Aquaporins in cerebrovascular disease: a target for treatment of brain edema?

In cerebrovascular disease, edema formation is frequently observed within the first 7 days and is characterized by molecular and cellular changes in the neurovascular unit. The presence of water channels, aquaporins (AQPs), within the neurovascular unit has led to intensive research in understanding the underlying roles of each of the AQPs under normal conditions and in different diseases. In this review, we summarize some of the recent knowledge on AQPs, focusing on AQP4, the most abundant AQP in the central nervous system. Several experimental models illustrate that AQPs have dual, complex regulatory roles in edema formation and resolution. To date, no specific therapeutic agents have been developed to inhibit water flux through these channels. However, experimental results strongly suggest that this is an important area for future investigation. In fact, early inhibition of water channels may have positive effects in the prevention of edema formation. At later time points during the course of disease, AQP is important for the clearance of water from the brain into blood vessels. Thus, AQPs, and in particular AQP4, have important roles in the resolution of edema after brain injury. The function of these water channel proteins makes them an excellent therapeutic target.

Elevated total peripheral leukocyte count may identify risk for neurological disability in asphyxiated term neonates.

OBJECTIVE: The present study investigated the relationship between neurologic outcome and total circulating white blood cell (WBC) and absolute neutrophil counts (ANCs) in the first week of life in term infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Long-term neurologic outcome at 18 months was measured retrospectively in 30 term neonates with HIE using the Pediatric Cerebral Performance Category Scale (PCPCS) score with outcomes dichotomized as either good or poor. We then compared white blood cell and ANC levels during the first 4 days of life and magnetic resonance imaging (MRI) obtained within the first month life between the two PCPCS groups. MRI was quantified using a validated scoring system. RESULTS: Neonates with good long-term outcomes had significantly lower MRI scores (indicating lesser injury) than neonates with poor outcomes. More importantly, neonates with poor outcomes had significantly higher WBC and ANC levels as early as12 h after birth and up to 96 h after birth compared to those with good outcomes. These data suggest that elevated peripheral neutrophil counts in the first 96 h of life may signal or predict adverse long-term outcome. CONCLUSIONS: Our findings suggest that elevated peripheral neutrophil counts in the first 96 h of life in term infants with HIE may contribute to abnormal neurodevelopmental outcome.

Incontinentia pigmenti: association with anterior horn cell degeneration.

Incontinentia pigmenti (IP) has been associated with CNS involvement, including seizures, retardation, motor abnormalities, and malformations in greater than 30% of patients. Motor symptoms include spasticity and hyperreflexia; however, weakness and flaccidity have also been described. Peripheral nervous system neuropathology in patients with IP has not previously been reported. The infant with IP in this report showed generalized weakness due to anterior horn cell degeneration. The neuropathologic findings in both the central and peripheral nervous systems will be reviewed and contrasted to previous reports. Patients with IP and weakness should undergo neurodiagnostic evaluation of peripheral nervous system function.

Prognostic implications of hyperglycemia and reduced cerebral blood flow in childhood near-drowning.

We retrospectively examined the clinical courses of 20 children with severe near-drowning and divided their outcomes into 3 groups: normal (4), persistent vegetative state (9), and dead (7). We reviewed serial blood glucose levels and cerebral blood flow measured by stable xenon computed tomography within the 1st 48 hours of admission to determine whether they were predictive of outcome. Total, frontal gray, frontal white, and temporal and parietal gray matter cerebral blood flows were significantly decreased in children who died compared with those who completely recovered. Only 1/2 the children surviving in a vegetative state had decreased flows compared with those who recovered. An elevated initial blood glucose was highly predictive of those patients who died (mean, 511 +/- 110 mg%) or those with vegetative survival (465 +/- 104 mg%) compared with those who recovered completely (238 +/- 170 mg%). The predictive value of initial blood glucose alone (68%) or CBF alone (50%) was similar to that of clinical rating scales or immersion/resuscitation times. The combination of blood glucose with CBF improved predictability to 79%. Our results suggest that CBF measurements are predictive of eventual death but cannot differentiate normal from vegetative survival. Combining multiple laboratory studies may be of value in predetermining the eventual outcome in near-drowning.

Bacterial meningitis in children: pathophysiology and treatment.

