Ischemic Edema Research Articles

Histopathologic studies of ischemic optic neuropathy

To define the histopathologic features of eyes in which a pathologic diagnosis of ischemic optic neuropathy had been made in the years 1951 through 1998.The following data were documented: age of patient, race, sex, source of tissue, cause of death, clinical history, interval from loss of vision to death, enucleation, exenteration, and biopsy. The histopathologic criteria for diagnosis of ischemic optic neuropathy were the presence of localized ischemic edema, cavernous degeneration, or an area of atrophy located superior or inferior in the optic nerve. Cases with history of abrupt loss of vision were combined with reports from the literature to construct a time table of histopathologic features and associated conditions.Ischemic optic neuropathy was present in 193 eyes. There were 88 females and 65 males. The average age was 71.6 years. Ischemic edema without (early) and with (later) gitter macrophages was present in 26 (13.5%). Cavernous degeneration was present in 69 nerves (36%). Mucopolysaccharide (MPS) was present in 37 cavernous lesions 1 month or longer after loss of vision. Cavernous lesions were seen in 3 eyes in which peripapillary retinal nerve fiber layer hemorrhage had been observed prior to death. Atrophic lesions, the most common pattern, were observed in 133 optic nerves (66.8%). More than 1 ischemic lesion was seen in 38 optic nerves (19.7%). Bilateral ischemic lesions were seen in 50 (35.2%) of 142 paired eyes.Ischemic optic nerve lesions are initially acellular and later show macrophage infiltration. Cavernous lesions with MPS are present 4 weeks or longer after vision loss. The location of MPS posteriorly and along the internal margin suggests that MPS is produced at the edges of lesions. Progressive vision loss in ischemic optic neuropathy may be secondary to compression of intact nerve from ischemic edema and cavernous swelling, or a second ischemic lesion.

Patterns of skin flowmotion in the lower limbs of patients with chronic critical limb ischaemia (CLI) and oedema.

To study flowmotion (FM) in lower limbs with critical limb ischaemia (CLI) and oedema and to elucidate FM patterns when skin viability is threatened. Fourteen patients with unilateral CLI and oedema and two control groups were included - one consisting of 10 healthy participants and the other nine patients with unilateral CLI without oedema. Laser Doppler was used to evaluate the foot skin microcirculation simultaneously at four different areas, with the limbs in supine and dependent position. FM was expressed using fast Fourier transformation (FFT) as low frequency (LF) and high frequency (HF) waves and their respective FFT-powers. All patients with CLI, both with and without oedema, showed HF waves in both diseased and contralateral limbs. These were absent in healthy controls. There were no regional differences in frequency in the critically ischaemic feet (with and without oedema) and between ischaemic and their contralateral feet. Changing the position of ischaemic limbs from supine to dependency had no significant effect on the frequency, while a significant increase of the median FFT-powers of LF and HF waves at the pulp of the first toe was observed. This manoeuvre resulted in decrease of the median FFT-powers of LF in healthy controls. HF waves are associated with CLI. Ischaemia also appears to influence the FFT-power of each frequency domain. Ischaemic oedema does not seem to affect the pattern of FM in the foot of patients with CLI.

Vascular and Stromal Features in the Skin of the Lower Limb in Patients with Chronic Critical Limb Ischaemia (CLI) and Oedema

