Robert Whytt (1714-1766): from dropsy in the brain to tuberculous meningitis.

Robert Whytt was born and educated in Edinburgh and served the City in the Royal Infirmary. A prolific author, his major work is usually said to be his Essay on the Vital and other Involuntary Movements of Animals (1751), based on his belief that a 'sentient principle' was not limited to the nervous system but was distributed throughout the body, a view that brought him into conflict with Albrecht von Haller, who held that the sentient and motor powers of the body were those of a machine. Whatever about the speculative nature of the sentient principle, Whytt was a clinician blessed with unusual clarity, and he is remembered today for his Observations on the Dropsy in the Brain (1768). Therein he described the clinical signs and symptoms of what later came to be recognised as tuberculous meningitis, the acute disease which appears early in the haemic spread of the infection in a child, and which was fatal until the discovery of chemotherapy and antimicrobials. John Cheyne, in describing two terminal cases, recognised the connexion between hydrocephalus and scrophula, and Dorothy Price provided a precise guide to the clinical picture in 1942. When streptomycin became available Christopher McSweeney used it to alter the bleak picture in Dublin, and was helped by the prevention resulting from neonatal BCG immunisation. Later antimicrobials have facilitated the avoidance of emergent bacillary resistance.

The history of urea as a hyperosmolar agent to decrease brain swelling.

In 1919, it was observed that intravascular osmolar shifts could collapse the thecal sac and diminish the ability to withdraw CSF from the lumbar cistern. This led to the notion that hyperosmolar compounds could ameliorate brain swelling. Since then, various therapeutic interventions have been used for the reduction of intracranial pressure and brain volume. Urea was first used as an osmotic agent for the reduction of brain volume in 1950. It was associated with greater efficacy and consistency than alternatives such as hyperosmolar glucose. Its use became the standard of clinical practice by 1957, in both the intensive care unit and operating room, to reduce intracranial pressure and brain bulk and was the first hyperosmolar compound to have widespread use. However, the prime of urea was rather short lived. Reports of side effects and complications associated with urea emerged. These included coagulopathy, hemoglobinuria, electrocardiography changes, tissue necrosis with extravasation, and a significant potential for rebound intracranial hypertension. Mannitol was introduced in 1961 as a comparable and potentially superior alternative to urea. However, mannitol was initially purported to be less effective at rapidly reducing intracranial pressure. The debate over the two compounds continued for a decade until mannitol eventually replaced urea by the late 1960s and early 1970s as the hyperosmolar agent of choice due to the ease of preparation, chemical stability, and decreased side effect profile. Although urea is not currently the standard of care today, its rise and eventual replacement by mannitol played a seminal role in both our understanding of cerebral edema and the establishment of strategies for its management.

International brain edema symposia 1967-2011.

This is a brief review of previous international brain edema symposia. The symposia that took place from 1965 to 1999 were summarized by Igor Klatzo and A. Marmarou in the proceedings Brain Edema XI [1]. In this article the author summarized the symposia, including latest five. Images from previous symposia such as the cover pages of the proceedings and snapshots of organizers were included. The outline and key words of the symposia were summarized in tables. The name of the prize winner and the title of the memorial lectures in recent symposia were also summarized in a table.

A neurologist in the origin of European and International neurosurgery: Clovis-Julien-Désiré Vincent (1879-1947).

Vincent Clovis began his carrier as a neurologist and finally became neurosurgeon at an advanced age. He is considered the founder of French neurosurgery, and after Harvey Williams Cushing, Europe's first neurosurgeon. He was mainly interested in pituitary tumors, in cerebral abscesses and in cerebral oedema.

Bulk flow and diffusion revisited, and clinical applications.

The first Klatzo-Lecture pays homage to an exceptional academician, scientist and teacher. The author spent nearly 1 year in Klatzo's laboratory at the NHI in Bethesda, and the first part of results presented here originate directly from this collaboration. It was shown that following cortical injury, movement of edema fluid into the tissue occurs by bulk flow, and that the driving force is a small tissue pressure gradient. Resolution of edema fluid is achieved by clearance into the ventricular and subarachnoid CSF, is enhanced in the presence of pressure gradients and is supported by re-absorption into capillaries. Using appropriate techniques, the formation rate as well as clearance of edema into CSF and tissue resorption could be determined in human brain metastases and malignant gliomas. Three examples of clinical applications based on the discussed mechanisms are presented: a. Fluorescence-guided surgery of gliomas is based on the accumulation of 5-ALA in tumour cells; there being enzymatically converted to PP-IX, a compound with deep red fluorescence. This fluorescence is used for the more accurate surgical removal of gliomas. b. Radioimmunotherapy of gliomas uses an anti-tenascin antibody, coupled with a nuclide, administered postoperatively into the tumour cavity, from where it diffuses into tissue, couples to the receptor at the glioma cells. Then the isotope destroys the tumour cells. c. Convection-enhanced delivery is based on the interstitial infusion of an appropriate cytotoxic drug into the white matter at low pressure. Thus, the method employs bulk flow, distributes a drug in a larger tissue volume and eventually achieves drug concentrations greater than systemic levels. Experimental studies and clinical results are presented for all three clinical applications.I am very grateful to Z. Czernicki and the organizing group for being offered the great honour of presenting the first Igor Klatzo Lecture. In this report first previous results of bulk flow and diffusion in the development and resolution of brain edema will be revisited, then some recent examples will be shown as to how this knowledge of diffusion and bulk flow can be transferred into clinical applications.A great part of the work on bulk flow and diffusion was done during a stay in I. Klatzo's laboratory in Bethesda in 1973/1974 (Fig. 1). Since then a long collaboration developed with I. Klatzo and M. Spatz. Due to given limits, I will concentrate on the studies of our group. Unfortunately it will not be possible to mention all the important groups who have contributed by essential studies.

