Mild hypothermia in the prevention of brain edema in acute liver failure: mechanisms and clinical prospects.

Mild hypothermia (32 degrees C-35 degrees C) reduces intracranial pressure in patients with acute liver failure and may offer an effective adjunct therapy in the management of these patients. Studies in experimental animals suggest that this beneficial effect of hypothermia is the result of a decrease in blood-brain ammonia transfer resulting in improvement in brain energy metabolism and normalization of glutamatergic synaptic regulation. Improvement in brain energy metabolism by hypothermia may result from a reduction in ammonia-induced decrease of brain glucose (pyruvate) oxidation. Restoration of normal glutamatergic synaptic regulation by hypothermia may be the consequence of the removal of ammonia-induced decreases in expression of astrocytic glutamate transporters resulting in normal glutamate neurotransmitter inactivation in brain. Randomized controlled clinical trials of hypothermia are required to further evaluate its clinical impact.

Mild hypothermia prevents brain edema and attenuates up-regulation of the astrocytic benzodiazepine receptor in experimental acute liver failure.

BACKGROUND/AIMS: Mild hypothermia has proven useful in the clinical management of patients with acute liver failure. Acute liver failure in experimental animals results in alterations in the expression of genes coding for astrocytic proteins including the "peripheral-type" (astrocytic) benzodiazepine receptor (PTBR), a mitochondrial complex associated with neurosteroid synthesis. To gain further insight into the mechanisms whereby hypothermia attenuates the neurological complications of acute liver failure, we investigated PTBR expression in the brains of hepatic devascularized rats under normothermic (37 degrees C) and hypothermic (35 degrees C) conditions. METHODS: PTBR mRNA was measured using semi-quantitative RT-PCR in cerebral cortical extracts and densities of PTBR sites were measured by quantitative receptor autoradiagraphy. Brain pregnenolone content was measured by radioimmunoassay. RESULTS: At coma stages of encephalopathy, animals with acute liver failure manifested a significant increase of PTBR mRNA levels. Brain pregnenolone content and [(3)H]PK 11195 binding site densities were concomitantly increased. Mild hypothermia prevented brain edema and significantly attenuated the increased receptor expression and pregnenolone content. CONCLUSIONS: These findings suggest that an attenuation of PTBR up-regulation resulting in the prevention of increased brain neurosteroid content represents one of the mechanisms by which mild hypothermia exerts its protective effects in ALF.

Increased brain lactate is central to the development of brain edema in rats with chronic liver disease

The pathogenesis of brain edema in patients with chronic liver disease (CLD) and minimal hepatic encephalopathy (HE) remains undefined. This study evaluated the role of brain lactate, glutamine and organic osmolytes, including myo-inositol and taurine, in the development of brain edema in a rat model of cirrhosis.Six-week bile-duct ligated (BDL) rats were injected with (13)C-glucose and de novo synthesis of lactate, and glutamine in the brain was quantified using (13)C nuclear magnetic resonance spectroscopy (NMR). Total brain lactate, glutamine, and osmolytes were measured using (1)H NMR or high performance liquid chromatography. To further define the interplay between lactate, glutamine and brain edema, BDL rats were treated with AST-120 (engineered activated carbon microspheres) and dichloroacetate (DCA: lactate synthesis inhibitor).Significant increases in de novo synthesis of lactate (1.6-fold, p<0.001) and glutamine (2.2-fold, p<0.01) were demonstrated in the brains of BDL rats vs. SHAM-operated controls. Moreover, a decrease in cerebral myo-inositol (p<0.001), with no change in taurine, was found in the presence of brain edema in BDL rats vs. controls. BDL rats treated with either AST-120 or DCA showed attenuation in brain edema and brain lactate. These two treatments did not lead to similar reductions in brain glutamine.Increased brain lactate, and not glutamine, is a primary player in the pathogenesis of brain edema in CLD. In addition, alterations in the osmoregulatory response may also be contributing factors. Our results suggest that inhibiting lactate synthesis is a new potential target for the treatment of HE.

