Study of subclinical cerebral edema in diabetic ketoacidosis by magnetic resonance imaging T2 relaxometry and apparent diffusion coefficient maps

Cerebral edema is the most significant complication in children with diabetic ketoacidosis (DKA). Our goal was to study whether subclinical cerebral edema was preferentially vasogenic or cytotoxic. Magnetic resonance imaging (MRI)--diffusion-weighted imaging (DWI) and T2 relaxometry (T2R)--were obtained in pediatric patients presenting with severe diabetic ketoacidosis (DKA) 6-12 hours after initial DKA treatment and stabilization and 96 hours after correction of DKA. T2 relaxometry was significantly increased during treatment in both white and gray matter, in comparison to the absolute T2R values 96 hours after correction of DKA (p = .034). Classic intracellular cytotoxic edema could not be detected, based on the lack of a statistically significant decrease in ADC values. ADC values were instead elevated, implying a large component of cell membrane water diffusion, correlating with the elevated white and gray matter T2R We discuss the findings in relation to cerebral blood volume, cerebral vasoregulatory dysfunction, and cerebral hyperemia.     

Postpartum blindness: two cases

We present 2 cases, one eclamptic patient and one noneclamptic patient, of headache, cortical blindness, and seizures. Both patients demonstrated findings consistent with posterior leukoencephalopathy syndrome. Posterior leukoencephalopathy syndrome is a rapidly evolving neurologic condition that is characterized by headache, nausea and vomiting, seizures, visual disturbances, altered sensorium, and occasionally focal neurologic deficits. Posterior leukoencephalopathy syndrome can be triggered by numerous conditions, including preeclampsia-eclampsia, and can be seen in the postpartum period. It is characterized predominately by white matter vasogenic edema of the occipital and posterior parietal lobes. This condition can be difficult to differentiate clinically from cerebral ischemia, and magnetic resonance imaging with diffusion-weighted imaging and apparent diffusion coefficient are needed to do so. In most cases of posterior leukoencephalopathy syndrome, the prognosis is excellent, with full resolution of symptoms.     

Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure.

Cerebral edema is a serious complication of the encephalopathy in fulminant hepatic failure. It is a major cause of death. The mechanisms responsible for its formation are unclear, and the aim of this study was to investigate the ultrastructural appearance of brain capillaries by scanning electron microscopy. Samples of cerebral cortex were obtained immediately after death from nine patients with fulminant hepatic failure (seven cases due to acetaminophen overdose, one caused by hepatitis B and one caused by non-A, non-B hepatitis) by needle biopsy at the site of insertion of an extradural pressure transducer to monitor intracranial pressure. The intercellular tight junctions between capillary endothelial cells were intact. The endothelial cells were swollen, with increased numbers of vesicles and vacuoles. The basement membranes were enlarged and vacuolized and the pericytes had increased numbers of vesicles and vacuoles, indicative of passage of fluid by this route. Marked intracellular swelling of the perivascular astroglial foot processes was present. Thus mainly cytotoxic mechanisms, with cellular swelling, and to a lesser extent vasogenic mechanisms, with altered blood-brain barrier permeability, appear to be involved in the cerebral edema of fulminant hepatic failure.     

Electron microscopic evaluation of brain edema in rabbits with galactosamine-induced fulminant hepatic failure: ultrastructure and integrity of the blood-brain barrier

Brain edema is a major complication of fulminant hepatic failure and is responsible for death in a large percentage of patients. We previously demonstrated the progressive accumulation of water in grey matter areas of the brain in the rabbit with galactosamine-induced fulminant hepatic failure. We now report the electron microscopic morphology of the brain in the same model of acute hepatic failure following the intravenous injection of horseradish peroxidase, an intravascular tracer which forms an electron-dense reaction product. Rabbits with both mild and severe encephalopathy had normal blood pressures and blood gases at the time of study. Fixation of brain tissue was obtained by whole-body perfusion. Marked swelling of the cytoplasm, perineuronal and perivascular processes of astrocytes were noted in cortical gray, but not white, matter areas; the other cellular components of the brain had normal morphology. Capillary endothelial cells were normal, and there was no evidence of horseradish peroxidase in endothelial cell vesicles, basement membranes or the brain parenchyma, suggesting that the blood-brain barrier was impermeable to large molecules. Histologic evidence of brain edema is seen in this model, with swelling of astrocytes as the primary manifestation of the accumulation of water. Damage to astrocytes or inhibition of their function may contribute to the pathogenesis of hepatic encephalopathy in this model.     

