Don M. Long

Early Histochemical Changes in Perinatal Asphyxia

Histochemical observations were carried out on newborn monkeys delivered by caesarean section at 153 to 163 days of gestation and immediately asphyxiated for approximately 12 minutes. The main histochemical finding consisted in widespread, abnormal accumulation of glycogen in glial cells (predominantly astrocytes) of both gray and white matter, which became conspicuous approximately 10 hours after asphyxia and tended to disappear after several days. Abnormal deposition of glycogen in glial cells was also demonstrated by electron microscopy. Glycogen accumulation was preceded by a marked increase in phosphorylases and UDPG-glycogen transferase activities already demonstrable in animals sacrificed 1 hour after asphyxia. Similarly early was the appearance of abnormal activity of aminopeptidase in neuronal groups which were shown to be especially susceptible to asphyxia and displayed evidence of histopathological damage at later stages. The changes in respiratory enzymes were generally of a nature previously described, and they were characterized mainly by reduction in the activity of individual enzymes in regions of the gray matter which later showed evidence of histopathological damage. Disturbances of the blood-brain barrier were demonstrable in animals sacrificed 10 hours and later after asphyxia. The main feature consisted in selective localization of the tracer in the cellular components of the parenchyma, mainly in the neurons. The changes were confined mostly to the gray matter without any clear correlation to the intensity of the histopathological damage.

The Clinical Effects of a Synthetic Gluco-Corticoid used for Brain Edema in the Practice of Neurosurgery

The clinical effect of dexamethasone, a potent, synthetic gluco-corticoid, was studied in a large series of neurosurgical patients with brain edema seen over a 12 year period. A protocol was established at the beginning of the study to evaluate the severity of the edema and its clinical response to steroid therapy. The results showed that the treatment of brain edema with dexamethasone was highly effective in patients with focal lesions where edema production persists or progresses with time, as is the case particularly with brain tumors and abscesses. Patients with metastatic tumors, glioblastomas and abscesses responded better to steroid therapy than patients with low grade infiltrating astrocytomas and meningiomas. This correlated well with the relative severity of the edema associated with these respective tumors. Steroid administration proved least effective in patients with generalized brain lesions of acute onset as seen in severe closed head injuries. The prevention of severe operative and post-operative edema in patients started on dexamethasone prior to brain surgery was apparent. This was particularly emphasized in the group of patients who had craniotomies for the excision of large meningiomas and the pathophysiology of this response was discussed. Steroid therapy proved to be safe when administered for the brief period of time usually necessary in neurosurgical problems. Gastrointestinal bleeding was not a serious problem except in very ill patients who were either comatose and on the respirator, or moribund following severe head injuries with brain stem involvement.

The effects of glucosteroids upon cold induced brain edema. II. Ultrastructural evaluation.

The acute brain edema which follows a cortical cold lesion is characterized by the appearance of fibril-filled astrocytes within hours of lesion production. This gliosis is steadily progressive for many months after injury. Prompt alleviation of the edema with glucosteroids greatly reduces the severity of the process.

Multiple Therapeutic Approaches in the Treatment of Brain Edema Induced by a Standard Cold Lesion

Brain edema was produced by a standard cortical freezing lesion. The temporal course of the evolution and resolution of this edema has been reported elsewhere in detail. The effects of many types of therapy, both standard and investigational, upon this model of brain edema have been employed. Osmotic diuretics were found to have no effect upon the edema itself, but a reduction in the bulk of normal brain was evident. Maintenance of hypotension after lesion production essentially eliminated brain edema whereas prolonged hypertension increased brain edema dramatically. Focal excision of the cold injury itself immediately after lesion production prevented the development of brain edema. A beneficial effect on brain edema by focal excision was evident up to 24 h after injury at all time points from 6 h on. The addition of glucosteroids to focal excision reduced edema even further. Treatment of animals with dibenzyline, dimethyl sulfoxide, and diphenyl-p-phenylenediamine also had a beneficial effect upon the development of edema. Combination of steroids and osmotic diuretics was not of value. Focal excision with acetazolamide was extremely effective in reducing brain edema. A combination of DMSO and dexamethasone was more effective than either drug alone. Detailed studies to elucidate the effects of hypotension or hypertension in each of these therapeutic regimens were carried out.

The Effects of Glucosteroids upon Experimental Brain Edema

Brain edema has been produced in rabbits, cats, dogs, and monkeys by the intracranial implantation of hydrophillic materials, stab wounds, implantation of viable brain tumors, inflation of extradural or subdural balloons, and cortical or spinal cord freezing injury. The temporal course of the evolution and resolution of brain edema in each of these models has been studied by gross photography, the extravasation of fluorescent protein tracers, wet weight/dry weight determinations, light microscopy, histochemistry, and electron microscopy. In a similar series of animals, the effects of glucosteroids given in several ways have been evaluated. Dexamethasone, cortisone, prednisone, and prednisolone have been utilized in dosages varying from 0.25 to 2.5 mg/kg/24 h. Animals have been pre-treated with steroids for 24 and 48 h prior to lesion production, and steroids have then been begun at the time of lesion production and at regular intervals up to 72 h after lesion production. The effects of the administration of glucosteroids upon the same parameters of edema estimation have been assessed. The cold injury model provides the best quantitative data. The administration of glucosteroids to animals in which a cold or spinal cord freezing injury has been inflicted results in a gross reduction in brain edema with reduced extravasation of dye protein complexes. Wet weight/dry weight determinations demonstrate significant retardations in the development of brain edema. At 24 and 48 h there is an approximate 50% reduction in edema, and at 72 h, a reduction of almost 30% persists. Light microscopic and histochemical differences were not striking. Electron microscopic studies revealed definite reduction in astrocytic volume and in white matter extracellular space in treated animals. The resolution of edema appeared to be accelerated. In addition, there was a marked reduction in postedema astrogliosis in animals receiving glucosteroids.

Ultrastructural Substrates of Experimental Cerebral Edema

The developing clinical interest in cerebral edema and its neuropathological definition has been paralled by an increasing number of attempts to produce an adequate experimental model for the study of this process. The entity has been vigorously studied and there is a voluminous literature on the subject filled with conflicting reports and divergent opinions with regard to both reliability of methods and morphological changes produced.

The effects of glucosteroids upon cold-induced brain edema. 3. Prevention of gliosis following brain edema.

The acute brain edema which follows a cortical cold lesion is characterized by the appearance of fibril-filled astrocytes within hours of lesion production. This gliosis is steadily progressive for many months after injury. Prompt alleviation of the edema with glucosteroids greatly reduces the severity of the process.