Quantitative CT-scan to evaluate cerebral edema secondary to hyperammonemia in ICU: A proof-of-concept study

BackgroundAcute treatment of cerebral edema and elevated intracranial pressure is a common issue in patients with neurological injury. Practical recommendations regarding selection and monitoring of therapies for initial management of cerebral edema for optimal efficacy and safety are generally lacking. This guideline evaluates the role of hyperosmolar agents (mannitol, HTS), corticosteroids, and selected non-pharmacologic therapies in the acute treatment of cerebral edema. Clinicians must be able to select appropriate therapies for initial cerebral edema management based on available evidence while balancing efficacy and safety.MethodsThe Neurocritical Care Society recruited experts in neurocritical care, nursing, and pharmacy to create a panel in 2017. The group generated 16 clinical questions related to initial management of cerebral edema in various neurological insults using the PICO format. A research librarian executed a comprehensive literature search through July 2018. The panel screened the identified articles for inclusion related to each specific PICO question and abstracted necessary information for pertinent publications. The panel used GRADE methodology to categorize the quality of evidence as high, moderate, low, or very low based on their confidence that the findings of each publication approximate the true effect of the therapy.ResultsThe panel generated recommendations regarding initial management of cerebral edema in neurocritical care patients with subarachnoid hemorrhage, traumatic brain injury, acute ischemic stroke, intracerebral hemorrhage, bacterial meningitis, and hepatic encephalopathy.ConclusionThe available evidence suggests hyperosmolar therapy may be helpful in reducing ICP elevations or cerebral edema in patients with SAH, TBI, AIS, ICH, and HE, although neurological outcomes do not appear to be affected. Corticosteroids appear to be helpful in reducing cerebral edema in patients with bacterial meningitis, but not ICH. Differences in therapeutic response and safety may exist between HTS and mannitol. The use of these agents in these critical clinical situations merits close monitoring for adverse effects. There is a dire need for high-quality research to better inform clinicians of the best options for individualized care of patients with cerebral edema.

Dexamethasone is prescribed routinely to reduce cerebral oedema in neurosurgical patients undergoing craniotomy for tumour and is used increasingly as an anti-emetic. Dexamethasone, however, has been shown to cause hyperglycaemia. We describe a case of hyperglycaemic crisis, cerebral oedema and death secondary to dexamethasone in a patient with a frontal meningioma. We highlight the risks of peri-operative dexamethasone and discuss the diagnosis, treatment and complications of hyperglycaemic crises and cerebral oedema.

Advanced age and hypertension have each been associated with changes in brain morphology and cognitive function. To investigate the interaction of age and hypertension with structural brain changes and neuropsychological performance in otherwise healthy patients with essential hypertension, we compared young-old (ages 56 to 69 years) and old-old (ages 70 to 84 years) hypertensive patients (n = 27) with 20 age-matched normotensive healthy control subjects, using quantitative volumetric MRI and a battery of neuropsychological tests. Quantitative regions of interest and segmentation analyses were applied to MRI scans of brain to measure volumes of different brain structures and of cerebrospinal fluid (CSF). Severity of white matter hyperintensities (WMHs) was qualitatively rated in the MRI scans. A battery of neuropsychological tests was administered to each subject. The combined hypertensive group (young-old and old-old) had smaller volumes of thalamic nuclei and larger volumes of CSF in the cerebellum and temporal lobes and showed poorer performance in memory and language tests than did the control subjects. Main effects for age were significant in multiple brain regions of interest. The old-old hypertensive patients and age-matched control subjects demonstrated volume reductions in brain structures and increases in ventricular and peripheral CSF volumes compared with the younger subjects. There was a significant group x age-group interaction in temporal and occipital CSF, not related to WMH, with the old-old hypertensive patients having significantly larger CSF volumes in these regions than the young-old hypertensives and both healthy control groups. Hypertension exacerbates the morphological changes accompanying advanced age. Temporal and occipital regions appear most vulnerable to brain atrophy due to the interactive effects of age and hypertension.

Hyperammonemia in adults is generally associated with cerebral edema, decreased cerebral metabolism, and increased cerebral blood flow. The aim of this study was to evaluate the association between non-hepatic hyperammonemia and intracranial hypertension assessed by Doppler flowmetry and measurement of the optic nerve sheath. A prospective cohort study in critically ill patients hospitalized in intensive care units of a University Hospital between March 2015 and February 2016. Clinical data and severity scores were collected and the Glasgow coma scale was recorded. Serial serum ammonia dosages were performed in all study patients. Transcranial Doppler evaluation was carried out for the first 50 consecutive results of each stratum of ammonemia: normal (<35μmol/L), mild hyperammonemia (≥35μmol/L and < 50μmol/L), moderate hyperammonemia (≥50μmol/L and < 100μmol/L), and severe hyperammonemia (≥100μmol/L). The measurement of the optic nerve sheath was performed at the same time as the Doppler examination if the patient scored less than 8 on the Glasgow coma scale. There was no difference in flow velocity in the cerebral arteries between patients with and without hyperammonemia. Patients with hyperammonemia presented longer ICU stay. Optic nerve sheath thickness was higher in the group with severe hyperammonemia and this group presented an association with intracranial hypertension. Higher mortality was observed in the severe hyperammonemia group. There was an association between severe hyperammonemia and signs of intracranial hypertension. No correlation was found between ammonia levels and cerebral blood flow velocity through the Doppler examination.