Posterior reversible encephalopathy syndrome: magnetic resonance imaging and diffusion-weighted imaging in 12 cases

Posterior reversible encephalopathy syndrome (PRES) is a potentially devastating neurologic syndrome, but timely treatment may lead to complete reversal of the disease course. We reviewed 12 cases of PRES and describe the clinical history and imaging findings, including conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), and calculated apparent diffusion coefficient (ADC) maps, used to establish the diagnosis of PRES. Three male and nine female patients aged between 11 and 70 years (mean, 37 years) with clinical and imaging findings consistent with PRES were enrolled in the study. All patients had undergone conventional MRI and 10 had undergone additional DWI studies. Ten patients had follow-up MRI studies. DWI was performed using a 1.5T system with a single-shot spin-echo echoplanar pulse sequence. Initial and follow-up neuroimaging and clinical history were reviewed. Lesions were almost always present over the posterior circulation, mainly the parieto-occipital region, affecting primarily the white matter. The anterior circulation region, brainstem, cerebellum, deep cerebral white matter, and thalamus were also involved in five cases. Conventional MRI revealed hyperintensity on T2-weighted and fluid-attenuated inversion recovery images. DWI showed isointensity and increased signal intensity on ADC values in all cases, indicating vasogenic edema. Clinical and MRI follow-up showed that the symptoms and radiologic abnormalities could be reversed after appropriate treatment of the causes of PRES in most patients (9 of 10). In one patient, the ADC value was lower on follow-up images, indicating cytotoxic edema with ischemic infarct. DWI was a useful complement to MRI in the diagnosis of PRES.     

Regional cerebral edema and chloride space in galactosamine-induced liver failure in rats

The pathogenesis of cerebral edema, which is a major complication of fulminant hepatic failure, is poorly understood. In previous studies, increased regional brain water content was observed in rats at an early stage of acute liver failure caused by galactosamine. At a later stage when the animals had developed deep coma, brain water content was reduced, possibly as a result of generalized dehydration. In the present investigation, we have determined brain water content at a late stage of liver failure, 48 hours after galactosamine, in animals that had been maintained in fluid balance by continuous intraperitoneal infusion of glucose solution. In these animals, brain water content, determined from the ratio of wet to dry weight, showed a greater increase than that observed previously at the early stage (hindbrain region [cerebellum, pons, and brain stem] increased by 4.2%; forebrain region increased by 1.4% compared with controls). Regional analysis of brain water, using a tissue-specific gravity method, showed a significant increase in cerebellar gray matter water content. Analysis of chloride space showed the extra fluid to be mainly extracellular in the hindbrain region, but not in the forebrain region. Ultrastructural examination of capillaries in gray matter from cerebellum and cerebrum showed no evidence of gross disruption of the tight junctions. Swelling of the astroglial foot processes was observed in the cerebellar gray matter. These results suggest that both vasogenic and cytotoxic mechanisms of edema formation occur in the brain during liver failure.(Hepatology 1997 Feb;25(2):295-301)     

Value of the apparent diffusion coefficient for quantification of low-grade hepatic encephalopathy

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (HE) is associated with poorer quality of life and increased work disability. Recently, low-grade cerebral edema has been implicated in chronic liver disease.
METHODS: We measured the apparent diffusion coefficient (ADC) of water in various regions of the brains of patients with cirrhosis, and elucidated the significance of the evaluation of ADC in quantifying low-grade HE and predicting overt HE and survival. Forty patients with cirrhosis and 24 controls underwent diffusion-weighted imaging, and patients were followed up every month.
RESULTS: The mean ADC values were increased in cirrhotic patients with minimal HE versus no HE or controls. Minimal HE patients separated from no HE patients with a sensitivity of 70∼90% and a specificity of 85∼90%. ADC values correlated with individual neuropsychological tests. ADC values of white matter, such as the frontal (log-rank test 4.35, P < 0.05) and parietal (log-rank test 5.98, P < 0.05) white matter, was predictive of further bouts of overt HE.
CONCLUSIONS: ADC is a reliable tool for quantification of low-grade HE, and could predict the development of overt HE.     