Experimental cerebral ischemia: the contribution of the Bethesda Group.

Igor Klatzo started his research on cerebral ischemia at the NIH in the 1960s. The mechanism that produces the blood-brain barrier change after ischemia was a focus of interest in Klatzo's experiments, which used larger mammals. Studies using Mongolian gerbils, started by U. Ito, resulted in several important findings, including observation of the maturation phenomenon in 1975. Using newly developed ischemia models, the mechanism of postischemic neuronal/tissue injury was extensively studied. The cumulative effect was observed after repetitive cerebral ischemia. The protective mechanism of cortical spreading depression after global ischemia was investigated. Projects including in vitro studies of human brain endothelial cells and mucosal tolerance to E-selectin were performed in the Stroke branch after Klatzo retired from the NIH. Klatzo published a biography of Cecil and Oskar Vogt after retirement. He passed away in May 2007 in Gaithersburg, Maryland a few months after he completed the first part of his autobiography.

Past and recent BBB studies with particular emphasis on changes in ischemic brain edema: dedicated to the memory of Dr. Igor Klatzo.

The blood-brain barrier (BBB) functions to protect the environment of the brain through endothelial cells and their interactions with other cells and components of the cerebral vasculature and the brain parenchyma. Alterations in the BBB as a result of injuries (i.e., brain ischemia and traumatic brain injury) play a crucial role in the pathophysiological response.The following is a brief review of the BBB and the mechanisms by which its cellular elements participate in barrier disruptions such as those associated with ischemia and resulting brain edema formation.

Genesis of the use of corticosteroids in the treatment and prevention of brain edema.

BACKGROUND: Since the groundbreaking article from the University of Minnesota in 1961 by Drs. Galicich, French, and Melby describing the use of dexamethasone for peritumoral cerebral edema, the use of corticosteroids in patients with brain tumors has become routine. Unfortunately, little has been reported regarding the environment that fostered arguably the greatest translational research contribution in the history of neurosurgery. METHODS: During a pilot study to assess corticosteroid uptake in brain tumors, Dr. Galicich observed that patients given a large dose of corticosteroids just before craniotomy had a relatively benign postoperative course. This led, in October 1959, to the administration of high-dose corticosteroids to a patient with a large recurrent glioblastoma who was semicomatose and severely hemiparetic. The results were dramatic, with almost complete resolution of neurological deficit during a period of several days and marked reduction of midline shift on repeat angiograms. This finding prompted the studies that confirmed the efficacy of high-dose corticosteroids in reducing peritumoral brain edema in humans reported in the 1961 article. RESULTS: After publication, a revolution in brain tumor management occurred because corticosteroid therapy markedly reduced the morbidity and mortality associated with brain tumors both in the United States and worldwide. CONCLUSION: The combination of astute clinical observation and follow up by rigorous clinical research at the University of Minnesota resulted in one of the greatest contributions in the history of neurosurgery, rivaled only by the operative microscope in its effect on morbidity, and unsurpassed in reduction of mortality.

[Brain edema--historical aspects and contemporary suggestions].

The aim of this article was to show the historical aspects of elaboration of the brain edema study. To draft the main stages of study development from naive medievals suggestions till the creation of modern technologies and the possibility of the brain edema neurovisualization. The possibility to watch and control these processes grants the real perspective to enhance the effectiveness of the brain edema therapy.

High altitude cerebral edema.

Acute mountain sickness (AMS) is usually a benign and self-limited illness that befalls previously healthy individuals who ascend rapidly to high altitude without sufficient acclimatization. In its more severe forms, AMS can progress to a life-threatening condition in which pulmonary or cerebral edema can occur singly or in concert. High altitude cerebral edema (HACE) is a little-known clinical entity that manifests itself by a perplexing array of both generalized and localized neurological symptoms and signs. Furthermore, the development of HACE in climbers offers a unique experimental situation in which to examine the effects of hypoxia on the central nervous system. The epidemiology and clinical picture of HACE are reviewed. In addition, the pathology and predominant pathophysiological mechanisms postulated to explain HACE are examined, and the present recommendations for the prevention and treatment of this dangerous and unusual form of brain swelling are discussed.

A history of the study of cerebral edema.

A brief review of the historical concepts underlying our present knowledge of cerebral edema is presented, together with the evolution of attempts to measure the edema.

Historical aspects of normal and abnormal brain fluids. III. Cerebral edema.

The early life, death, and revival of the concept of cerebral edema are discussed. This unusual sequence has been related to a clinical syndrome, a vascular hypothesis, a unique brain circulation, and a new investigative technique: electron microscopy.