Objective: peripheral oedema is often observed in limbs affected by chronic critical limb ischaemia (CLI) and is mainly subcutaneous in distribution. Previous work has shown that capillary filtration coefficient (CFC) in limbs with CLI and oedema was twice as great as that in the contralateral limb. These changes might be due to morphological changes. Transmission electron microscopy (TEM) was used to examine the morphological features of the capillary walls and surrounding stromal tissues in the skin of these limbs. Material and methods: eight patients with unilateral CLI and peripheral pitting oedema (four men, four women, a mean age of 81±6.9 years) was studied. Skin biopsies were taken from the pulp of the first toe, interdigital space between the first and second digits and dorsal part of forefoot just prior to amputation.Results : stromal oedema and dilated capillaries were most prominent in the distal part of the foot. Some of the capillaries were filled with blood cells and some were empty. The endothelium of the dilated vessels was elongated and distended. In some patients a number of capillaries were collapsed with degenerate endothelial cells. ««Gaps»», i.e. large openings, were found between the elongated oedematous endothelial cells. The basal lamina was thickened in all patients. Stromal haemorrhage and degeneration were seen in approximately 50% of patients. Conclusion: CLI causes ultrastructural changes in the capillary endothelium and surrounding stroma. The presence of large gaps between endothelial cells as well as an increased capillary pressure may enhance transcapillary transudation, and are most likely the causative factors in the formation of the ischaemic oedema. The stromal haemorrhage as well as degeneration probably signifies a terminal stage of CLI.

Veränderungen der Kapillarpermeabilität bei Patienten mit chronischer kritischer Extremitätenischämie und Ödem

Background: Oedema formation in lower limbs of patients with chronic critical limb ischaemia (CLI) is a common clinical feature. The rate of fluid filtration through the capillary wall depends on the capillary permeability, i.e. capillary filtration coefficient (CFC). In order to elucidate the pathogenesis of this ischaemic oedema, CFC was measured in the limbs with CLI and oedema and was compared with CFC measurements both in the contralateral sides and in the lower limbs of a control group. Patients and methods: Eleven women and 4 men, with a mean age of 75 ± 8.8 years, with unilateral CLI and leg and foot oedema were included. Leg and foot volume was measured with water displacement volumetry (WDV). CFC was measured in both limbs by strain-gauge plethysmography using a double-stranded mercury in silicone strain gauge around the middle portion of the foot. As a control group, 8 patients, 5 women and 3 men, with a mean age of 77 ± 7.6 years with a proximal femur fracture were included and the CFC in this group was measured in the foot of the non-fractured limb. Results: Mean CFC in the limbs with CLI and oedema was 0.0036 ± 0.001 ml/min · 100 ml · mmHg, significantly greater than both the contralateral limbs (0.0019 ± 0.0003 ml/min · 100 ml · mmHg, p < 0.01) and mean CFC in the control limbs (0.0017 ± 0.0002 ml/min · 100 ml · mmHg, p < 0.003). There was a mean volume difference of 13 ± 9 % between limbs with CLI and contralateral sides measured by WDV. There was no significant correlation between total leg-foot volume and CFC (p > 0.05). Conclusion: CFC in the ischaemic limb was twice as great as both the contralateral side and the limbs of the control group. It is therefore concluded that an increased CFC is probably one of the important factors in the development of this ischaemic oedema.

Lipocortin-1 fails to ameliorate ischemic brain edema in the cat.

It has been reported that corticosteroids exert their anti-inflammatory action through de novo synthesis of phospholipase-inhibitory proteins called lipocortins (annexins). We postulated that the following may lessen the effectiveness of corticosteroids on acute ischemic brain edema: 1) lipocortins are induced several hours after administration of steroids; 2) de novo synthesis of lipocortins is suppressed in the ischemic brain; and 3) lipocortins induced systemically do not pass through the blood-brain barrier (BBB) to reach the sites of ischemic edema. To test this hypothesis, we examined whether dexamethasone, given long before ischemia or direct administration of recombinant lipocortin-1, combined with or without BBB opening, ameliorate ischemic brain edema. Three hours before occlusion of the middle cerebral artery (MCA) in the cat, 4 mg/kg of dexamethasone was injected intravenously. The animals were subjected to 4 hours of ischemia. Alternatively, 2 ug/ml (total volume 10 ml) of recombinant human lipocortin-1 (annexin-I) was perfused intermittently into the ischemic focus by catheterization into the MCA. Artificial opening of the BBB was performed by intra-arterial mannitol infusion. None of these strategies demonstrated amelioration of ischemic edema. We conclude that: Dexamethasone and recombinant lipocortin-1 seem unlikely to have robust effects on amelioration of acute ischemic edema.