Recent studies of the pathophysiology of bacterial meningitis have suggested that the development of neuronal injury is related to the release of vasoactive substances or alteration of blood-brain barrier permeability. Cerebral edema, increased intracranial pressure (ICP), systemic hypotension, decreased cerebral perfusion pressure, vascular inflammation, thrombosis, and a variety of other vascular changes may result in global or regional reductions in cerebral blood flow (CBF), which contribute to this insult. Approximately one-third of infants and children with bacterial meningitis will have markedly reduced CBF, and even in those children with normal total flow, regional hypoperfusion is common. Reduced CBF is associated with cerebral edema and a poor prognosis. A poor prognosis also is associated with reduced cerebral perfusion pressure. This occurs early in the course of meningitis and is primarily due to increased ICP rather than systemic hypotension. Autoregulation is preserved, suggesting that local ischemic tissue injury is more related to factors such as regional edema formation, focal vascular pathology, or specific intrinsic flow/metabolic abnormalities than to a reduction in systemic blood pressure. In contrast with other acute CNS insults, CBF/PCO2 reactivity is well preserved in many patients with meningitis; this raises the possibility that hyperventilation may cause further ischemic injury in those patients with marginal CBF. Although it is still unclear that treatment of increased ICP will affect outcome, we propose a treatment paradigm based on the results of neuroimaging studies and ICP measurements.

Acute flaccid neonatal paraplegia: a case report.

A 3-day-old neonate became acutely and irreversibly paraplegic below L1/L2 after umbilical artery catheterization. The paraplegia was attributed to infarction of the spinal cord because of thrombosis of the artery of Adamkievicz or injection of drugs through the catheter into the spinal cord circulation. Catheterization of a more peripheral artery or placement of the umbilical catheter tip at a lower level in the aorta may prevent similar complications.

Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society.

OBJECTIVE: The Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society develop practice parameters as strategies for patient management based on analysis of evidence. For this parameter, the authors reviewed available evidence on the evaluation of the child with recurrent headaches and made recommendations based on this evidence. METHODS: Relevant literature was reviewed, abstracted, and classified. Recommendations were based on a four-tiered scheme of evidence classification. RESULTS: There is inadequate documentation in the literature to support any recommendation as to the appropriateness of routine laboratory studies or performance of lumbar puncture. EEG is not recommended in the routine evaluation, as it is unlikely to define or determine an etiology or distinguish migraine from other types of headaches. In those children undergoing evaluation for recurrent headache found to have a paroxysmal EEG, the risk for future seizures is negligible; therefore, further investigation for epilepsy or treatments aimed at preventing future seizures is not indicated. Obtaining a neuroimaging study on a routine basis is not indicated in children with recurrent headaches and a normal neurologic examination. Neuroimaging should be considered in children with an abnormal neurologic examination or other physical findings that suggest CNS disease. Variables that predicted the presence of a space-occupying lesion included 1) headache of less than 1-month duration; 2) absence of family history of migraine; 3) abnormal neurologic findings on examination; 4) gait abnormalities; and 5) occurrence of seizures. CONCLUSIONS: Recurrent headaches occur commonly in children and are diagnosed on a clinical basis rather than by any testing. The routine use of any diagnostic studies is not indicated when the clinical history has no associated risk factors and the child's examination is normal.

Practice parameter: evaluating a first nonfebrile seizure in children: report of the quality standards subcommittee of the American Academy of Neurology, The Child Neurology Society, and The American Epilepsy Society.

OBJECTIVE: The Quality Standards Subcommittee of the American Academy of Neurology develops practice parameters as strategies for patient management based on analysis of evidence. For this practice parameter, the authors reviewed available evidence on evaluation of the first nonfebrile seizure in children in order to make practice recommendations based on this available evidence. METHODS: Multiple searches revealed relevant literature and each article was reviewed, abstracted, and classified. Recommendations were based on a three-tiered scheme of classification of the evidence. RESULTS: Routine EEG as part of the diagnostic evaluation was recommended; other studies such as laboratory evaluations and neuroimaging studies were recommended as based on specific clinical circumstances. CONCLUSIONS: Further studies are needed using large, well-characterized samples and standardized data collection instruments. Collection of data regarding appropriate timing of evaluations would be important.

The minimally conscious state: definition and diagnostic criteria.

