Brain ultrastructure in Reye's disease. II. Acute injury and recovery processes in three children.

Acute and recovery biopsies of three patients with Reye's Disease are described. Pleomorphic changes of neuronal mitochondria were identified in all of the acute biopsies, similar in appearance to the characteristic alterations of hepatic mitochondria. Distinctive myelin bleb formation may be directly attributable to the mitochondrial injury. The mitochondrial lesion is reversible. There is morphologic evidence for regeneration and repair of myelin; but the presence of myelin ovoids at long intervals after recovery indicates a loss of some myelinated fibers. The neuronal mitochondrial changes, pleomorphism with matrix expansion, and myelin bleb formation, reflect a specific biochemical injury be attributable to ischemic injury secondary to brain edema.

Brain ultrastructure in Reye's syndrome.

Cerebral biopsies were obtained for electron microscopy 48 and 72 hours after the onset of encephalopathy from a child with severe Reye's syndrome. Gravely ill at the time of craniectomy to relieve cerebral hypertension, the child survived and recovered good brain function; therefore, the biopsy findings appear to reflect the organelle pathology of the brain at a severe yet reversible stage in the disease process. The cardinal ultrastructural changes in the brain in Reye's syndrome are astrocyte swelling and partial deglycogenation, myelin bleb formation and universal injury of neuron mitochondria. The mitochondrial injury consists of matrix disruption with moderate but not massive swelling. Dilatation of rough endoplasmic reticulum and nuclear changes occurred only in neurons with severely altered mitochondria. The organelle pathology of the brain in this case did not resemble the organelle pathology of the brain in human "hepatic encephalopathy" or in experimental ammonia intoxication in primates. The mitochondrial ultrastructure of the cerebral neurons resembled the unique mitochondrial ultrastructural changes seen in the liver parenchyma in Reye's syndrome.

Childhood cerebellar astrocytoma presenting with hemorrhage.

A cerebellar astrocytoma presented with acute intracranial hemorrhage. Computerized tomography and vertebral arteriography defined the tumor and the vascular supply. The tumor was successfully removed. It is important to select the appropriate diagnostic studies so that the rate intracranial hemorrhage masking a brain tumor can be delineated.

Acute responses to experimental blunt head trauma: topography of white matter edema.

The location of edema and territory of extravasation of serum protein were examined in the white matter of cats with different forms of intracranial pathology following an impact-acceleration injury to the head. Edema was tested with an organic density gradient and Evans blue dye was used as a marker for breakdown of the blood-brain barrier. Animals with tissue hemorrhage (contusions) involving both cerebral cortex and white matter had a substantial, progressive accumulation of Evans blue-stained edema near tissue hemorrhage during the 6 h following trauma. In addition, this category of cats had a widespread, mild edema at 15 min after injury that was usually unaccompanied by Evans blue stain. Cats with cortical contusions had rather mild edema neighboring tissue hemorrhage; animals with subarachnoid hemorrhage in the absence of cerebral contusions had neither measurable edema nor (usually) visible Evans blue staining. We conclude that: acute traumatic cerebral edema varies considerably in presence, magnitude and territory with different forms of intracranial pathology; and mechanically induced edema can occur that is independent of spread of fluid from areas of tissue hemorrhage.

Reversal sign on CT: effect of anoxic/ischemic cerebral injury in children.

A retrospective study was performed to determine the clinical and pathologic features, etiology, and outcome of children with the reversal sign. The reversal sign, a striking CT finding, probably represents a diffuse, anoxic/ischemic cerebral injury. CT features of the reversal sign are diffusely decreased density of cerebral cortical gray and white matter with a decreased or lost gray/white matter interface, or reversal of the gray/white matter densities and relatively increased density of the thalami, brainstem, and cerebellum. Twenty children with the reversal sign were retrospectively analyzed. We divided the patients into three groups: (1) acute reversal, (2) intermediate group, and (3) chronic reversal. There were nine cases of trauma (seven of child abuse); nine hypoxia/anoxia incidents (birth asphyxia, drowning, status epilepticus); one bacterial meningitis; and one degenerative encephalitis. All acute- and intermediate-group patients had respiratory problems requiring ventilator support and intensive care. In five of seven patients who died, autopsy findings were consistent with anoxic/ischemic encephalopathy. Surviving patients have profound neurologic deficits with severe developmental delay. The CT reversal sign carries a poor prognosis and indicates irreversible brain damage.

Traumatic longitudinal atlanto-occipital distraction injuries in children.

