Dystrophic neuritic processes in epileptic cortex.

Cortical dysplasia is a frequent finding in cortical resections from children with refractory epilepsy. Diagnostic criteria and a classification scheme for cortical dysplasia has been proposed, though the relationship between specific cortical dysplasia features and their causal relationship with epilepsy is poorly understood. We reviewed 28 surgical resections from children and identified a common and easily recognized feature of cortical dysplasia: maloriented, misshapen and occasionally coarse neurofilament stained process forming a dystrophic neuritic background. The dystrophic neuritic background was associated with other features of cortical dysplasia in all 28 patients with cortical dysplasia, 26 with refractory epilepsy and 2 patients with other neurologic diagnoses. In seven children with refractory epilepsy due to other pathologic diagnosis such as vascular or glial lesions, the dystrophic neuritic background was only found in one patient with a ganglioglioma and other features suggestive of an associated cortical dysplasia. Our data indicate that a dystrophic neuritic background is a common and relatively specific neuropathologic finding in cortical dysplasia.

Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation.

BACKGROUND: Lethal hyperammonemic coma has been reported in 2 adults after lung transplantation. It was associated with a massive elevation of brain glutamine levels, while plasma glutamine levels were normal or only slightly elevated. In liver tissue, glutamine synthetase activity was markedly reduced, and the histologic findings resembled those of Reye syndrome. The adequacy of therapy commonly used for inherited disorders of the urea cycle has not been adequately evaluated in patients with this form of secondary hyperammonemia. OBJECTIVE: To determine whether hemodialysis, in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy, would be efficacious in a patient with hyperammonemic coma after solid-organ transplantation. DESIGN: Case report. SETTING: A children's hospital. PATIENT: A 41-year-old woman with congenital heart disease developed a hyperammonemic coma with brain edema 19 days after undergoing a combined heart and lung transplantation. METHODS: Ammonium was measured in plasma. Amino acids were quantitated in plasma and cerebrospinal fluid by column chromatography. The effectiveness of therapy was assessed by measuring plasma ammonium levels and intracranial pressure and performing sequential neurological examinations. RESULTS: The patient had the anomalous combination of increased cerebrospinal fluid and decreased plasma glutamine levels. To our knowledge, she is the first patient with this complication after solid-organ transplantation to survive after combined therapy with sodium phenylacetate, sodium benzoate, arginine hydrochloride, and hemodialysis. Complications of the acute coma included focal motor seizures, which were controlled with carbamazepine, and difficulty with short-term memory. CONCLUSIONS: The aggressive use of hemodialysis in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy may allow survival in patients after solid-organ transplantation. An acute acquired derangement in extra-central nervous system glutamine metabolism may play a role in the production of hyperammonemia in this illness that resembles Reye syndrome, and, as in other hyperammonemic disorders, the duration and degree of elevation of brain glutamine levels may be the important determining factors in responsiveness to therapy.

Neurologic manifestations of the organoid nevus syndrome.

Prominent neurologic abnormalities were observed in six patients with epidermal or linear sebaceous nevi (organoid nevi). These cases were remarkable for unilateral facial nevi, cognitive impairment, seizures, and focal or lateralized epileptic EEG abnormalities. Additional manifestations included the onset of seizures in the neonatal period, unilateral hypsarrhythmia or Lennox-Gastaut EEG pattern, hemiparesis, asymmetric macrocephaly, and somatic growth disturbances. The full expression of this disorder was not apparent at birth, but emerged gradually during infancy. The neurologic abnormalities in these patients were attributed to unilateral or asymmetric malformations of the CNS as demonstrated by computed tomography. A lateralized disorder of neuroectodermal proliferation, differentiation, and migration could account for both the cutaneous and neurologic abnormalities in this disorder. The striking clinical similarities in these patients suggest a close link between epidermal and linear sebaceous nevi.

EEG in premature infants with intraventricular hemorrhage.

Seventy-eight EEGs from 44 premature infants with CT- or autopsy-verified intraventricular hemorrhage (IVH) were reviewed retrospectively. The patient's most abnormal EEG was a reliable predictor of outcome, independent of the estimated gestational age, 1- and 5-minute Apgar scores, and IVH grade. Nine of 12 infants who had all normal or mildly abnormal EEGs had favorable outcomes. The nine infants whose worst EEGs were moderately abnormal experienced mixed outcomes, ranging from normal survival to death. All 23 infants with one or more markedly abnormal EEGs suffered unfavorable outcomes. Positive rolandic sharp waves, a highly specific EEG pattern for IVH in premature infants, occurred in only 29.5% of the patients. The degree of EEG abnormality correlated significantly with the patient's mental status, but not with the IVH grade. Subarachnoid hemorrhage, hypoxia-ischemia, and focal parenchymal lesions caused electrographic seizures in 14 patients, 12 of whom died (85.7%). This study suggests that EEG has limited value in the diagnosis of IVH. However, it may play an important role in the neurologic assessment of the premature infant with established IVH by confirming clinically suspected seizures and providing reliable prognostic information.

Neurologic outcome after electroencephalographically proven neonatal seizures.