Experimental study on brain oxygenation in relation to tissue water redistribution and brain oedema.

The aim of the present experimental research was to study brain oxygenation parameters in relation to tissue water movement and brain cortex oedema caused by focal brain ischemia. It has been demonstrated that local osmotic dehydration of the parietal brain cortex, mercury compounds (aquaporin inhibitors) and brain cortex oedema resulting from focal brain ischemia all influence extra-capillary oxygen transport lowering tissue respiration rates and oxygen transfer coefficients. The changes of brain oxygenation parameters in case of cortex ischemic oedema are reflected in the gas composition (oxygen and carbon dioxide partial pressure) of the blood in v. jugularis. A short course of hyperbaric treatment results in normalization of water content in the brain. The results are interpreted in terms of the functioning of tissue microcirculation that might participate, at the extra-capillary level, in brain oxygenation.

Ischemic brain edema

Brain edema is a life-threatening complication of cerebral infarction. The molecular cascade initiated by cerebral ischemia includes the loss of membrane ionic pumps and cell swelling. Secondary formation of free radicals and proteases disrupts brain-cell membranes, causing irreversible damage. New diagnostic methods based on magnetic resonance imaging have markedly improved diagnostic accuracy. Cytotoxic and vasogenic edema is maximal by 24 to 72 hours after the ischemic event. Thrombolytics reperfuse tissue and improve outcome; when treatment is delayed, they can increase edema and blood-brain barrier opening. Although osmotherapy reduces brain water, and is used to treat ischemic edema, its efficacy remains to be proven. As the molecular events become clearer, novel treatments that block different stages of the injury cascade will be available for clinical testing. Copyright © 1999 by W.B. Saunders Company Progress in Cardiovascular Diseases, Vol. 42, No. 3 (November/December), 1999: pp 209-216

Optic disc and retinal microvasculopathy after high-dose chemotherapy and autologous hematopoietic progenitor cell support.

The purpose of this study was to prospectively evaluate the retinal and optic nerve changes in patients undergoing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell support (AHPCS). One hundred and forty patients undergoing HDC and AHPCS underwent extensive pre- and post-transplant ophthalmologic evaluations for development of retinal microvascular complications. One hundred and ten patients received high-dose cyclophosphamide, cisplatin and BCNU; thirty received identical doses of cyclophosphamide and cisplatin, but received paclitaxel instead of BCNU. Thirty-four patients (24%) had retinal findings of either cotton wool spots (CWS) (n = 20) or retinal hemorrhages (n = 18) during follow-up, which ranged from 1 to 12 months. Ten (7%) of these patients, all of whom received BCNU, showed ocular toxicity characterized by CWS 1 to 4 months post transplant (n = 10); optic disc edema (n = 3); and variable vision loss associated with the onset of BCNU-induced pulmonary toxicity. Retinal and optic disc microvascular complications may occur after high-dose chemotherapy followed by AHPCS. The association of ischemic retinal lesions and/or optic disc edema with BCNU-induced pulmonary toxicity and the lack of ocular toxicity in patients that did not receive BCNU may suggest that BCNU is the etiologic agent.

Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice.

Heme oxygenase-1 (HO-1, HSP32) is an early gene that is responsive to an array of pathological conditions including, but not limited to, hypoxia and cerebral ischemia. HO-1 cleaves the heme molecule and produces carbon monoxide (CO) and biliverdin (an antioxidant) and is essential for iron homeostasis. The purpose of this study was to investigate, using transgenic (Tg) mice, whether overexpression of HO-1 in the brain augments or attenuates cellular injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpress HO-1 under the control of the neuron-specific enolase promoter (characterized previously) were used. Under halothane anesthesia and normothermic conditions, wild-type nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice were subjected to middle cerebral artery occlusion (MCAo). Six hours after induction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm3, respectively (p < 0.01). No significant difference between the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significant neuroprotection as determined by the stroke volumes (41 +/- 2 mm3 in Tg vs. 74 +/- 5 mm3 in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 levels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO-1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.

