebral endothelial cells and caused many clinical, biochemical and pathologic features of Reye's syndrome. We used this model to study the pathogenesis of the hypoglycaemia. Beginning 6 hours after virus inoculation and persisting to death 18-30 hours later, blood glucose levels fell by 40% and glycogen disappeared from the liver. Gluconeogenesis in liver slices from a pyruvate substrate was significantly impaired. Pyruvate carboxylase, normally present in hepatocyte mitochondria, was largely displaced into the cytosol, rendering that enzyme fraction relatively useless in the gluconeogenesis pathway. Brain glucose levels fell proportionately to the depressed blood glucose level to a mean of 44 mg/100 g compared to 108 mg/100 g in control brains. We conclude that hypoglycaemia in the mouse model developed largely as a result of a non-permissive influenza viral infection of hepatocytes which impaired the mitochondrial phase of gluconeogenesis. The hypoglycaemia may have contributed to, but did not solely account for, the encephalopathy. A similar non-permissive influenza B infection may cause hypoglycaemia in Reye's syndrome.

Selective vulnerability of white matter during spinal cord ischemia.

The long-term effects of spinal cord ischemia were studied in 21 rats by lesion scores (LS, n = 21), somatosensory evoked potentials (SEP, n = 16), electromyographic measurements (EMG, n = 12) and histology of the spinal cord (n = 21) 48.5 +/- 57.2 days after 10- to 12-min occlusion of the thoracic aorta and subclavian arteries. All the animals were initially paraplegic with a spastic presentation but seven recovered within 2 days (group A), demonstrating low LS (3.4 +/- 1.05) normal EMGs (n = 3) and unremarkable histology. The 14 paraplegic animals presented relevant findings of the lumbar cord consisting of white matter lesions only (group B, n = 7) or white and gray matter lesions (group C, n = 7). Group B animals showed severe deficit (LS = 11.8 +/- 2.93) without denervation on EMG (n = 5) or muscle atrophy on histology. Group C animals displayed equal impairment (LS = 14.4 +/- 0.71), denervation on EMG (n = 4), and muscle atrophy. Resting motor unit activity of groups B and C were significantly different from group A (p < 0.001), while LS of groups B and C did not differ (p = 0.083). These data underscore the nature and the extent of white matter lesions during spinal cord ischemia, a finding which has generally been eclipsed by emphasis on gray matter lesions in previous studies.

Sudden death due to lymphoplasmacytic hypophysitis.

We report the case of a 37-year-old mentally retarded woman who died suddenly with premortem clinical signs of diabetes insipidus. At autopsy, her pituitary was infiltrated and destroyed by a lymphoplasmacytic infiltrate, affecting the posterior pituitary more severely than the anterior pituitary. Vitreous electrolytes showed a pattern of hypertonic dehydration, compatible with diabetes insipidus.

Oligodendroglial gliomatosis cerebri.

A 34-year-old man presented with progressive neurologic deterioration though clinically to be multiple sclerosis. At autopsy, the cerebral white matter, deep gray matter, and brain stem were diffusely infiltrated with cells characteristic of oligodendrocytes. Gliomatosis cerebri consisting predominantly of oligodendroglia is rare.

Neurotoxic effects of platinum compounds in cultured dorsal root ganglion cells.

The neurotoxic cancer chemotherapeutic agent cis-diamminedichloroplatinum (II) (cis-platin) was tested in a model system of cultured embryonic chick dorsal root ganglion cells, in order to investigate cellular mechanisms of toxicity. At 7.5 ug/ml, the drug caused mild toxicity. At doses of 75 ug/ml, cis-platin was toxic to cultures in 6 hours, in both neuronal and non-neuronal cell populations. After 24 hours of incubation with 75 ug/ml cis-platin, there was extensive cell death. The trans isomer of the drug, trans-platin, was less toxic than cis-platin at similar doses, causing less severe damage to the cells as well as less cell death. With both drugs, abnormalities in patterns of nuclear staining were prominent, whereas neuronal cell membrane staining patterns were less affected. Both drugs seemed to affect non-neuronal cells to a greater extent than neurons. Ultrastructural findings with both drugs included nucleolar segregation; mitochondrial changes were nonspecific. In this in vitro system, both cis- and trans-platin are toxic. The toxicity appears to predominantly affect the nucleus, and to preferentially involve non-neuronal cells.