OBJECTIVE: To establish consensus recommendations among health care specialties for defining and establishing diagnostic criteria for the minimally conscious state (MCS). BACKGROUND: There is a subgroup of patients with severe alteration in consciousness who do not meet diagnostic criteria for coma or the vegetative state (VS). These patients demonstrate inconsistent but discernible evidence of consciousness. It is important to distinguish patients in MCS from those in coma and VS because preliminary findings suggest that there are meaningful differences in outcome. METHODS: An evidence-based literature review of disorders of consciousness was completed to define MCS, develop diagnostic criteria for entry into MCS, and identify markers for emergence to higher levels of cognitive function. RESULTS: There were insufficient data to establish evidence-based guidelines for diagnosis, prognosis, and management of MCS. Therefore, a consensus-based case definition with behaviorally referenced diagnostic criteria was formulated to facilitate future empirical investigation. CONCLUSIONS: MCS is characterized by inconsistent but clearly discernible behavioral evidence of consciousness and can be distinguished from coma and VS by documenting the presence of specific behavioral features not found in either of these conditions. Patients may evolve to MCS from coma or VS after acute brain injury. MCS may also result from degenerative or congenital nervous system disorders. This condition is often transient but may also exist as a permanent outcome. Defining MCS should promote further research on its epidemiology, neuropathology, natural history, and management.

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society.

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Brain death in the newborn.

The clinical courses of 18 preterm and term infants less than 1 month of age in whom brain death was diagnosed were retrospectively reviewed. Clinical diagnosis was determined neurologically and included (1) coma, (2) apnea, manifested by inability to sustain respiration, and (3) absent brainstem reflexes. Electroencephalograms were performed in all patients; 17 patients had adequate cerebral blood flow as estimated by radionuclide imaging. The results indicate that (1) neurodiagnostic tests such as electroencephalograms and radionuclide scanning reconfirmed clinically determined brain death in only one half to two thirds of patients; (2) electrocerebral silence in the absence of barbiturates, hypothermia, or cerebral malformations during 24 hours was confirmatory of brain death if the clinical findings remained unchanged; (3) absence of radionuclide uptake associated with initial electrocerebral silence was associated with brain death; (4) term infants clinically brain dead for 2 days and preterm infants brain dead for 3 days did not survive despite electroencephalogram or cerebral blood flow status; and (5) phenobarbital levels greater than 25 micrograms/mL may suppress electroencephalographic activity in this age group. The findings suggest that determination of brain death in the newborn can be made solely by using clinical criteria. Confirmatory neurodiagnostic studies are of value because they can potentially shorten the period of observation.

Determination of cerebral death in the pediatric intensive care unit.

The clinical course, laboratory data, outcome, and autopsy findings in 61 pediatric patients with suspected brain death were reviewed. In 58% of patients, the initial EEG was isoelectric, and cerebral blood flow was absent. In six of nine children, the initial EEG, which showed activity, became isoelectric by 72 hours. In no child without demonstrable cerebral flow did flow resume in later studies. In four of five children who had initial EEG activity despite absent cerebral flow, an isoelectric EEG developed on repeated study. The average time from initial insult until clinically suspected brain death was 29.5 hours and 61.5 hours until brain death was confirmed. The time from confirmation of brain death until discontinuation of life support systems was 32 hours in the majority of patients. Our current protocol for evaluating pediatric patients with suspected brain death is reviewed with emphasis on the clinical examination, laboratory studies, and use of serial EEGs and radionuclide cerebral blood flow determinations.

Proton magnetic resonance spectroscopy in the evaluation of children with congenital heart disease and acute central nervous system injury.