Alpha-lipoic acid provides neuroprotection from ischemia-reperfusion injury of peripheral nerve.

Reperfusion aggravates nerve ischemic fiber degeneration, likely by the generation of reduced oxygen species. We therefore evaluated if racemic alpha-lipoic acid (LA), a potent antioxidant, will protect peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. We used male SD rats, 300+/-5 g. Ischemia was produced by the ligature of each of the supplying arteries to the sciatic-tibial nerve of the right hind-limb for predetermined periods of time (either 3 or 5 h), followed by the release of the ligatures, resulting in reperfusion. LA was given intraperitoneally daily for 3 days for both pre- and post-surgery. Animals received either LA, 100 mg/kg/day, or the same volume of saline intraperitoneally. Clinical behavioral score and electrophysiology of motor and sensory nerves were obtained at 1 week after ischemia-reperfusion. After electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. We evaluated for ischemic fiber degeneration (IFD) and edema, as we described previously. Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity (SCV) of digital nerve) was significantly improved in the 3-h ischemia group, treated with LA (P<0.05). LA also improved IFD of the mid tibial nerve (P=0.0522). LA failed to show favorable effects if the duration of ischemia was longer (5-h ischemia). These results suggest that alpha-lipoic acid is efficacious for moderate ischemia-reperfusion, especially on distal sensory nerves.

Intracranial vascular involvement of brain pathologies and venous occlusions.

In this paper, the authors present the contribution of CT and MRI to the diagnosis of acute stroke caused by arterial or venous occlusion. The term "early" used in this context means within 6 h of the onset of symptoms. Signs of early ischemic edema are subtle and sometimes difficult to detect by CT or MRI. The purpose of this presentation is to familiarize the clinician and the radiologist with the subtle brain parenchymal changes seen within the first 6 h after onset of symptoms, in order to improve detection of early ischemic infarction and to improve patient care.

Fructose-1,6-diphosphate enhanced oxyradicals and nitric oxide-dependent suppressions by dexamethasone of ischemic and histamine paw edema of mice

Dexamethasone (Dex, 0.1 mg kg , s.c.) suppressions of ischemic paw edema in mice at 1, 3, 6, 8, 18 hr were; 2, 22, 12, 11, 7 %. Dex suppression in fructose-1,6-diphosphate (FDP, 100 mg kg , i.p.)-treated mice were; 5, 49, 51, 42, 33 %. Suppressions by this dose of FDP alone were less than 10 % during 0 — 18 hr. ED 30 at 6 hr of Dex ± FDP was: 80 versus 500 mg kg in ischemic-, and 5 versus 30 mg kg in histamine edema. Endogenous oxyradicals or NO and protein synthesis were essential for suppressions. FDP may not change glucocorticoid receptor (GR) conformation, but increase ATP-dependent GR recycling efflux from nucleus. FDP is possible to supply this ATP. Clinical trial of FDP with low dose of Dex seems advantageous.

Ischemic edema and midline shift: Ambivalent effects of high & low-dose mannitol in experimental stroke

Ischemic edema and midline shift: Ambivalent effects of high & low-dose mannitol in experimental stroke

S-100 protein: serum marker of focal brain damage after ischemic territorial MCA infarction.