Traumatic atlanto-occipital dislocation with survival is possible and, in fact may be relatively more common than once thought. The spectrum of neurologic manifestations is broader than previously described and does not necessarily end in death or tragic neurologic deficit. Radiographic diagnosis of this injury may be difficult, particularly in the longitudinal distraction-dislocation type. Although several methods have been proposed to evaluate the atlanto-occipital relationship, none of these is infallible in the recognition of distraction injury in children. Immobilization rather than skeletal traction provides sufficient immediate stabilization when the dislocation at the atlanto-occipital junction is of the longitudinal distraction type. Three cases are reported: in one, death occurred early; in the second, recovery was partial, but sudden death occurred 2 years later; the third child recovered fully.

Shunt-associated glomerulonephritis.

Six patients with glomerulonephritis in association with a ventriculovascular shunt were treated with three basic modes of therapy. Direct intraventricular instillation of antibiotic was used on seven occasions in five patients either as the definitive mode of therapy or as an adjunct to shunt removal. Ventricular fluid antibiotic concentrations were monitored in two patients and demonstrate that effective levels as compared to the specific minimal inhibitory concentration can only be achieved by this method. With resolution of the shunt infection, improvement in the clinical and laboratory parameters of renal function was noted. A recommended treatment protocol is outlined, including specific dosages for intraventricular antibiotics. The need for detailed and frequent post-treatment examination including serum immunoglobulin profile is stressed.

Effect of furosemide on experimental traumatic cerebral edema.

The present study was designed to test the effectiveness of furosemide in reducing cerebral edema due to closed head trauma. A Remington Humane Stunner was used to deliver blows to the heads of anesthetized cats. Impacted animals were divided into three groups: (a) trauma, no drug, and ad lib. fluid intake after head injury; (b) trauma, no drug, and standardized fluid intake (0.9% NaCl; 10 ml/lb/day); and (c) trauma, furosemide (3 mg/lb/day), and standardized fluid intake. For the treated cats, we began furosemide therapy 1 hour after head injury and used three intramuscular injections/day. The animals were killed 48 hours after head trauma. From animals with unilateral contusion, we took bilateral white matter samples from five points along the centrum semiovale and tested for edema using density determinations with an organic density gradient. Serum electrolytes, blood urea nitrogen, and weight were determined before the cats were impacted and before they were killed. All impacted animals demonstrated weight loss. Density data showed a normal water content for white matter in the uncontused hemispheres of all impacted cats. Contused hemispheres showed a significant decrease in density (increase in brain water content) for both treated and untreated cats. In the furosemide-treated animals, however, the brain edema was significantly less than that found in the untreated groups. Analysis of data from individual brain sections of furosemide-treated animals suggested a reduction in the spread of edema fluid 48 hours after head injury.

Penetration of nafcillin, methicillin, and cefazolin into human brain tissue.

To determine the penetration of the antistaphylococcal antibiotics, nafcillin, methicillin, and cefazolin, into brain tissue, we gave to each of 27 patients undergoing craniotomy and brain biopsy one of the antibiotics in a 2-g intravenous infusion just before operation. At the time of brain tissue removal (30 to 225 minutes after the start of the infusion), a serum specimen was obtained, and tissue and serum were assayed for antibiotic concentration. Eleven of 13 brain specimens contained detectable nafcillin concentrations between 0.36 and 11 micrograms/g of tissue (mean, 2.7 micrograms/g for all 13 specimens). Fourteen of 18 brain tissue specimens contained detectable methicillin concentrations between 0.56 and 5.0 micrograms/g of tissue (mean, 2.0 micrograms/g for all 18 specimens). Ten of 11 brain tissue specimens contained detectable cefazolin concentrations between 2.0 and 40 micrograms/g of tissue (mean, 10.6 micrograms/g for all 11 specimens). Each antibiotic penetrated "abnormal" brain tissue better than "relatively normal" brain tissue. Because nafcillin is more active against Staphylococcus aureus, we conclude that nafcillin is preferable to methicillin for the therapy of central nervous system staphylococcal infections. Cefazolin achieves higher brain tissue concentrations than the penicillins, but has not been clinically evaluated for the therapy of central nervous system infections.

Mechanisms of hyperventilation in head injury: case report and review.

We report the case of a head-injured patient with spontaneous hyperventilation who had recurrent episodes of relative hypoventilation associated with increases in intracranial pressure. Detailed ventilatory studies were performed during the 2nd week after injury. Our findings in this patient prompted us to review the possible mechanisms underlying the observed changes. We suggest that spontaneous hyperventilation in head injury is secondary to a decrease in cortical inhibitory influences on respiratory control mechanisms and that the transient episodes of relative hypoventilation observed in our patient may reflect modified ventilatory responses dependent on the altered state of consciousness. (Neurosurgery, 5: 701--707, 1979).