We studied nine infants and children, aged 1 week to 42 months, with severe acute central nervous system injuries associated with cardiac disease or corrective operations by means of single-voxel proton magnetic resonance spectroscopy to determine whether this technique would be useful in predicting neurologic outcome. Proton magnetic resonance spectroscopic data were acquired from the occipital gray and parietal white matter (8 cm3 volume, stimulated echo-acquisition mode sequence with echo time of 20 msec and repetition time of 3.0 seconds) a median of 9 days after operation (range 3 to 42 days). Data were expressed as ratios of areas under metabolite peaks, including N-acetyl compounds, choline-containing compounds, creatine and phosphocreatine, and lactate. Four patients had cerebral insults before operation, one had both a preoperative and a perioperative insult, three had perioperative insults, and one had a prolonged cardiac arrest 2 days after operation. Outcomes (Glasgow Outcome Scale scores) were assigned at discharge and 6 to 12 months after injury. Six patients were in a vegetative state or had severe impairment at discharge, and two still had severe impairment at 6- to 12-month follow-up. Proton magnetic resonance spectroscopy showed lactate in these two patients, along with markedly reduced ratios of N-acetyl compounds to creatine compounds. The other four patients with severe impairment recovered to a level of mild disability at follow-up. Proton magnetic resonance spectroscopy showed no lactate in these four patients; however, one patient showed moderately reduced ratio of N-acetyl compounds to creatine compounds. The three patients who had mild or moderate impairment at discharge showed no lactate and mild or no changes in metabolite ratios; follow-up revealed normal or mild outcomes. Overall, we found that the presence of lactate and markedly reduced ratios of N-acetyl compounds to creatine compounds were predictive of severe outcomes at discharge and long-term follow-up, whereas no lactate and mild or no changes in ratios suggested potential for recovery with at least a mild disability. Continuing investigations are in progress to determine the optimal selection of candidates and timing of proton magnetic resonance spectroscopic studies.

The pathophysiology of stroke in mitochondrial disorders.

Stroke occurs with an increased frequency in patients with mitochondrial disorders and is a characteristic feature of the MELAS phenotype. This article explores the proposed mechanisms by which mitochondrial dysfunction may contribute to both vascular and non-vascular strokes and stroke-like episodes. The clinical features, neuroimaging, and pathologic findings of MELAS are reviewed as evidence for a cytopathologic basis for stroke in mitochondrial disorders.

Proton MR spectroscopy detected glutamate/glutamine is increased in children with traumatic brain injury.

Adults with traumatic brain injury (TBI) have been shown by invasive methods to have increased levels of the excitatory neurotransmitter glutamate. It is unclear whether glutamate release contributes to primary or secondary injury and whether its protracted elevation is predictive of a poor outcome. Preliminary studies at our institution in adults found that early increases in magnetic resonance spectroscopy (MRS)-detected glutamate/glutamine (Glx) were associated with poor outcomes. We therefore studied 38 children (mean age, 11 years; range, 1.6-17 years) who had TBI with quantitative short-echo time (STEAM, TE = 20 msec) proton MRS, a mean of 7 +/- 4 (range, 1-17) days after injury in order to determine if their occipital or parietal Glx levels correlated with the severity of injury or outcome. Occipital Glx was significantly increased in children with TBI compared to controls (13.5 +/- 2.4 vs. 10.7 +/- 1.8; p = 0.002), but there was no difference between children with good compared to poor outcomes as determined by the Pediatric Cerebral Performance Category Scale score at 6-12 months after injury. We also did not find a correlation between the amount of Glx and the initial Glasgow Coma Scale score, duration of coma, nor with changes in spectral metabolites, including N-acetyl aspartate, choline, and myoinositol. In part, this may have occurred because, in this study, most patients with poor outcomes were studied later than patients with good outcomes, potentially beyond the time frame for peak elevation of Glx after injury. Additional early and late studies of patients with varying degrees of injury are required to assess the importance to the pathophysiology of TBI of this excitatory neurotransmitter.

Brain death in early infancy.

Guidelines for the determination of brain death in infants and children are now well established. Coma, absence of cranial nerve reflexes, and apnea are required in all patients. In children less than 1 year of age, supportive neurodiagnostic studies (electroencephalograms and cerebral blood flow) are recommended. Data on 52 pediatric heart donor patients were reviewed to assess whether current criteria and procedures were used in the determination of brain death. The mean age of the donors (14.3 months) was higher than that of the recipients (2.6 months). In all patients the hospital records documented coma, fixed dilated pupils, absent brain stem reflexes, apnea, and verification of the diagnosis of brain death by two physicians who were not part of the transplantation team. In 27 of 52 patients, apnea challenge tests were performed; the mean PCO2 was 73.3 torr. Thirty-three of 52 patients had electroencephalograms performed; electrocerebral silence was found in 28 of 33 studies. Twenty-two of 52 patients had cerebral blood flow studies; in 19 of 22 studies the absence of flow was observed. Of the 52 patients the following number of organs were transplanted: heart (52), liver (34), kidneys (15), corneas (6), lung (4), and pancreas (2). These data indicate that the diagnosis of brain death is being made accurately and in a timely manner as is the harvesting of organs. Improvements could be made by requiring, if possible, the performance of an apnea challenge test in all patients. The data also suggest the potential to increase the donor yield.

