Biomedical subjects
Publications and source records attributed to P David Adelson.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
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Whether hippocampal neuron loss and/or hippocampal sclerosis is the 'cause' or 'consequence' of seizures has been a fundamental question in human epilepsy studies for over a century. To address this question, this study examined hippocampal specimens from temporal lobe epilepsy patients (TLE; n = 572) and those with extra-temporal seizures and pathologies (n = 73) for qualitative signs of hippocampal sclerosis and quantitative neuron loss using cell counting techniques. Patients were additionally classified based on pathological substrate, and history of an initial precipitating injury (IPI). Results showed that: (1) Hippocampal sclerosis was strongly linked with an IPI in both TLE and extra-temporal seizure patients. (2) In TLE cases, IPIs showed an early age preference and often involved seizures, but IPIs were not age dependent and older IPI cases showed sclerosis that was indistinguishable from younger IPI patients. (3) In TLE patients, longer seizure durations were associated with decreased neuronal densities in all hippocampal subfields. The decrease was independent of the neuron loss linked with IPIs, it occurred in all pathological groups, it occurred over 30 years or more, and was not a consequence of aging. (4) Intractable seizures in the young human hippocampus were not associated with neuronal damage, but were linked with decreased postnatal granule cell development and aberrant axon sprouting. These results support the concept that hippocampal sclerosis is likely an acquired pathology, and most of the neuronal loss occurs with the IPI. In addition, there is progressive hippocampal damage from intractable TLE regardless of pathology. Hence, hippocampal neuron loss can be the 'consequence' of repeated limbic seizures over 30 years or more, but is unlikely to 'cause' hippocampal sclerosis unless there is also an IPI.
Childhood victims of NAT with severe brain injury require a multidisciplinary approach to their management if a good outcome is to occur. Despite the grave prognosis of these patients, an initial aggressive treatment strategy is warranted, because enough children go on to a meaningful life. A vigilant evaluation for multisystem injuries and vigorous resuscitation should be followed by prompt surgical intervention as indicated. Most NAT victims do not require surgical treatment of their brain injury, but do require ICP monitoring. A stepwise approach to the treatment of elevated ICP optimizes CPP, minimizes secondary brain injury, and increases the chances of a meaningful recovery. The future holds promise for these patients because a concerted effort is underway to understand pediatric TBI on a molecular level, and targeted therapies based on current basic research will certainly improve the neurointensive care, and eventual neurologic outcomes, of these children.
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PURPOSE: There is considerable controversy whether childhood seizures damage existing neurons and/or adversely affect neurogenesis and synaptogenesis. This study addressed this question by examining fascia dentata neurogenesis, cell death, and aberrant axon connections in hippocampi from children with extratemporal seizure foci. METHODS: Surgically resected (n = 53) and age-comparable autopsy (n = 22) hippocampi were studied for neuronal densities, polysialic acid (PSA) neural cell adhesion molecule (NCAM) immunoreactivity (IR), TUNEL, and neo-Timm's histochemistry. RESULTS: Compared with autopsy cases, hippocampi from children with frequent seizures showed (a) decreased fascia dentata granule cell densities; (b) decreased PSA NCAM IR cell densities in the stratum granulosum, infragranular, and hilar regions; (c) no positive TUNEL-stained cells; and (d) aberrant supragranular mossy fiber axon connections. CONCLUSIONS: These results indicate that severe seizures during early childhood are associated with anatomic signs of decreased postnatal granule cell neurogenesis (PSA NCAM IR) and aberrant mossy fiber axon connections (neo-Timm's) without evidence of seizure-induced cell death (TUNEL). In humans, these results support the concept that seizures do not damage existing neurons, but adversely affect processes involved with normal postnatal neuronal development such as neurogenesis and axon formation. Such alterations probably negatively affect normal brain development, and/or promote epileptogenesis.
Traumatic brain injury (TBI) is a leading cause of death and disability in children. The current gold standards for diagnosis of TBI after closed head injury (CHI) have limitations, particularly in cases of inflicted injury. S100B is a protein that is specific to astrocytes. Serum S100B concentrations are increased in adults after CHI; there are no studies of serum S100B after CHI in children. The goal of this study was to measure the serum concentrations of S100B in children inflicted and noninflicted mild, moderate, and severe CHI. CHI severity was defined by initial Glasgow Coma Scale score. Forty-five children aged 0-13 years with mild (n = 27), moderate (n = 6), and severe (n = 12) CHI were enrolled prospectively. Blood was obtained as soon as possible after injury (range: 0.5-15.25 h) and every 12 h for up to 5 days when vascular access was available. Single control samples were obtained from 16 children aged 0-11 years with isolated long-bone fractures. Twenty-two patients (49%), including both patients with inflicted CHI, had an abnormal initial serum S100B concentration where an abnormal concentration was defined as greater than mean control concentration plus two standard deviations. S100B was detectable more than 12 h after injury only in patients with severe CHI. We conclude that serum S100B is increased in almost half of children after mild, moderate, and severe inflicted and noninflicted CHI. The increase is transient, lasting less than 12 h after injury, except in children with severe injury. Future research will focus on the possibility of using serum S100B as a screening test for inflicted CHI.