Efeitos in vitro de metabólitos acumulados na deficiência da acil-CoA desidrogenase de cadeia média (MCAD) sobre parâmetros do metabolismo energético em córtex cerebral de ratos jovens

A deficiência da desidrogenase de acilas de cadeia média (MCAD) é o mais freqüente erro inato da oxidação de ácidos graxos. Os indivíduos afetados por esse distúrbio apresentam-se sintomáticos durante períodos de descompensação metabólica, caracterizado pelo acúmulo de ácidos graxos de cadeia média (AGCM), particularmente os ácidos octanóico (AO), decanóico (AD) e cis-4-decenóico (AcD). Durante as crises, os pacientes apresentam hipoglicemia hipocetótica, hipotonia, rabdomiólise, edema cerebral e, finalmente, entram em coma, podendo ter um desenlace fatal. O tratamento de urgência é baseado na infusão de glicose nos pacientes durante as crises, enquanto uma dieta rica em carboidratos e pobre em gorduras é recomendada nos períodos fora das crises. Uma parte considerável dos pacientes que sobrevivem às crises apresenta um grau variável de manifestações neurológicas. Entretanto, os mecanismos responsáveis pelos sintomas neurológicos da deficiência de MCAD são praticamente desconhecidos. No presente estudo avaliamos a influência dos principais metabólitos acumulados na deficiência de MCAD, os ácidos AO, AD e AcD, e , em alguns casos, também de seus derivados de carnitina e glicina, sobre as atividades de enzimas importantes do metabolismo energético em córtex cerebral de ratos Wistar de 30 dias de vida. AO, AD, AcD e octanoilcarnitina inibiram a atividade da Na+, K+-ATPase, com ênfase ao AcD, o inibidor mais potente da atividade da enzima. Além disso, verificamos que a co-incubação do AO com glutationa (GSH) ou trolox (vitamina E solúvel) evitou seu efeito inibitório sobre a atividade da enzima. A inibição da enzima pelo AcD foi também prevenida quando o mesmo foi co-incubado com as enzimas catalase (CAT) e superóxido dismutase (SOD) juntas, mas não com GSH. Além disso, AO, AD e AcD aumentaram a lipoperoxidação em homogeneizados de córtex cerebral de ratos, medidos por quimioluminescência e TBA-RS. Tais resultados sugerem que esses metabólitos inibiram a atividade da Na+, K+-ATPase via radicais livres. Observamos ainda que somente AD e AcD inibiram atividades dos complexos da cadeia respiratória, ao contrário do AO que não teve qualquer ação sobre essas atividades. Enquanto o AD diminuiu somente a atividade do complexo IV a uma concentração muito alta (3 mM), o AcD diminuiu as atividades dos complexos II, II-III e IV dentro da faixa de concentrações encontrada na deficiência de MCAD (0,25-0,5 mM). Além disso, AO, AD e AcD inibiram a produção de CO2 a aprtir de glicose e acetato radiativos como substratos, indicando uma inibição do ciclo de Krebs. No entanto, somente AD e AcD reduziram a produção de CO2 a partir de citrato, enquanto AO não alterou a mesma. Além disso, nenhum dos três metabólitos testados alterou a atividade da citrato sintase. Demonstramos ainda que o AcD reduziu as atividades da creatinaquinase mitocondrial e citosólica, mas em uma concentração muito alta não encontrada na deficiência de MCAD. Este efeito não foi evitado por GSH, vitamina C+E ou L-NAME, sugerindo que o mesmo deve ter ocorrido via mecanismo distinto do estresse oxidativo. AcD foi o inibidor mais potente das atividades enzimáticas testadas neste trabalho, indicando que deve ser o metabólito de maior toxicidade nesta doença, ao menos no que se refere ao comprometimento do metabolismo energético. Espera-se que nossos resultados possam contribuir para um melhor entendimento dos mecanismos responsáveis pelos sintomas neurológicos envolvidos na deficiência de MCAD.