Pituitary hormone response to head injury.

Measurements of the serum levels of pituitary hormones were made in six patients with uncomplicated head injury. Samples were obtained at 4-hour intervals for 72 hours to evaluate diurnal rhythms. Three of the six patients revealed elevations of serum growth hormone (GH) and prolactin, but no trends could be established. Likewise, three patients had marked elevations of luteinizing hormone and lesser elevations of follicle-stimulating hormone, but no pattern was discernible. The level of thyroid-stimulating hormone was stable and remained in the normal range throughout. GH was measured after intravenous glucose loading. A paradoxical rise reverted to normal at the late follow-up evaluation. It is suggested that the abnormal levels were related to abnormal hypothalamic function rather than to pituitary damage.

Treatment of CSF shunt infections with intrashunt plus oral antibiotic therapy.

Infections of 12 cerebrospinal fluid (CSF) shunts in 11 children were treated with oral systemic antibiotic therapy plus daily intrashunt injections of antibiotics. Eight patients were infected with Staphylococcus epidermidis (four patients) or Staphylococcus aureus (four patients), and were treated with intrashunt vancomycin, plus oral trimethoprim/sulfamethoxazole (T/S), plus oral rifampin. One of these eight patients was later changed to a course of intrashunt cephapirin and oral cephalexin plus oral rifampin. One patient with Micrococcus varians infection was treated with oral T/S and rifampin, without intrashunt therapy, another patient with Pseudomonas cepacia infection was treated with intrashunt kanamycin plus oral T/S, and a third with Corynebacterium sp. infection was treated with intrashunt vancomycin plus oral T/S. Eight of the 11 patients required some form of shunt surgery, the most common being temporary externalization of the peritoneal end of the catheter. Only two shunts were completely replaced (both were ventriculojugular shunts which were changed to ventriculoperitoneal shunts). Nine of 10 evaluable cases were considered cured of their infections. The patient treated with cephalosporins had an uncorrected shunt malfunction and relapsed 1 month after completing therapy. The authors have shown that CSF shunts infected with Staphylococci can be effectively cleared with daily intrashunt vancomycin plus systemic therapy with oral T/S and rifampin. Less common infections may also be amenable to this form of therapy. Revision surgery, if necessary, should be carried out during the antibiotic therapy.

Cerebrospinal fluid antibiotic levels during treatment of shunt infections.

Twenty patients with documented cerebrospinal fluid shunt infections were treated with daily intraventricular injections of methicillin, cephalothin, or gentamicin without removal of the shunt or external ventricular drainage. Periodic determinations of intraventricular antibiotic concentration revealed significant levels in relation to the established minimum inhibitory concentration in all cases.

Asymptomatic subdural chondrosarcoma. Case report.

This report describes a large, asymptomatic, subdural skeletal-type condrosarcoma originating from the meninges. Distinction between the mesenchymal and skeletal types of intracranial chondrosarcoma is important since they have different prognoses.

Effect of dexamethasone on cerebral edema from cranial impact in the cat.

A Remington humane stunner was used to deliver blows to the skulls of anesthetized cats. Alternate animals were post-treated with either dexamethasone (4 mg/kg/day) or a comparable volume of saline. Each animal was tested for cerebral edema 48 hours after impact by measurement of the change in density of white matter from normal values. Dexamethasone therapy did not reduce the change in density of hemispheres with contusions involving both cortex and underlying white matter. For hemispheres with contusions limited to cerebral cortex, there was minimal edema of the white matter, which was reduced a slight amount by dexamethasone.

Giant serpentine aneurysm. Report of two cases.

The authors describe two cases of giant middle cerebral artery aneurysms presenting as mass lesions. Angiograms in each case revealed a distinctive serpentine vascular channel surrounded by an avascular area causing a "mass effect." Both lesions were resected in toto with excellent clinical results. Similar lesions in the literature are noted and the pathophysiology and origin of this group of aneurysms are discussed.

Acute changes in regional brain water content following experimental closed head injury.