W1869 Discrepancy in Neurologic Status and Liver Dysfunction in Fulminant Hepatic Failure, Leading to the Discovery of a Missense Mutation Causing Ornithine Transcarbamylase Deficiency in An Adult

Differential growth between the fetal brain and its infratentorial part

Genetic and phenotypic variation in weight of brain and spinal cord between inbred strains of mice.

Urea cycle disorders (UCDs) can lead to irreversible neurological injury due to elevated ammonia levels. While most cases present in neonates, milder forms may manifest in adults under physiological stress. We report a case of suspected UCD in a 27-year-old male with a history of epilepsy and paranoid schizophrenia, who presented to the ICU with status epilepticus secondary to hyperammonemia. On admission, his oxygen saturation was 90% on 15 L oxygen, with arterial blood gas showing a pH of 6.75, carbon dioxide of 36, and ammonia level of 680. Lactic acid was elevated at &amp;gt;15, with normal liver function tests. The infectious workup was negative, and a urine drug screen was positive for cannabis. Imaging showed diffuse cerebral edema on head Computerized Tomography, while ultrasound of the liver was normal. The patient was dialyzed for hyperammonemia, treated with hypertonic saline for cerebral edema, and managed for seizures with levetiracetam, lacosamide, and topiramate. Cerebral edema resolved on repeat imaging within 3 days. He had a history of mild hyperammonemia in the past that had been attributed to valproic acid which had since been discontinued. Pediatric genetics was consulted, and a potential diagnosis of UCDs was made. The patient is currently awaiting the results of whole exome sequencing to identify a specific type of UCD. UCDs can cause life-threatening cerebral edema by raising serum ammonia levels. Early identification of these disorders is essential to prevent recurrent hyperammonemia episodes. Diagnosis is through serum and urine amino acid levels, as well as whole genome sequencing. Our patient presented with lactic acidosis with hyperammonemia, which was an unusual combination and warranted early recognition and workup in the ICU setting. This case also demonstrates the importance of early aggressive treatment for the consequences of UCDs in the ICU in the form of hypertonic saline for cerebral edema, seizure management and urgent hemodialysis for hyperammonemia greater than 200 µmol/l. This can then be followed by outpatient amino acid supplementation, dietary protein restriction, in some cases, nitrogen scavenger therapy (such as sodium phenylbutyrate or glycerol phenylbutyrate) and avoidance of medications that raise ammonia levels, such as valproic acid in our patient. Mild cases of UCDs can present in adults during physiologic distress, requiring high suspicion as delays may lead to irreversible cerebral injury or death. In patients with unclear neurologic symptoms, particularly new-onset seizures or cerebral edema checking ammonia levels is crucial for prompt identification and treatment.

Is Fluid Therapy Associated With Cerebral Edema in Children With Diabetic Ketoacidosis?