Elevations of protein S-100 (S-100) in cerebrospinal fluid and serum have been reported after cerebral infarctions. The aim of our study was to evaluate the time course of serum S-100 concentrations after territorial middle cerebral artery (MCA) infarctions in correlation with clinical data and prognosis. S-100 serum levels were serially determined in 26 patients with an acute infarction in the territory of the MCA at day 0 (within 12 hours after onset of symptoms), day 1 (24 hours after stroke onset), and days 2, 3, 4, 5, 7 or 8, and 10 after stroke and in 26 age- and sex-matched control subjects. S-100 assays were performed using a two-site radioimmunoassay technique. The clinical status was documented using the Scandinavian Stroke Scale. The functional deficit 4 weeks after stroke onset was scored by use of the modified Rankin scale. A cranial computed tomography (CCT) was performed initially and at day 4 or 5. Elevated concentrations of S-100 (> 0.2 microgram/L) were observed in 21 of 26 patients with MCA infarction but in none of the control subjects. S-100 levels peaked at days 2 and 3 after stroke. The S-100 concentrations in serum were significantly higher in patients with severe neurological deficits at admission, with extensive infarctions and a space-occupying effect of ischemic edema as compared with the rest of the population. S-100 values were not significantly correlated with the functional prognosis. Presence of S-100 in serum after ischemic stroke may be due to combined leakage out of necrotic glial cells and passage through an impaired brain-blood barrier, indicating severe ischemic cell injury. Therefore, S-100 in serum can be used as a peripheral marker of ischemic focal brain damage and may be helpful for therapeutic decisions in acute ischemic stroke.

New therapeutic possibility of blocking cytokine-induced neutrophil chemoattractant on transient ischemic brain damage in rats

Earlier we indicated that neutrophilic invasion into cerebral parenchyma is an important step in rat cerebral ischemia-reperfusion injury and the production of chemotactic factors, cytokine-induced neutrophil chemoattractant (CINC) precede the neutrophilic invasion. The aim of the present study was to evaluate the role of CINC production and the therapeutic possibility of blocking CINC activity in the transient ischemic brain damage in rats. Focal transient ischemia was produced by intraluminal occlusion of the right middle cerebral artery for 60 min. An enzyme immunoassay was used to measure the brain concentration of CINC and myeloperoxidase activity in ischemic areas was measured as a marker of neutrophilic accumulation. An immunohistochemical staining technique was used to detect the immunopositive cells for anti-CINC antibody. Further, application of anti-CINC antibody or anti-neutrophil antibody to rats was used to evaluate the role of CINC production. In ischemic areas, CINC production was detected and peaked 12 h after reperfusion, which followed 60 min of ischemia. Intraperitoneal injection of anti-neutrophil antibody 24 h before and immediately after reperfusion significantly reduced the brain water content and partially reduced the CINC production in ischemic areas. Further, immunohistochemical staining showed that anti-CINC antibody was found on the endothelial surface of venules and on parts of neutrophils that had invaded the ischemic area 6 to 24 h after reperfusion. Also, treatment with anti-CINC antibody reduced ischemic edema formation 24 h after reperfusion and the size of infarction areas 7 days after reperfusion. It thus appears that CINC, mainly produced by endothelium activated by factors released from neutrophils, plays an important role in ischemic brain damage. Furthermore, the blocking of CINC activity with antibody suggests an immuno-therapeutic approach to the treatment of stroke patients.

Reduction of ischemic reperfusion edema with corticotropin-releasing factor (CRF) in rat hind limb replantation.

Corticotropin-releasing factor (CRF), a peptide neurotransmitter, is suggested as a novel agent to reduce reperfusion edema following ischemia. In a rat hind limb replantation model, animals underwent amputation followed by 2.5 hours of ischemia with replantation and 2 hours of reperfusion. Animals were randomized to seven groups: a nonischemic control group and six experimental groups receiving treatment prior to reperfusion with (1) saline control, (2) alpha 9,41-CRF-a CRF receptor blocking agent (98 micrograms/per kilogram), (3) subcutaneous CRF (320 micrograms/per kilogram), (4) intravenous CRF (80 micrograms/per kilogram), (5) alpha-CRF and subcutaneous CRF, and (6) alpha-CRF and intravenous CRF. Comparison of preischemic amputated limb weight with weight after ischemia and reperfusion showed a reproducible and significant gain in limb weight after 2 hours (p = 0.004). A significant reduction in limb weight gain (49%) was achieved with both subcutaneous (p < 0.04) and intravenous CRF (p < 0.036). With the dose used in this model, alpha 9,41 CRF attenuated but did not completely block the effects of intravenous or subcutaneous CRF.