Ammonia-induced swelling of rat cerebral cortical slices: Implications for the pathogenesis of brain edema in acute hepatic failure

The pathogenesis of brain edema in fulminant hepatic failure is incompletely understood. Our previous studies in models of this disease suggest the presence of a cytotoxic mechanism; as cortical astrocytes appeared predominantly swollen, we hypothesized that ammonia, metabolized to glutamine solely within this cell, could play a role in brain water accumulation. We determined ammonia levels in different brain regions of rats after hepatic devascularization, a model previously shown to exhibit brain edema. Concentrations of 2.5 mM were observed in the edematous cerebral cortex. We then added several concentrations of ammonium chloride to the first cortical brain slice, a preparation used to study cytotoxic brain edema. At a final bath concentration of ammonia of 5 and 10 mM, swelling could be detected; a decrease in the space of distribution of inulin was seen at the 10 mM concentration, suggesting intracellular water accumulation. Neuropathologically, astrocytes appeared involved even at subswelling doses of ammonia. Octanoic acid, at a 10 mM concentration, also resulted in demonstrable swelling. Ammonia, at concentrations in the incubation bath that approach the levels seen in anin vivo model of brain edema, results in water accumulation of cortical brain slices. Toxins implicated in the pathogenesis of hepatic encephalopathy, such as ammonia and octanoic acid, may, result in brain water accumulation.     

Cerebral diffusion tensor imaging and in vivo proton magnetic resonance spectroscopy in patients with fulminant hepatic failure

Background and Aim:  Cerebral edema is a major complication in patients with fulminant hepatic failure (FHF). The aim of this study was to evaluate the metabolite alterations and cerebral edema in patients with FHF using in vivo proton magnetic resonance spectroscopy (MRS) and diffusion tensor imaging, and to look for its reversibility in survivors.
Methods:  Ten FHF patients along with 10 controls were studied. Five of the 10 patients who recovered had a repeat imaging after three weeks. N-acetylaspartate, choline (Cho), glutamine (Gln), glutamine/glutamate (Glx), and myoinositol ratios were calculated with respect to creatine (Cr). Mean diffusivity (MD) and fractional anisotropy (FA) were calculated in different brain regions.
Results:  Patients exhibited significantly increased Gln/Cr and Glx/Cr, and reduced Cho/Cr ratios, compared to controls. In the follow-up study, all metabolite ratios were normalized except Glx/Cr. Significantly decreased Cho/Cr were observed in deceased patients compared to controls. In patients, significantly decreased MD and FA values were observed in most topographical locations of the brain compared to controls. MD and FA values showed insignificant increase in the follow-up study compared to their first study.
Conclusions:  We conclude that the Cho/Cr ratio appears to be an in vivo marker of prognosis in FHF. Decreased MD values suggest predominant cytotoxic edema may be present. Persistence of imaging and MRS abnormalities at three weeks' clinical recovery suggests that metabolic recovery may take longer than clinical recovery in FHF patients.     

Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization

Brain edema is a fatal complication of fulminant hepatic failure and its pathogenesis remains unclear. To determine its presence in a model of ischemic hepatic failure, rats were subjected to a portacaval anastomosis followed by hepatic artery ligation. Brain water was measured using the sensitive gravimetric method. Preliminary studies revealed marked hypothermia in devascularized animals kept at room temperature (26.9 degrees +/- 2.8 degrees C). An additional group of devascularized rats was kept in an incubator. As expected for hypothermia, such animals had a lower arterial pressure and heart rate; the duration of encephalopathy was markedly prolonged. Water content of the cortical gray matter was only increased in normothermic devascularized rats: 80.14% +/- 0.31%, normal; 80.06% +/- 0.22%, portacaval shunt only; 80.42% +/- 0.26%, devascularized at room temperature; 81.29% +/- 0.38%, devascularized at controlled temperature (p less than 0.001). Such differences could not be detected using the dry-weight technique in whole cerebral hemispheres. Astrocyte changes in the cortical gray matter were noted in both edematous and nonedematous devascularized groups, coupled with the presence of vesicles containing horseradish peroxidase in the endothelial capillary cell. This suggests that in this model, brain edema may be due to both a cytotoxic mechanism and changes in the permeability of the blood-brain barrier. Future studies with this widely used model will require strict control of temperature to allow interpretation of experimental results. A therapeutic role for hypothermia in the management of brain edema deserves further attention.     

Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats.

The pathogenesis of brain edema in acute liver failure is poorly understood. We have previously shown that rats with ischemic acute liver failure (portacaval anastomosis followed by hepatic artery ligation) exhibit brain edema and intracranial hypertension, with swelling of cortical astrocytes as the most prominent neuropathological abnormality. Because ammonia has been shown to induce swelling of astrocytes in vivo and in vitro, we examined the relationship between brain ammonia, amino acids generated from ammonia metabolism and brain water content in this model. Four groups of animals were studied: rats subjected to two sham operations, rats subjected to portacaval anastomosis and a sham operation, rats subjected to a sham operation and hepatic artery ligation and rats subjected to portacaval anastomosis and hepatic artery ligation. The last group of animals was studied at three progressive stages of encephalopathy. Cortical gray matter water increased from 80.26% +/- 0.22% (sham + sham) to 82.46% +/- 0.06% (last stage of devascularization). In cerebral cortex, brain ammonia increased to a maximum of 5.4 mmol/L. Glutamine, generated in glial cells from ammonia and glutamate, increased sixfold to 24 mmol/L and remained at this level throughout all stages of encephalopathy. Alanine, which may be generated from the transamination of glutamine, increased in parallel to the increase in water (r = 0.80, n = 15). In this model of fulminant liver failure and associated brain edema, brain ammonia increases to levels associated with in vitro swelling of brain slices and glial cells. The accumulation of osmogenic aminoacids such as glutamine and alanine may contribute to the selective astrocyte swelling seen in this condition.(ABSTRACT TRUNCATED AT 250 WORDS)     

可逆性后部白质脑病综合征的临床和影像学特征:9例回顾性病例系列研究

目的 探讨可逆性后部白质脑病综合征(reversible posterior leukoencephalopathy syndrome,RPLS)的临床和影像学特征.方法 回顾性分析9例RPLS患者的临床和影像学资料.结果 继发于妊娠高血压综合征4例(44%),短肠综合征1例(11%),急性淋巴细胞白血病1例(11%)...     

Synergistic effect of bile acid,endotoxin, and ammonia on brain edema

The effects of cytotoxic substances such as ammonia, bile acids and endotoxin, all of which increase in the circulating blood during fulminant hepatic failure (FHF), on the blood-brain barrier (BBB) permeability and development of brain edema were examined in the rats. Direct intracarotid injection of various bile acids resulted in the staining of the cerebral hemisphere with Evans blue as well as the increase of brain water contents. Elevation of ammonia was also observed in the cerebral hemisphere where the reversible opening of the BBB was induced by deoxycholate under hyperammonemic conditions. To see the synergistic significance of cytotoxic substances (ammonia, bile acid and endotoxin) under the more physiological condition as FHF, they were simultaneously injected into a peripheral vein. Brain uptake index of 14C-inulin and brain water content increased, and electron micrographs showed the swollen astrocytic foot processes surrounded brain capillary, but not opening of tight junction, the same as an animal model of fulminant hepatic failure. The results suggest that ammonia, bile acids and endotoxin might have a possible synergistic role in the pathogenesis of the brain edema, mainly cytotoxic, and vasogenic due to acceleration of vesicular transport, in FHF.     

Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging

Hepatic encephalopathy is a common problem in cirrhosis. The pathogenesis of this complication of advanced liver disease still remains unclear. Magnetic resonance spectroscopy was used to assess prospectively cerebral metabolism in 51 patients with histologically proven cirrhosis (Child-Pugh classes A, B, and C, 18, 18, and 15, respectively) and 36 healthy volunteers. According to the results of psychometric tests, overt hepatic encephalopathy, subclinical encephalopathy, and no encephalopathy were found in 14, 21, and 16 patients, respectively. Myoinositol/creatine ratios in gray (.36 +/- .17) and white (.35 +/- .22) matter voxel were reduced significantly (P < .0001) in cirrhotic patients compared with healthy volunteers (gray matter, .51 +/- .11; white matter, .64 +/- .16). In addition, patients showed a significant reduction (P = .024) in white matter choline/creatine ratio (.77 +/- .27) compared with controls (.92 +/- .25), and glutamine/glutamate level was elevated in cirrhotic patients compared with controls (gray matter, P < .0001; white matter, P = .036). Changes in cerebral myoinositol and glutamine/glutamate levels correlated significantly with the severity of hepatic encephalopathy (P < .0001). However, these metabolic alterations were also detected in patients without hepatic encephalopathy (normal psychometric test results). N-acetyl aspartate/creatine ratios did not differ between patients and controls. Magnetic resonance imaging detected bright basal ganglia in 37 patients, which correlated significantly with portal-systemic shunting and elevation of glutamine/glutamate, but not with the degree of hepatic encephalopathy. In conclusion, magnetic resonance imaging and spectroscopy showed that alterations of cerebral metabolism are common in patients with cirrhosis, even without evidence of clinical or subclinical hepatic encephalopathy.(Hepatology 1997 Jan;25(1):48-54)     

Electron microscopic study of the blood-brain barrier in rats with brain edema and encephalopathy due to acute hepatic failure

An electron microscopy study was conducted to investigate structural as well as functional changes of the blood-brain barrier in hepatic encephalopathy. Hepatic encephalopathy was induced in rats by two-stage hepatic devascularization producing ischemic liver damage. The permeability of the blood-brain barrier to lanthanum, horseradish peroxidase and [3H]inulin was determined, with electron microscopy performed on capillaries from different regions of rat brain. Marked swelling of the perivascular astroglial foot process and dilatation of extracellular spaces were observed in the cerebral cortex, pons, basal ganglia and cerebellar cortex in rats with acute hepatic failure. Diffusion of lanthanum and reaction products of horseradish peroxidase were completely restricted by intercellular tight junctions, but there was a significant increase in the amount of [3H]inulin leaking out of the capillaries in the cerebral cortex in rats with acute hepatic failure as compared with controls. [3H]inulin was found mainly in vesicles, vacuoles and endoplasmic reticulum. Our results indicate that brain edema in acute hepatic encephalopathy is mainly of the cytotoxic type and, to a lesser extent, of the vasogenic type, due to the increase of vascular permeability via the vesicle system.     

Pathophysiology of Brain Edema in Fulminant Hepatic Failure,Revisited

We have proposed a combined osmolar-hemodynamic disturbance to explain the presence of brain edema in fulminant hepatic failure, a major cause of death in this disorder. The concept of an osmotic disturbance in the brain, emphasizing the presence of astrocyte swelling and low-grade cerebral edema, has been expanded to the entire spectrum of liver disease. The mechanism of cerebral hyperemia in patients with FHF and brain swelling has been studied in experimental models linking hyperammonemia and glutamine generation in astrocytes to the development of this hemodynamic alteration. Measures to control cerebral hyperemia, such as mild hypothermia, are effective in preventing the development of brain edema in experimental models as well as intracranial hypertension in human disease.     