Phenylephrine-induced hypertension during transient middle cerebral artery occlusion alleviates ischemic brain injury in spontaneously hypertensive rats

Arterial hypertension is a major risk factor for ischemic stroke. However, the management of preexisting hypertension is still controversial in the treatment of acute stroke in hypertensive patients. The present study evaluates the influence of preserving hypertension during focal cerebral ischemia on stroke outcome in a rat model of chronic hypertension, the spontaneously hypertensive rats (SHR). Focal cerebral ischemia was induced by transient (1 h) occlusion of the middle cerebral artery, during which mean arterial blood pressure was maintained at normotension (110-120 mm Hg, group 1, n=6) or hypertension (160-170 mm Hg, group 2, n=6) using phenylephrine. T2-, diffusion- and perfusion-weighted MRI were performed serially at five different time points: before and during ischemia, and at 1, 4 and 7 days after ischemia. Lesion volume and brain edema were estimated from apparent diffusion coefficient maps and T2-weighted images. Regional cerebral blood flow (rCBF) was measured within and outside the perfusion deficient lesion and in the corresponding regions of the contralesional hemisphere. Neurological deficits were evaluated after reperfusion. Infarct volume, edema, and neurological deficits were significantly reduced in group 2 vs. group 1. In addition, higher values and rapid restoration of rCBF were observed in group 2, while rCBF in both hemispheres was significantly decreased in group 1. Maintaining preexisting hypertension alleviates ischemic brain injury in SHR by increasing collateral circulation to the ischemic region and allowing rapid restoration of rCBF. The data suggest that maintaining preexisting hypertension is a valuable approach to managing hypertensive patients suffering from acute ischemic stroke. Published by Elsevier B.V.

Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation

Brain edema is the main cause of death from brain infarction. The polarized expression of the water channel protein aquaporin-4 (AQP4) on astroglial endfeet surrounding brain microvessels suggests a role in brain water balance. Loss of astrocyte foot process anchoring to the basement membrane (BM) accompanied by the loss of polarized localization of AQP4 to astrocytic endfeet has been shown to be associated with vasogenic/extracellular edema in neuroinflammation. Here, we asked if loss of astrocyte polarity is also observed in cytotoxic/intracellular edema following focal brain ischemia after transient middle cerebral artery occlusion (tMCAO). Upon mild focal brain ischemia, we observed diminished immunostaining for the BM components laminin α4, laminin α2, and the proteoglycan agrin, in the core of the lesion, but not in BMs in the surrounding penumbra. Staining for the astrocyte endfoot anchorage protein β-dystroglycan (DG) was dramatically reduced in both the lesion core and the penumbra, and AQP4 and Kir4.1 showed a loss of polarized localization to astrocytic endfeet. Interestingly, we observed that mice deficient for agrin expression in the brain lack polarized localization of β-DG and AQP4 at astrocytic endfeet and do not develop early cytotoxic/intracellular edema following tMCAO. Taken together, these data indicate that the binding of DG to agrin embedded in the subjacent BM promotes polarized localization of AQP4 to astrocyte endfeet. Reduced DG protein levels and redistribution of AQP4 as observed upon tMCAO might therefore counteract early edema formation and reflect a beneficial mechanism operating in the brain to minimize damage upon ischemia.

rCBF in hemorrhagic, non-hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow

Intracerebral contusions can lead to regional ischemia caused by extensive release of excitotoxic aminoacids leading to increased cytotoxic brain edema and raised intracranial pressure. rCBF measurements might provide further information about the risk of ischemia within and around contusions. Therefore, the aim of the presented study was to compare the intra- and perilesional rCBF of hemorrhagic, non-hemorrhagic and mixed intracerebral contusions. In 44 patients, 60 stable Xenon-enhanced CT CBF-studies were performed (EtCO2 30 +/- 4 mmHg SD), initially 29 hours (39 studies) and subsequent 95 hours after injury (21 studies). All lesions were classified according to localization and lesion type using CT/MRI scans. The rCBF was calculated within and 1-cm adjacent to each lesion in CT-isodens brain. The rCBF within all contusions (n = 100) of 29 +/- 11 ml/100 g/min was significantly lower (p < 0.0001, Mann-Whitney U) compared to perilesional rCBF of 44 +/- 12 ml/100 g/min and intra/perilesional correlation was 0.4 (p < 0.0005). Hemorrhagic contusions showed an intra/perilesional rCBF of 31 +/- 11/44 +/- 13 ml/100 g/min (p < 0.005), non-hemorrhagic contusions 35 +/- 13/46 +/- 10 ml/100 g/min (p < 0.01). rCBF in mixed contusions (25 +/- 9/44 +/- 12 ml/100 g/min, p < 0.0001) was significantly lower compared to hemorrhagic and non-hemorrhagic contusions (p < 0.02). Intracontusional rCBF is significantly reduced to 29 +/- 11 ml/100 g/min but reduced below ischemic levels of 18 ml/100 g/min in only 16% of all contusions. Perilesional CBF in CT normal appearing brain closed to contusions is not critically reduced. Further differentiation of contusions demonstrates significantly lower rCBF in mixed contusions (defined by both hyper- and hypodense areas in the CT-scan) compared to hemorrhagic and non-hemorrhagic contusions. Mixed contusions may evolve from hemorrhagic contusions with secondary increased perilesional cytotoxic brain edema leading to reduced cerebral blood flow and altered brain metabolism. Therefore, the treatment of ICP might be individually modified by the measurement of intra- and pericontusional cerebral blood.

Determinants of cerebral extracellular potassium after severe human head injury

The key role players of brain swelling seen after severe human head injury have only been partly determined. We used our human head injury data base to determine relationships between potassium, glutamate, lactate and cerebral blood flow (CBF). A total of 70 severely head injured patients (GCS < or = 8) were studied using intracerebral microdialysis to measure extracellular glutamate, potassium and lactate. Xenon CT was used to determine regional cerebral blood flow (rCBF). The mean +/- SEM of the r value of all patients, between potassium and glutamate, and potassium and lactate was 0.25 +/- 0.04 (p < 0.0001) and 0.17 +/- 0.06 (p = 0.006), respectively, demonstrating in both cases a positive relationship. rCBF was negatively correlated with potassium with marginal significance (r = -0.35, p = 0.08). When separated into two groups, patients with contusion had higher potassium levels than patients without contusion (1.55 +/- 0.03 mmol/l versus 1.26 +/- 0.02 mmol/l, respectively). These results in severely head injured patients confirm previous in vitro and animal studies in which relationships between potassium, glutamate, lactate and CBF were found. Potassium efflux is a major determinant of cell swelling leading to clinically significant cytotoxic edema due to increased glutamate release during reduced cerebral blood flow.

Cerebral Cortex Involvement In Machado-joseph Disease.

Machado-Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.

Aneurisma gigante da artéria cerebral média

A case of giant aneurysm of the left middle cerebral artery, in a 28-year-old right-handed woman, successfuly operated is reported. The aneurysm measur- ing 35 x 27 x 23 mm showed clinical manifestations as a space-occupying lesion. The patient recovered completely after the total excision of the aneurysm.