Defining hypertension in older people from primary care case notes review.

A method of defining blood pressure (BP) status from a review of primary care patient records was developed and then validated using the case notes of a general practitioner with an interest in hypertension. Data were drawn from the records of the previous 6 years of all 65 to 80-year-old patients in the practice (n = 263). Patients were then categorised as hypertensive, normotensive or 'undetermined' by using a flowchart based on the mean of the three most recent BP measurements, antihypertensive medication and comorbidities of ischaemic heart disease, myocardial infarction, angina, oedema or cardiac failure. Mean systolic BP of > or = 160 mm Hg and/or diastolic BP of > or = 90 mm Hg were used as a threshold definition of hypertension and of BP control. Disagreement between general practitioner and the notes based definition occurred in 11% of patients (5% hypertensive, 6% normotensive). Reasons for disagreement were: controlled hypertensives with comorbidities such as angina or heart failure (4%), isolated elevated readings (3%), use of antihypertensive medication for separate indications (2%), other reasons (2%). The resulting sensitivity and specificity was 86% and 88% respectively. Including the recording of a diagnosis of hypertension in the definition increased the sensitivity to 98% with specificity unchanged at 88%. Actual sensitivity of the instrument when used in other practices is likely to lie between 88% and 98% depending on the quality of the doctor's recording of the diagnosis of hypertension. These findings suggest that data from primary care case notes can provide a ready and valid means of defining cases of hypertension for studying the management of hypertension in primary care and for research purposes.

The effect of nitric oxide inhibition on ischemic brain edema.

The involvement of nitric oxide (NO) in the development of ischemic cytotoxic edema was investigated by inhibiting nitric oxide synthase (NOS) activity with N omega-nitro-L-arginine (NLA). Bilateral carotid artery occlusion (15 min) alone or with release (15 and 60 min) served as a model for edema induction. NLA, N omega-nitro-D-arginine methyl ester (D-NAME) or Ringer's solution were administered 4 hr prior to ischemia or sham operation. Treatment with a stable nitroxide radical, 4-hydroxy-2,2, 6,6-tetramethylpiperidine-L-oxyl (TPL), was used to assess free radical involvement in edema. Accumulation of tissue water was evaluated by measuring specific gravity (SG) of brain cortex and histological examination. There was a greater reduction of cortical SG in early reperfusion (15 min) and a lesser decrease in SG (60 min later) in NLA-than in D-NAME- or Ringer's-treated gerbils. The NLA effect was confirmed by histological examination of the brain tissue. TPL treatment (pre- and postischemic) ameliorated the formation of edema to the same degree as NLA. The findings indicate a biphasic NLA modulation of cytotoxic edema most likely mediated through absence or presence of NO-derived free radicals.

Natural antioxidants enhance and prolong the oxyradical/no-related suppression by dexamethasone of ischemic and histamine paw edema in mice.

Dexamethasone (0.1 mg/kg, s.c.) suppressed 2, 22, 12, 6, and 4% of ischemic paw edema of mice at 1, 3, 6, 18, and 40 h. Various antioxidants when given with 0.1 mg/kg Dex enhanced and prolonged the suppression. For example, 30 mg/kg of tannic acid induced suppression of 6, 52, 59, 42 and 27%, whereas no increase of Dex suppression at 1 h was observed with any of the antioxidants tested. The prolonging effect of antioxidants may be due to the change of glucocorticoid (GC) receptor signaling under new redox state, because oxyradicals modified the suppression, whereas nitric oxide (NO) showed no effect on Dex suppression enhanced by antioxidants. ED30 (mg/kg, i.p.) at 6 h after Dex was: morin (0.02) > alpha-tocopherol (0.03) > tannic acid (0.12) > rutin (0.2) = bilirubin (0.2) > beta-carotene (0.3) >> quercetin (6) > melatonin (8) > ascorbic acid (12), whereas none of the antioxidants alone afforded more than 10% suppression even at 30 mg/kg. Similar Dex plus antioxidant actions were observed in histamine paw edema. Clinical trials of nontoxic natural antioxidants might be successful when coinjected with low dose of GC which shows very little side effects.