Trauma is the leading cause of both morbidity and mortality in the pediatric population, and traumatic injury causes > 50% of all childhood deaths. Significant mortality rates have been reported for children with traumatic brain injury. Although children have better survival rates as compared with adults with traumatic brain injury, the long-term sequelae and consequences are often more devastating in children due to their age and developmental potential. The costs involved in the care of a child with severe traumatic brain injury, extended over that child's lifetime, are significant. It is unfortunate that despite preventive measures, traumatic brain injury remains the major morbidity and mortality factor for children.
OBJECTIVE: To determine the relationship between cerebrospinal fluid procalcitonin concentration and severe traumatic brain injury in children. DESIGN: Prospective, observational clinical study. SETTING: A multidisciplinary, tertiary-care pediatric intensive care unit. PATIENTS: Twenty-eight patients who required external ventricular drainage for management of severe traumatic brain injury (Glasgow Coma Scale score of <8) and 22 control patients for whom lumbar cerebrospinal fluid evaluation excluded possible meningitis. INTERVENTIONS: Standard intracranial pressure-directed neurointensive care, including intraventricular catheter placement and continuous cerebrospinal fluid drainage, was used to manage patients with severe traumatic brain injury. MEASUREMENTS AND MAIN RESULTS: Demographic data including age, mechanism of injury, time of injury, initial Glasgow Coma Scale score, and outcome were collected. Cerebrospinal fluid procalcitonin concentration was determined by immunoluminometric assay. Initial cerebrospinal fluid procalcitonin concentration (median [range]) in patients with severe traumatic brain injury was increased greater than three-fold vs. controls (0.41 ng/mL [0.15-2.14] vs. 0.12 ng/mL [0.00-0.24], p <.001). Initial cerebrospinal fluid procalcitonin concentration among patients with abusive head trauma (0.31 ng/mL [0.29-0.50]) also was increased vs. controls (p <.05), although this increase was less robust than patients with accidental trauma (0.41 ng/mL [0.15-2.14], p <.001 vs. controls). Additional examination of key demographic and outcome variables with a generalized linear regression model was performed for patients with severe traumatic brain injury. Univariate analysis revealed that both time after injury (p <.01) and abusive head trauma as a mechanism of injury (p <.001) were associated with attenuation of the increased cerebrospinal fluid procalcitonin response after traumatic brain injury. CONCLUSION: Cerebrospinal fluid procalcitonin concentration is increased in children after traumatic brain injury. The attenuated increase in cerebrospinal fluid procalcitonin among victims of abusive head trauma warrants further study because it may reflect impairment of endogenous neuroprotective mechanisms or delay in seeking medical attention. The significance of these observations remains to be determined as future studies elucidate the physiologic and mechanistic properties of procalcitonin.
Studies in experimental traumatic brain injury (TBI) support a key role for oxidative stress. The degree of oxidative injury in clinical TBI, however, remains to be defined. We assessed antioxidant defenses and oxidative stress in pediatric TBI by applying a comprehensive battery of assays to cerebrospinal fluid samples. Using a protocol approved by our institutional review board, 87 cerebrospinal fluid samples from 11 infants and children with severe TBI (Glasgow Coma Scale score < or = 8) and 8 controls were studied. Cerebrospinal fluid was drained as standard care after TBI. CSF was assessed on d 1, 2, and 5-7 after ventricular drain placement. Biochemical markers of oxidative stress included F(2)-isoprostane and protein sulfhydryl (detected by ELISA and fluorescence assay, respectively). Antioxidant defenses were measured by determination of total antioxidant reserve (via chemiluminescence assay), and ascorbate (via HPLC) and glutathione (via fluorescence assay) concentrations. Free radical production (ascorbate radical) was assessed by electron paramagnetic resonance spectroscopy. F(2)-isoprostane was markedly increased versus control, maximal on d 1 (93.8 +/- 30.8 pg/mL versus 7.6 +/- 5.1 pg/mL, p < 0.05). Total antioxidant reserve was reduced versus control. Reduction was maximal on d 5-7 (81.8 +/- 3.7 microM versus 178.9 +/- 2.2 microM, p < 0.05). Ascorbate was remarkably reduced (53.8 +/- 8 microM versus 163.8 +/- 21 microM on d 1, p < 0.05). Ascorbate depletion was likely associated with its free radical oxidation, as evidenced by electron paramagnetic resonance spectroscopy. Glutathione levels increased on d 1, then decreased versus control (0.19 +/- 0.05 microM versus 1.2 +/- 0.16 microM, p < 0.05). This is the first comprehensive study of antioxidant reserve and oxidative injury in clinical TBI. Progressive compromise of antioxidant defenses and evidence of free radical-mediated lipid peroxidation are noted. These markers could be used to monitor antioxidant strategies in clinical trials.
BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in children. Considerable insight into the mechanisms involved in secondary injury after TBI has resulted from analysis of ventricular cerebrospinal fluid (CSF) obtained in children with severe noninflicted and inflicted TBI (nTBI and iTBI, respectively). Neuron-specific enolase (NSE) is a glycolytic enzyme that is localized primarily to the neuronal cytoplasm. S100B is a calcium-binding protein localized to astroglial cells. In adults, CSF and serum concentrations of NSE and S100B have served as markers of neuronal damage after TBI. Neither NSE nor S100B has previously been studied in CSF after TBI in infants or children. OBJECTIVE: To compare the time course and magnitude of neuronal and astroglial death after nTBI and iTBI by measuring CSF concentrations of NSE and S100B using a rapid enzyme-linked immunosorbent assay. METHODS: Severe nTBI and iTBI were defined by strict clinical criteria. Serial ventricular CSF samples (n = 35) were obtained from children 1.5 to 9 years with severe nTBI (n = 5) and children 0.2 to 1.5 years (n = 5) with severe iTBI. Lumbar CSF samples from 5 children 0.1 to 2.3 years evaluated for meningitis were used as a comparison group. CSF NSE and S100B concentrations were quantified by an enzyme-linked immunosorbent assay (SynX Pharma Inc, Ontario, Canada). RESULTS: There was no difference in age between patients with iTBI (median [range]: 0.2 years [0.2-1.8]), nTBI (2.0 years [1.5-9]), and the comparison group (0.2 years [0.2-1.8]). The initial Glasgow Coma Scale score was higher in the iTBI group (9 [4-14]) versus the nTBI group (3 [3-7]). NSE was increased in TBI versus the comparison group in 34 of 35 samples. Mean NSE was markedly increased (mean +/- SEM, 117.1 +/- 12.0 ng/mL vs 3.5 +/- 1.4 ng/mL). After nTBI, a transient peak in NSE was seen at a median of 11 hours after injury (range: 5-20 hours). After iTBI, an increase in admission NSE was followed by a sustained and delayed peak at a median of 63 hours after injury (range: 7-94). The magnitude of peak NSE was similar in nTBI and iTBI. S100B was increased versus the comparison group in 35 of 35 samples. Mean S100B was markedly increased in TBI versus the comparison group (1.67 +/- 0.2 ng/mL vs 0.02 +/- 0.0 ng/mL). S100B showed a single peak at 27 hours (range: 5-63 hours) after both nTBI and iTBI. The mean S100B concentration, peak S100B concentration, and the time to peak were not associated with mechanism of injury. CONCLUSIONS: Markers of neuronal and astroglial death are markedly increased in CSF after severe nTBI and iTBI. ITBI produces a unique time course of NSE, characterized by both an early and late peak, presumably representing 2 waves of neuronal death, the second of which may represent apoptosis. Delayed neuronal death may represent an important therapeutic target in iTBI. NSE and S100B may also be useful as markers to identify occult iTBI, help differentiate nTBI and iTBI, and assist in determining the time of injury in cases of iTBI.
ALTHOUGH ADVANCES IN prenatal care and diagnosis have reduced the incidence of spina bifida, repair of neural tube defects remains one of the standard cases encountered by pediatric neurosurgeons. The operative techniques used in closure of these congenital defects have remained essentially unchanged during the past 2 decades; however, the operative nuances for closure often are based on the variability in configuration and size of the open defects, which can present a challenge. Repair of the open spinal dysraphism may require only a simple closure, but extensive dissection and reconstruction of the neural, meningeal, fascial, and epidermal tissues, including the use of specialized vascularized flaps, may be required in some cases. In this article, we briefly describe the preoperative evaluation, decision process, and standard techniques for the repair of myelomeningocele and myeloschisis.
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This article summarizes major developments of the past 20 years in both acute and chronic management of children with traumatic brain injury. The article begins with brief summaries of developments in acute and rehabilitative medical management and physical rehabilitation. Because long-term cognitive, behavioral, academic, and family issues tend to be dominant after pediatric TBI, more attention is given to these topics. The article ends with a list of general themes that have been identified as critical in providing effective long-term services and supports to children with TBI and their families.
Although surgical treatment of brachial plexus birth palsy has yielded encouraging results, persistent inability to abduct and elevate the shoulder is common even in children with excellent return of arm and hand function. The reason for deltoid weakness in the afflicted children is not completely understood and may be multifactorial. Clinical observations, including a pattern of position-dependent weakness, suggest that primary nerve damage may not be the sole cause. The authors performed a retrospective chart study to investigate the outcome of surgical treatment to augment shoulder function in a series of 10 children (ages 9 months to 8 years) with inadequate external rotation of the shoulder and inability to actively raise the arm beyond 90 degrees from a birth brachial plexus injury. At follow-up 6 months after surgery, increased shoulder range of motion was noticed in all, with significantly increased abduction/elevation in 8 of the 10 children. Analysis of data, including pre- and postoperative functional testing and intraoperative electrophysiologic monitoring, led to the conclusion that secondary compression of the axillary nerve in the quadrangular space is a separate and common reason for impairment in children with brachial plexus birth palsy and persistent weakness of the deltoid muscle and may provide an important reason for early intervention.