Aspecto tumoral da cisticercose intracraniana: abordagem cirúrgica

The cerebral cysticercosis can produce intracranial hypertension by inflammatory obstruction of the basal cysterns or by expansive lesion in the cerebral parenchima or ventricular cavities. In the latter and in tumor cases the clinical picture is very similar and only after surgery can the etiology be determined. We present 11 operated cases of intracranial cysticercosis which presented the clinical picture of an expansive lesion. There were 7 females and 4 males with ages between 4 and 65 years. Nine patients were admitted because of headache, vomiting and visual disturbances suggestive of intracranial hypertension. One patient was admited with lymphocytic meningitis and another with focal seizures following hemiparesis. Five patients presented focal signs and six edema of the papilla. Epileptic manifestations were present in 45.5% of the cases. A plain X-ray films of the skull failed to reveal calcificatons, however signs of chronic hypertension were present in three cases. The electroencephalogram showed slow focal waves in 8 patients The spinal fluid examination revealed lymphocytosis in 4 cases, increased protein content in another 4 and complement fixation for cysticercosis was positive in 2 cases. The expansive lesions were localized by angiograph and ventriculography. In these the location was temporal in 4, frontal in 3, parietal in 2, in the third ventricle in one and in the fourth ventricle in another. At surgery we removed a large cyst from the cerebral parenchyma in six cases. Around the cyst a thick glial reaction was present. In the other cases the cyst was small but fixed to the ventricular trigone and produced dilatation of the inferior horn of the lateral ventricle. In two cases we removed a solitary intraventricular cyst from the third and fourth ventricles. In the two children operated upon there were several small hard cysts involving the cerebral parenchyma which displayed intense gliosis. There were no postoperative complications.

Ficomicose (mucormicose) orbito-rino-cerebral: registro de um caso

The case of a 15 years old white man, diabetic in cetoacidosis, with a orbit-rhino-cerebral phycomycosis is reported. The illness had an acute onset and the treatment was iniciated early with Amphotericin-B and unilateral osteotomy of maxillary and ethmoidal sinus. With this treatment the patient did well with residuals of ophtalmoplegia and amaurosis on the right. Interesting investigation aspects are the occluded internal carotid on the same side of the affected orbit and the CAT-SCAN finding of moderated ventricular dilatation (two month after hospital admission). Mycology, pathophysiology, histopathology, clinical aspects, diagnosis and therapy are discussed, comparing the findings of this case with available literature. An increased number of survivors can be expected with earlier recognition and more aggressive therapy. Treatment of the underlying debilitating disease, Amphotericin-B and surgical debridement of necrotic tissue, are frequently necessary such as observed in the case reported. The favorable results ootaineü with the proposed managment are stressed.

Herpes Zoster oftálmico e posterior acidente vascular cerebral: relato de caso

A sixty-nine year old man suffered a stroke fourteen weeks after the onset of right herpes zoster ophthalmicus (HZO). Hemispheric infarction was documented by a computed tomography which showed a small hypodense zone in the right internal capsula; after contrast there was enhancement of this hypodense area. Cerebral angiography and cerebral-spinal fluid were not done. Despite of a diagnosis of probability the authors report the case and review the literature. A long latency between the HZO and onset of neurological deficit is stressed. New antiviral agents may prevent the ictus.

Função vísuo-espacial em paralisia cerebral e proposta de novo teste com a ajuda de computador

The first idea of this study is trat there may be a disturbance of the visuo-spatial function in cerebral palsy. This idea is based upon the theories of Luria and Piaget. The second idea of this study is that the computer can help the investigation of visuo-spatial function. With the intention of evaluating the spatial function in cerebral palsy, the literature related to these themes was revised. We justify the proposal of a new test to study visuo-spatial function. This test uses straight lines in four different orientations and the subject has to recognize and arrange them individually or sets of them. This was done through the use of pencil and papel, and computer. The results confirm that there is a spatial disturbance and that a better understanding of the subject's difficulties was made possible through the use of the computer and the Logo computer language.

Brincando no ambiente natural : uma contribuição para o desenvolvimento sensorio-motor da criança portadora de paralisia cerebral

Universidade Estadual de Campinas . Faculdade de Educação Física