The normal and pathological physiology of brain water.

The physicochemical properties of water enable it to act as a solvent for electrolytes, and to influence the molecular configuration and hence the function--enzymatic in particular--of polypeptide chains in biological systems. The association of water with electrolytes determines the osmotic regulation of cell volume and allows the establishment of the transmembrane ion concentration gradients that underlie nerve excitation and impulse conduction. Fluid in the central nervous system is distributed in the intracellular and extracellular spaces (ICS, ECS) of the brain parenchyma, the cerebrospinal fluid, and the vascular compartment--the brain capillaries and small arteries and veins. Regulated exchange of fluid between these various compartments occurs at the blood-brain barrier (BBB), and at the ventricular ependyma and choroid plexus, and, on the brain surface, at the pia mater. The normal BBB is relatively permeable to water, but considerably less so to ions, including the principal electrolytes Brain fluid regulation takes place within the context of systemic fluid volume control, which depends on the mutual interaction of osmo-, volume-, and pressure-receptors in the hypothalamus, heart and kidney, hormones such as vasopressin, renin-angiotensin, aldosterone, atriopeptins, and digitalis-like immunoreactive substance, and their respective sites of action. Evidence for specific transport capabilities of the cerebral capillary endothelium, for example high Na+K(+)-ATPase activity and the presence at the abluminal surface of a Na(+)--H+ antiporter, suggests that cerebral microvessels play a more active part in brain volume regulation and ion homoeostasis than do capillaries in other vascular beds. The normal brain ECS amounts to 12-19% of brain volume, and is markedly reduced in anoxia, ischaemia, metabolic poisoning, spreading depression, and conventional procedures for histological fixation. The asymmetrical distributions of Na+ K+ and Ca2+ between ICS and ECS underlie the roles of these cations in nerve excitation and conduction, and in signal transduction. The relatively large volume of the CSF, and extensive diffusional exchange of many substances between brain ECS and CSF, augment the ion-homeostasing capacity of the ECS. The choroid plexus, in addition to secreting CSF principally by biochemical mechanisms (there is an additional small component from the extracellular fluid), actively transports some substances from the blood (e.g. nucleotides and ascorbic acid), and actively removes others from the CSF. In contrast with CSF secretion, CSF reabsorption is principally a biomechanical process, passively dependent on the CSF-dural sinus pressure gradient. Pathological increases in intracranial water content imply development of an intracranial mass lesion. The additional water may be distributed diffusely within the brain parenchyma as brain oedema, as a cyst, or as increase in ventricular volume due to hydrocephalus. Brain oedema is classified on the basis of pathophysiology into four categories, vasogenic, cytotoxic, osmotic and hydrostatic. The clinical conditions in which brain oedema presents the greatest problems are tumour, ischaemia, and head injury. Peritumoural oedema is predominantly vasogenic and related to BBB dysfunction. Ischaemic oedema is initially cytotoxic, with a shift of Na+ and CI- ions from ECS to ICS, followed by osmotically obliged water, this shift can be detected by diffusion-weighted MRI. Later in the evolution of an ischaemic lesion the oedema becomes vasogenic, with disruption of the BBB. Recent imaging studies in patients with head injury suggest that the development of traumatic brain oedema may follow a biphasic time course similar to that of ischaemic oedema. Hydrocephalus is associated in the great majority of cases with an obstruction to the circulation or drainage of CSF, or, occasionally, with overproduction of CSF by a choroid plexus papilloma. In either case, the consequence is a ris