Availability and selection of donors for pediatric heart transplantation.

METHODS: Applying generally accepted criteria for selection of adult heart donors, we conducted a retrospective study of brain-dead infants and children for assessment of suitability as donors for heart transplantation. Cardiac histopathologic studies were evaluated in all subjects undergoing autopsy. RESULTS: In 5 years there were 58 such patients, the majority of whom had head injury, near-drowning, near-miss sudden infant death syndrome, infection, or asphyxia. Of these, only five met the proposed clinical criteria. Most prospective donors were eliminated on the basis of prolonged cardiac arrest (n = 33), pressor dependency (n = 25), and/or infection (n = 10). Forty-two subjects underwent autopsy, of whom 36 would not have been excluded as donors except on the basis of ischemic cardiac insult. Of these, 18 subjects were found to have essentially normal myocardium, nine had abnormal but potentially reversible microscopic changes, and nine had myocardial infarction. The pathologic findings were not predicted by the selection criteria, but severe chest trauma was not associated with infarction, eight of the nine patients with infarction had had cardiac arrest, and most of those with infarction had drowned or had had sudden infant death syndrome. CONCLUSIONS: The supply of donor organs for pediatric heart transplantation is very limited if selection criteria used for adult donors are applied. These criteria, however, do not correlate well with myocardial pathologic findings in infants and children. More accurate predictors of donor suitability are needed.

Growth and neurodevelopmental outcome of infants undergoing heart transplantation.

The purpose of this study was to examine the long-term growth and developmental outcome of infants undergoing heart transplantation. We studied weight, length, and head circumference from birth to 12 months after surgery in 110 infant recipients less than 6 months of age. Forty-eight early transplant recipients (0 to 30 days) were compared with 62 late transplant recipients (31 to 180 days). Late transplant recipients showed less growth in all parameters at the time of transplant. However, by 6 months after transplantation, there were no differences between the two groups. Growth in 20 infants, now 3 to 7 years old, appears normal. Neurodevelopmental outcome was evaluated prospectively in 57 infants. Four months after transplantation, 11 infants (19%) had abnormal neurologic examinations, with generalized hypotonia (64%) being the most common finding. The Bayley Scale of Infant Development was administered to 48 of 57 infants. The Mental Developmental Index averaged 87 (+/- 21) and the Psychomotor Developmental Index averaged 90 (+/- 21). Of 140 infants who have undergone heart transplantation, transient postoperative seizures occurred in 23 survivors (21%) and 10 nonsurvivors (33%). Our findings suggest that growth, neurologic outcome, and development are normal in the majority of infants who undergo transplantation before 6 months of age.

Neurologic evaluation of the patient with acute bacterial meningitis.

Major advances in our understanding of the pathophysiology of bacterial meningitis have been made in the past decade. It is likely that interventional strategies that mediate the effects of vasoactive metabolites and neuronal and glial toxins will improve the outcome of patients with meningitis as well as other neurologic disorders. Of critical importance, as demonstrated in the case history, is the realization that many of the serious complications of meningitis occur very early in the course of the disease. If new treatment strategies are to be effective, they should be started as soon as possible. Emerging technologies such as proton magnetic resonance spectroscopy may be of benefit in helping physicians decide which patients require treatment.

Intravenous immunoglobulin as therapy for pediatric Guillain-Barré syndrome.

Seven children with Guillain-Barré syndrome were treated with intravenous immunoglobulin. Median patient age was 5.8 years. A standard dosage of 0.4 g/kg/day for 5 days was administered. Clinical improvement occurred on average within 2.4 +/- 1.3 days of beginning intravenous immunoglobulin. One child required mechanical ventilation for 7 days. Eight comparable children with Guillain-Barré syndrome at our institution in a prior study treated with plasmapheresis alone had similar clinical results. However, the need for admission to the pediatric intensive care unit and duration of pediatric intensive care unit stay were lower in the intravenous immunoglobulin treated group (P < .05). There were no complications with intravenous immunoglobulin therapy except for a brief episode of hypotension in one patient. Review of the literature identified 74 additional children with Guillain-Barré syndrome successfully receiving intravenous immunoglobulin therapy. We suggest intravenous immunoglobulin as initial therapy for pediatric Guillain-Barré syndrome, because it appears equally as effective as plasmapheresis and is associated with fewer complications.