This review highlights the causes, types and clinical staging of hepatic encephalopathy (HE). Current concepts on the probable pathogenetic mechanisms and currently practiced therapeutic options are discussed. HE may be covert and overt. Also known as minimal HE. Covert HE, where there are behavioral abnormalities and impairment in activities of daily living with intact sensorium. The pathophysiology of HE remains poorly understood. There is disturbance of the urea cycle due to liver disease leading to increased production of ammonia. The ammonium ion enters the astrocytes along with glutamate (converted to glutamine by ammonia) and myo-inositol, thereby increasing the osmolality of the astrocytic cytoplasm. This osmotic gradient results in accumulation of water inside the astrocytes resulting in cerebral edema and increase in brain volume. Additionally, current research has noted the role of cerebral oxidative/nitrosative stress and the synergistic effects of increased cerebral ammonia and alteration in neurotransmitters, neurometabolites, and cortical excitability due to systemic inflammation. In advanced liver disease with systemic infection or inflammation, neuroinflammatory processes play significant role in the development of HE. Inflammatory cytokines like TNF-α, IL-6, IL-17 in presence of hyperammonemia have been found to induce neurotoxicity of ammonia by passing through the blood brain barrier and causing enlarged/swollen pale astrocytes, resulting in HE. Disrupted enterohepatic circulation in end stage liver disease also causes elevation of bile acids which induces neuroinflammation. Manganese and zinc play as co-factors of enzymatic reaction. These metal deposition causes multiple psychomotor symptoms observed in HE. The gut environment has a major impact on brain function in patients with HE. Toxins such as ammonia and inflammatory cytokines produced by this impaired intestinal flora access the circulation through porto-systemic anastomoses and exacerbate or precipitate HE. Finally, as a result of recurrent cerebral edema from astrocytic dysfunction and neuroinflammation, permanent neurodegeneration occurs with cognitive decline and motor disturbances, especially parkinsonian features and gait disturbances. This is the stage of chronic hepatic encephalopathy. Currently L-ornithine L-aspartate (LOLA) is being used to lower the ammonia level by stimulating the urea cycle. HE comprises a broad spectrum of neurological and/or psychiatric abnormalities caused by hepatic insufficiency and/or portal-systemic shunting in the absence of any other causes of brain dysfunction. HE may be caused or precipitated by several factors like infections, intoxications and drugs. The encephalopathic features may be covert or overt. The pathogenetic mechanisms for HE may be different. In the presence of liver disease, HE primarily results from disturbed urea cycle with hyperammonemia causing astrocytic swelling and cerebral edema. Porto-systemic anastomoses with intact liver function can cause HE by allowing ammonia and other toxins produced by the gut microbial flora and allowing these to bypass detoxification by the liver and exposing the brain to their harmful effects. Principles of therapy are twofold. First protecting the liver and the brain from gut generated ammonia and other toxins by ensuring smooth bowel function and avoiding stagnation with the use of osmotic laxatives like lactulose or lactitol and also reducing the gut microbial load with use of anti-bacterials/bacteriophages like neomycin and rifaximin along with metronidazole. Second, reducing the already generated cerebral edema by use of mannitol and appropriate ventilatory support. Currently L-ornithine L-aspartate (LOLA) is being used to reduce the ammonia load to the liver. LOLA is a stable compound formed from two amino acids. L-ornithine plays a crucial role in stimulating the urea cycle, leading to a reduction in ammonia levels. Both L-ornithine and L-aspartate serve as substrates for the enzyme glutamate transaminase, and their administration results in elevated glutamate concentrations. Ammonia is subsequently utilized in the conversion of glutamate to glutamine through the action of glutamine synthetase. Finally in resistant cases the use of liver transplant needs to be considered. Alternatively extracorporeal liver assist devices may be used like Molecular Adsorbent Recirculating System (MARS) or Single-Pass Albumin Dialysis (SPAD).

The relevance of studies of adult neurogenesis is evident in connection with the potential use of these new neurons to replace neurons lost in the process of life. Despite considerable efforts, little is known about the fnal fate of these cells, the functional signifcance of their connections and the regulation of their development. It is known that physical activity signifcantly increases the number of fssile progenitors, the precursors of new neurons in the dentate gyrus of the hippocampus. The existing immunohistochemical methods for labeling new neurons do not allow tracing the temporal dynamics of changes in the volume of brain structures in the same animal, induced by external impacts, such as voluntary exercise. This makes it an urgent task to develop and improve methods for long­term control of changes that occur in the adult hippocampus due to the induction of neurogenesis. The main purpose of this work was to non­invasively track, by using magnetic resonance imaging (MRI), the temporal dynamics of changes in the volume of the hippocampus in the same animals that had voluntary physical activity. It was found that voluntary exercise did not change the total volume of the mouse hippocampus. However, the difference in the volume ratio between the right and left parts of the hippocampus was signifcantly lower compared with the control group. The reconstruction and analysis of protein­protein interactions that ensure the survival of a large number of new neurons and their integration into existing neural networks in the hippocampus have been carried out. The proposed approach allows the non­invasive registration of changes in the ratio of the volumes of these paired brain structures.

Background:A large infarct and expanding cerebral edema (CED) due to a middle cerebral artery occlusion confers a 70% mortality unless treated surgically. There is still conflicting evidence whether reperfusion is associated with a lower risk for CED in acute ischemic stroke.Aim:To investigate the association of reperfusion with development of early CED after stroke thrombectomy.Methods:From the SITS-International Stroke Thrombectomy Registry, we selected patients with occlusion of the intracranial internal carotid or middle cerebral artery (M1 or M2). Successful reperfusion was defined as mTICI ⩾ 2b. Primary outcome was moderate or severe CED, defined as focal brain swelling ⩾1/3 of the hemisphere on imaging scans at 24 h. We used regression methods while adjusting for baseline variables. Effect modification by severe early neurological deficits, as indicators of large infarct at baseline and at 24 h, were explored.Results:In total, 4640 patients, median age 70 years and median National Institutes of Health Stroke Score (NIHSS) 16, were included. Of these, 86% had successful reperfusion. Moderate or severe CED was less frequent among patients who had reperfusion compared to patients without reperfusion: 12.5% versus 29.6%, p < 0.05, crude risk ratio (RR) 0.42 (95% confidence interval (CI): 0.37–0.49), and adjusted RR 0.50 (95% CI: 0.44-0.57). Analysis of effect modification indicated that severe neurological deficits weakened the association between reperfusion and lower risk of CED. The RR reduction was less favorable in patients with severe neurological deficits, defined as NIHSS score 15 or more at baseline and at 24 h, used as an indicator for larger infarction.Conclusion:In patients with large artery anterior circulation occlusion stroke who underwent thrombectomy, successful reperfusion was associated with approximately 50% lower risk for early CED. Severe neurological deficit at baseline seems to be a predictor for moderate or severe CED also in patients with successful reperfusion by thrombectomy.