Relative lack of toxicity of transplatin compared with cisplatin in rodents.

The differential toxicity of the cis- and trans-isomers of diamminedichloroplatinum (II) (cisplatin and transplatin) was investigated in rats and guinea pigs. In both species, repeated daily administration of 1 to 2 mg per kg cisplatin produced severe histological and/or functional damage to renal and gastro-intestinal systems and resulted in death of the animals. Quantification of tissue platinum by atomic absorption spectroscopy demonstrated accumulation of large amounts of platinum in the kidney of the animals, with lesser amounts in the liver and gastro-intestinal tract. Transplatin, administered at total doses two- to four-fold that of cisplatin, was essentially non-toxic by histological and functional assessment. However, the amounts of tissue platinum measured in transplatin-treated animals were no smaller than those measured in cisplatin-treated animals; indeed, platinum concentrations in kidneys of transplatin-treated rats were more than 2.5 times those in cisplatin-treated rats. Thus tissue platinum content did not correlate with organ damage. These data suggest that mechanism(s) involving steric interactions of platinum species, perhaps with cellular macromolecules such as DNA or RNA, may be important in the differential toxicity of these two compounds.

Cardiac laceration and pericardial tamponade due to cardiopulmonary resuscitation after myocardial infarction.

Complications of cardiopulmonary resuscitation (CPR), such as rib fractures and pneumothorax, are not uncommon. The authors report the case of a 69-year-old woman who underwent surgery for a perforated duodenal ulcer. Eighteen hours postoperatively she sustained a cardiac arrest; vigorous resuscitation efforts, using advanced cardiac life-support procedures, failed. At autopsy, she had 350 mL of fresh blood in her pericardial sac, which had caused cardiac tamponade. Three ribs were fractured at the left sternal border. Directly underneath the fractured ribs were a 0.4-cm laceration of the pericardium and an accompanying 0.7-cm laceration of the left ventricle. There was an acute thrombus in the left anterior descending artery. Microscopic examination of the heart showed acute infarction of the left ventricle in the vicinity of the laceration. This case demonstrates that vigorous CPR performed on an acutely infarcted heart can result in lethal cardiac laceration and tamponade.

Influenza A virus in the mouse: hepatic and cerebral lesions in a Reye's syndrome-like illness.

To develop an animal model of Reye's syndrome using a virus associated with the human disease, mice were intravenously inoculated with influenza A/PR8 virus (LD50 4000 haemagglutinin units). One to 3 days later the mice developed lethargy, seizures, coma and death. The cerebrospinal fluid cell count was normal. Serum aspartate aminotransferase levels increased 24-fold. Diffuse microvesicular fatty metamorphosis along with multiple small foci of necrosis developed in the liver. Influenza virus-like particles were seen by electron microscopy in the liver, primarily in areas of liver necrosis, but were not seen in the brain. Cerebral oedema without inflammation developed in the brain. Limited viral replication occurred within the liver. Influenza viral antigens were seen in 5-20% of hepatocytes from both necrotic and non-necrotic areas as well as in brain endothelial cells. Many of the clinical, biochemical and pathologic features of the mouse illness resemble those seen in Reye's syndrome. However, this model differs from the human disease in that focal areas of liver necrosis occurred along with limited complete viral replication in liver.

Role of nucleus basalis in cholinergic control of cortical blood flow.

The present investigation was designed to determine the effect of lesions localized to the nucleus basalis/substantia innominata (NB) on resting and cholinergically activated regional cerebral cortical blood flow (rCBF). Ibotenic acid (10 micrograms) was infused locally at 1 mm caudal to bregma, 3 mm lateral to the midline, and 8 mm below the cortical surface. Effectiveness of lesions was demonstrated by histological verification of lesion sites and determination of choline acetyltransferase activity in cerebral cortex homogenates. rCBF was measured with the autoradiographic iodo-14C-antipyrine technique. Resting rCBF was similar in the hemisphere that received the NB lesion and in the contralateral (intact) side in all regions examined. Physostigmine intravenous infusion (3.3 micrograms.kg-1.min-1) enhanced rCBF in frontal, parietal, occipital, and temporal cortex. The increase was symmetrical, however, indicating inability of NB lesion to affect this phenomenon. It is concluded that the cortical cholinergic afferents originating in the NB are not involved in the control of rCBF.