A Remington humane stunner was used to deliver blows to the skulls of anesthetized cats. The animals were sacrificed at 30 minutes or 1, 2, or 6 hours after trauma and selected for data collection on the basis of the following two categories of gross intracranial pathology: 1) unilateral contusion, with subarachnoid hemorrhage (SAH); or 2) SAH only. For selected cats, specific gravity was measured in 5- to 10-mg samples of uncontused tissue taken from coronal slices at the level of the frontoparietal suture. The regions tested included dorsal cerebral cortex, subcortical white matter, deep white matter, and caudate nucleus. Specific gravity data from injured animals were compared with those from similar areas in uninjured anesthetized cats to test for cerebral edema. At 30 minutes after head injury, contused hemispheres had significant edema of all tested except the caudate nucleus. Edema of the subcortical and deep white matter increased with time after the injury. Increase in water content of the cerebral cortex was transient and appeared unrelated to contusion. The caudate nucleus was edematous only at 6 hours, suggesting movement of fluid from the deep white matter compartment into the nucleus. The hemispheres opposite the contusion and those related to SAH had, with one exception, an absence of edema in the white matter and caudate nucleus, but a transient increase in water content of the cerebral cortex. These findings suggest that, in the presence of contusion, cerebral edema can contribute to brain swelling as early as 30 minutes after closed head trauma. In addition, a transient and minimal cortical edema, perhaps related to ischemia, occurred in all groups of hemispheres examined.

Dandy-Walker syndrome. Clinical analysis of 23 cases.

A clinical analysis of 23 patients with Dandy-Walker malformation indicates that more than 85% of them were diagnosed at or before 1 year of age, and that the incidence of associated anomalies is approximately 50%, with a 17% incidence for agenesis of the corpus callosum. The significance of the presence of these anomalies is substantiated by the fact that of the seven deaths recorded, six were related to this disease and five were affected by associated anomalies. The high mortality rate (26%) is comparable to that of other series. The differential diagnosis with posterior fossa extra-axial cysts is discussed. Ten patients were primarily treated with excision of the cyst membrane; all of them required subsequent shunting to control the intracranial pressure, demonstrating the futility of this approach. None of the patients treated with lateral ventricle shunting suffered an upward herniation of the posterior fossa contents, suggesting that combined shunting of the lateral and fourth ventricles is rarely necessary. The technical advantages of posterior fossa shunting alone are outlined. Of the 16 survivors, 14 were assessed for their mental development by means of standard psychometric testing. The results of the intelligence quotient (IQ) scoring have indicated that 71% of the patients have subnormal mental development (IQ less than 83). There was no significant relationship between retardation and associated anomalies, although agenesis of the corpus callosum was related to poor intellectual development in the two patients so affected (IQ's of 50 and 73).

Oral glycerol for the treatment of traumatic intracranial hypertension.

Hyperosmolar agents are a primary therapeutic modality employed in the treatment of traumatic intracranial hypertension. Profound hyperosmolarity accompanied by systemic dehydration is a potentially serious problem when these drugs are used repeatedly for control of intracranial pressure. Because glycerol, a water-soluble alcohol, is metabolized in the liver, its dehydrating capacity may be reduced in comparison to other agents. A series of 15 patients were treated with oral glycerol (0.5 to 1.0 gm/kg) with only minor changes in serum electrolytes, glucose, and urea nitrogen. Serum osmolarity rose from a baseline of 305 mOsm/liter to 355 mOsm/liter after 10 days of therapy. Glycerol was found to be effective and safe when employed in this protocol and proved to be a valuable adjunct to the standard methods available for control of intracranial hypertension.

Acute responses to experimental blunt head trauma. Topography of cerebral cortical edema.

Anesthetized cats subjected to impact followed by acceleration and rotation of the skull were sacrificed at 15 minutes or 6 hours after injury and were selected for study if unilateral cerebral contusion was present. Widespread areas of cerebral cortex were examined bilaterally for edema, using measurement of tissue density with an organic gradient, and for breakdown of the blood-brain barrier to plasma protein tagged with Evans blue dye. At both times tested, a halo of vasogenic edema (Evans blue stain plus decreased density) was present in the cortex surrounding areas of contusion. At 15 minutes after injury, animals with deep contusions also had a slight decrease in density without Evans blue staining, interpreted as cytotoxic edema, in some gyri neighboring the contusion. At 6 hours, cytotoxic edema was not evident, but some animals had vasogenic edema in the gyri adjoining the contusion. Most gyri contralateral to contused areas had neither Evans blue staining nor changes in tissue density. These findings suggest that, with the present head-injury model, acute changes in tissue density and vascular permeability occur in the cerebral cortex of hemispheres with contusion. These responses are related topographically to contusion sites, and change over the two times studied. The authors conclude that events in addition to spread of fluid from areas of contusion contribute to the edema of head injury, and that more than one form of edema can follow mechanical trauma to the brain.