Currently, there are several published articles detailing brain growth in modern humans. The contained databases were derived using disparate methodologies. The objective of the present investigation was to determine the level of agreement among several collections of immature modern human brains. Twenty-one developmental collections of endocranial volume, brain weight, or brain volume were selected for analysis, including one skeletal, six autopsy, and 14 computed tomography/magnetic resonance imaging samples. Step-wise comparisons were determined, using conversion factors for brain specific gravity and size of the subarachnoid space. Derived brain weights are comparable and increase especially during the first year of postnatal life, with a further slight increase (+8-10%) between one and five years, and little change thereafter. The expansion in brain size occurs earlier than body size. Significant sex differences are apparent at all stages of development. Combining all datasets produced a composite database consisting of 3,491 brain weight values, with ages near birth through 18 years. Individual brain weights ranged from 190 to 1,792 g, and mean brain weights ranged from 457 to 1,365 g, with an overall mean and standard deviation of 897 ± 387 g. The investigation compares modern human collections regarding brain size trajectories from birth through 18 years of age. The 21 datasets are then incorporated into a single composite database. All major age groups and both sexes are well represented. The composite database should prove useful to other investigators interested in developmental aspects of the modern human brain.

BackgroundThe vertebrate brain is composed of several interconnected, functionally distinct structures and much debate has surrounded the basic question of how these structures evolve. On the one hand, according to the 'mosaic evolution hypothesis', because of the elevated metabolic cost of brain tissue, selection is expected to target specific structures mediating the cognitive abilities which are being favored. On the other hand, the 'concerted evolution hypothesis' argues that developmental constraints limit such mosaic evolution and instead the size of the entire brain varies in response to selection on any of its constituent parts. To date, analyses of these hypotheses of brain evolution have been limited to mammals and birds; excluding Actinopterygii, the basal and most diverse class of vertebrates. Using a combination of recently developed phylogenetic multivariate allometry analyses and comparative methods that can identify distinct rates of evolution, even in highly correlated traits, we studied brain structure evolution in a highly variable clade of ray-finned fishes; the Tanganyikan cichlids.ResultsTotal brain size explained 86% of the variance in brain structure volume in cichlids, a lower proportion than what has previously been reported for mammals. Brain structures showed variation in pair-wise allometry suggesting some degree of independence in evolutionary changes in size. This result is supported by variation among structures on the strength of their loadings on the principal size axis of the allometric analysis. The rate of evolution analyses generally supported the results of the multivariate allometry analyses, showing variation among several structures in their evolutionary patterns. The olfactory bulbs and hypothalamus were found to evolve faster than other structures while the dorsal medulla presented the slowest evolutionary rate.ConclusionOur results favor a mosaic model of brain evolution, as certain structures are evolving in a modular fashion, with a small but non-negligible influence of concerted evolution in cichlid fishes. Interestingly, one of the structures presenting distinct evolutionary patterns within cichlids, the olfactory bulbs, has also been shown to evolve differently from other structures in mammals. Hence, our results for a basal vertebrate clade also point towards a conserved developmental plan for all vertebrates.

Hypertonic saline was recently introduced as a new hyperosmolar agent for treatment of intracranial hypertension and cerebral edema. It has the potential to cause a rebound phenomenon similar to other osmotic agents. The authors report on two patients with cerebral edema caused by hypertensive intracerebral hemorrhage who were treated with hypertonic saline infusion. Both patients improved clinically after 24 hours of hypertonic saline administration. However, both patients deteriorated clinically, 48 and 96 hours after initiation of therapy, despite continued hypertonic saline administration. Compared with pre-treatment computed tomographic scans, edema volume on repeat scans increased from 131 cc to 262 cc, and from 171 cc to 239 cc in the first and second patients, respectively, despite the lack of change in hematoma volume. Malignant edema formation late in the course of intracerebral hemorrhage after prolonged administration of hypertonic saline may represent a rebound phenomenon of hyperosmolar therapy. Further studies are warranted to identify the occurrence of this phenomenon and the subset of patients susceptible to it.