Neuropathologic findings in Reye syndrome.

Brain tissue from three patients with a clinical diagnosis of Reye syndrome was compared with tissue from three control patients. All Reye syndrome patients demonstrated cytotoxic cerebral edema, with swelling of astrocyte foot processes, which was not seen in controls. Myelin sheath splitting was seen both in controls and patients, but myelin blebs were uncommon in both. Mitochondrial changes also were not seen. Although cerebral edema is a nonspecific finding, it appears to be characteristic of Reye syndrome.

Toxicity of cis-diamminedichloroplatinum (II) (cisplatin) in the frog, Rana pipiens.

The toxicity of the anti-cancer drug cis-diamminedichloroplatinum (II) (cisplatin), at 2 to 40 mg per kg, was studied in the frog, Rana pipiens. The LD50 for the drug was approximately 17 mg per kg. Major non-nervous system toxicity occurred in the kidney. Renal failure was manifested as anasarca and increasing blood urea nitrogen (BUN). Histopathological changes included acute tubular necrosis and tubular dilatation, which were more severe at higher doses. Interstitial fibrosis occurred after prolonged survival after a single dose. Ultrastructurally, there was increased electron-dense material in tubular cells, but no specific changes in mitochondria or nuclear structures were seen. Gastro-intestinal toxicity was less severe than in other species and was more prominent at higher doses. Pathological changes consisted of epithelial nuclear atypia and apoptosis. By electron microscopy, there was increased separation of cell borders, depletion of chylomicrons and mucin granules and increases in electron-dense material. Again no specific mitochondrial or nuclear changes were seen. Relatively slight changes were seen in the liver, consisting of altered distribution of rough endoplasmic reticulum and dispersion of nuclear chromatin. Minimal pathology was demonstrated in the haematopoietic system or in the gonads. Thus toxicity of cisplatin in the frog is similar to that seen in mammals, including rodents and man.

Pre-mortem diagnosis of Creutzfeldt-Jakob disease by detection of abnormal cerebrospinal fluid proteins.

Creutzfeldt-Jakob disease (CJD) may be difficult to diagnose early or when it has an atypical presentation. We describe two patients with progressive dementia in whom the results of diagnostic brain biopsies were unhelpful. Spinal fluid from these patients, analyzed by two-dimensional electrophoresis, contained two abnormal proteins (Nos. 130 and 131, with relative molecular masses of 26,000 and 29,000 daltons and isoelectric points of 5.2 and 5.1). These findings suggested a provisional diagnosis of Creutzfeldt-Jakob disease, which was confirmed in both patients at autopsy. Detection of these abnormal cerebrospinal fluid proteins appears to be a valuable laboratory adjunct in evaluating patients with an unexplained progressive dementia.

The sequence of changes in liver and brain in the influenza B virus mouse model of Reye's syndrome.

The time course of morphologic changes in the influenza B mouse model of Reye's syndrome is described and compared to the clinical, virologic, and biochemical changes. Following an intravenous inoculation of a lethal dose of an egg adapted strain of influenza B/Lee/40 virus, mice first showed clinical signs of lethargy and ruffled fur at 12 hours (h) post inoculation (pi). The earliest morphologic changes in the liver occurred at 12 h pi, and consisted of a slight increase in fat and loss of glycogen in hepatocytes. Over the next 36 h, the accumulation of microvesicular fat increased, and mitochondrial abnormalities such as pleomorphism and loss of dense bodies developed. There was no increase in peroxisomes. In the brain, focal cerebral edema was detected as early at 6-12 h pi. The edema, manifested as swelling of astrocytic foot processes, increased in severity with time. Endothelial cells were not abnormal. Myelin sheath splitting rarely was observed. Since changes occurred simultaneously in the liver and in the brain, we suggest that influenza B virus caused a simultaneous primary insult to both organs.