Brain edema in rabbits with galactosamine-induced fulminant hepatitis. Regional differences and effects on intracranial pressure

Brain edema and intracranial hypertension are major complications of fulminant hepatic failure. We investigated the development of brain edema and monitored intracranial pressure in rabbits with toxic hepatitis induced by galactosamine. Using a gravimetric technique to assay small tissue samples, we found that brain water was increased in cortical grey matter, but not in subcortical, mesencephalic, and pontine white matter, or in the cerebellum. The proportion of water in cerebral grey matter in control animals was 80.96% +/- 0.49% with significant elevations to 81.96% +/- 0.47% and 82.95% +/- 1.49% in mild and severe encephalopathy, respectively. This corresponds to mean increases in tissue volume of 5.5% and 11.7%. The hippocampal grey matter also accumulated water in severe encephalopathy with a 30% increase in mean tissue volume. The regional increase in brain water was confirmed by the wet-dry weight method. Neither hypotension, hypoxia, nor severe hypoglycemia were present to account for the edema. Intracranial pressure was monitored continuously in unanesthetized rabbits via an intraventricular cannula as encephalopathy developed. The pressure was normal in the mild stage, but was intermittently elevated in animals with severe encephalopathy. The normal range of intracranial pressure was 2-9 mmHg and the range of peak values in galactosamine-treated rabbits was 18-55 mmHg. The regional differences in brain water accumulation suggest that cellular swelling and abnormalities in the movement of water across the blood-brain barrier may account for the brain edema in this model.     

Interferon‐free therapy as the cause of white matter tracts and cerebral perfusion recovery in patients with chronic hepatitis C

The purpose of this study was to assess cerebral microstructural and perfusion changes in patients with chronic hepatitis C virus (HCV) infection before and after interferon‐free therapy, using advanced magnetic resonance (MR) techniques. Eleven HCV‐positive patients underwent diffusion tensor imaging (DTI) and perfusion‐weighted imaging (PWI) using a 1.5T MR unit, before and 24 weeks after completion of interferon‐free therapy. DTI fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values were obtained from 14 white matter tracts. PWI values of relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were assessed from 8 areas, including basal ganglia, and cortical and white matter locations. In HCV‐positive patients therapy with ombitasvir, paritaprevir boosted with ritonavir and dasabuvir, with or without ribavirin, was scheduled. Cognitive tests were used to assess cognitive function. We found increased FA values after interferon‐free therapy compared to values obtained before treatment in HCV patients in almost all white matter tracts. We also observed elevated rCBV values in basal ganglia after therapy. There were significant correlations between improvement in the score of cognitive tests and increased FA values in both inferior fronto‐occipital fascicles and left posterior cingulum after treatment. Liver fibrosis regression in elastography, APRI and improvement in cognitive tests were observed. This is the first report of interferon‐free therapy as the cause of white matter tracts recovery as well as cerebral perfusion improvement in HCV‐infected patients, indicating better functioning of frontal lobes after interferon‐free treatment.     

Elevated intracranial pressure and computed tomography of the brain in fulminant hepatocellular failure

Cerebral herniation is a leading cause of death in patients with fulminant hepatocellular failure. Classical signs of elevated intracranial pressure are often absent in these patients. A reliable noninvasive method by which the presence of cerebral edema could be determined is much needed. To assess the efficacy of computed tomography of the brain in this setting, we compared the radiographic findings to the intracranial pressure measured by an epidural monitor in patients with fulminant hepatic failure. Unfortunately, a considerable difference existed between the presence of cerebral edema diagnosed by computed tomography of the brain and elevation of the intracranial pressure. Our observations suggest that in patients with fulminant hepatic failure and advanced hepatic encephalopathy, computed tomography of the brain is of little value in detecting cerebral edema. Pressure monitoring is most important to establish the presence and guide the therapy of intracranial hypertension.     

Endothelial-astrocytic interactions in acute liver failure

Brain edema and the subsequent increase in intracranial pressure are major neurological complications of acute liver failure (ALF), and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in ALF. Recent studies, however, have suggested the co-existence of cytotoxic and vasogenic mechanisms in the brain edema associated with ALF. This review 1) summarizes the nature of the brain edema in humans and experimental animals with ALF; 2) reviews in vitro studies supporting the presence of cytotoxic brain edema (cell swelling in cultured astrocytes); and 3) documents the role of brain endothelial cells in the development of astrocyte swelling/brain edema in ALF.