Infants in whom neonatal seizures were confirmed by randomly recorded ictal electroencephalographic (EEG) tracings were retrospectively examined to determine their global neurologic outcome and the specific frequency of epilepsy, development delay, and cerebral palsy. Perinatal and postnatal clinical and EEG variables were also examined for their relevance to the neurologic outcome. Forty infants with EEG documented seizures of diverse etiologies were studied. The 27 survivors were followed up at a mean of 31 months. The outcome was unfavorable in 70%. The rate of epilepsy was 56%, of developmental delay 67%, and of cerebral palsy 63%. The etiology of seizures was an important factor influencing the outcome. Other clinical factors that showed a significant relationship with global or specific aspects of the neurologic outcome included the age at the onset of seizures, birth weight, and neurologic examination results. The EEG parameters that significantly predicted the neurologic outcome were interictal EEG background, increased seizure frequency, and decreased seizure duration.

Acquired neuropathologic lesions associated with the hypoplastic left heart syndrome.

This study details the type, frequency, clinical presentation, and etiologic associations of acquired brain lesions in 40 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Detailed postmortem neuropathologic examinations showed that 55% of the infants were free of acquired brain lesions. However, the other 45% had combinations of hypoxic-ischemic lesions and intracranial hemorrhage. Central nervous system perfusion and glucose-oxygen delivery appeared to be important factors in the occurrence of hypoxic-ischemic lesions or intracranial hemorrhage, whereas acidosis and hypercarbia were not. Cerebral necrosis may be a predisposing factor for a major intracranial hemorrhage. A duration of cardiopulmonary bypass with hypothermic total circulatory arrest longer than 40 minutes was associated with a higher incidence of acquired neuropathology. These results indicate that the majority of infants with hypoplastic left heart syndrome are free of acquired neuropathology and suggest practical ways to reduce the risks in the others.

Congenital brain anomalies associated with the hypoplastic left heart syndrome.

This study details the type, frequency, and clinical presentation of developmental brain anomalies in 41 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Overall, 29% of the infants had either a major or minor central nervous system abnormality. Overt central nervous system malformations, including 3 cases of agenesis of the corpus callosum and 1 case of holoprosencephaly, were seen in 4 infants (10%). Micrencephaly (brain weight at autopsy more than 2 SDs below the mean for age) was found in 27% of the infants. An immature cortical mantle was seen in 21% of the study group. Seven infants (17%) had specific recognizable patterns of malformation. The absence of dysmorphic physical features did not preclude overt or subtle central nervous system malformations. Conversely, the presence of dysmorphic features did not reliably indicate an underlying brain anomaly. Infants who had hypoplastic left heart syndrome as one of multiple nonneurologic malformations were more likely to have micrencephaly than those infants with hypoplastic left heart syndrome as an isolated abnormality. Occurrence of developmental neuropathology was elevated in those infants with hypoplastic left heart syndrome who did not have a recognizable pattern of malformation but who were small for gestational age, microcephalic, or had ocular abnormalities. Infants with hypoplastic left heart syndrome deserve careful genetic, opthalmologic, and neurologic evaluations, imaging of their intracranial anatomy, and long-term neurologic follow-up.

The pharmacokinetics of injectable allopurinol in newborns with the hypoplastic left heart syndrome.

OBJECTIVE: The purpose of this investigation was to determine the pharmacokinetic disposition of intravenous allopurinol and its metabolite oxypurinol in neonates with the hypoplastic left heart syndrome (HLHS) and to evaluate the subsequent degree of xanthine oxidase inhibition using serum uric acid as a marker. METHODS: Pharmacokinetic data were evaluated in 12 stable preoperative neonates with HLHS after a single intravenous allopurinol administration of 5 mg/kg or 10 mg/kg. Pharmacokinetic parameters were determined for elimination half-life, clearance, volume of distribution, and mean residence time. Xanthine oxidase inhibition, measured by serum uric acid reduction, was also measured. RESULTS: Pharmacokinetic parameters revealed no statistically significant differences between a 5-mg/kg and 10-mg/kg dose of intravenous allopurinol on elimination half-life, clearance, volume of distribution, and mean residence time. Mean serum uric acid levels were significantly reduced from baseline by 39.99 and 42.94%, respectively, in the 5- and 10-mg/kg treatment groups. DISCUSSION: The enzyme xanthine oxidase plays a key biochemical role in the generation of toxic oxygen-derived free radicals during ischemia-reperfusion conditions. Allopurinol and its active metabolite oxypurinol inhibit xanthine oxidase, and significantly reduce the conversion of hypoxanthine to xanthine and xanthine to uric acid. Cell injury may be caused by toxic oxygen free radicals produced by ischemia-reperfusion injury such as could occur during the repair of HLHS under hypothermic total circulatory arrest. We hypothesize that allopurinol may provide protection from cellular injury in this clinical context.

Preoperative risk-of-death prediction model in heart surgery with deep hypothermic circulatory arrest in the neonate.

OBJECTIVE: Our goal was to generate a preoperative risk-of-death prediction model in selected neonates with congenital heart disease undergoing surgery with deep hypothermic circulatory arrest. METHODS: We completed a single-center, prospective, randomized, double-blind, placebo- controlled neuroprotection trial in selected neonates with congenital heart disease requiring operations for which deep hypothermic circulatory arrest was used. An extensive database was generated that included preoperative, intraoperative, and postoperative variables. Variables (delivery, maternal, and infant related) were evaluated to produce a preoperative risk-of-death prediction model by means of logistic regression. An operative risk-of-death prediction model including duration of deep hypothermic circulatory arrest was also generated. RESULTS: Between July 1992 and September 1997, 350 (74%) of 473 eligible infants were enrolled with 318 undergoing deep hypothermic circulatory arrest. The mortality was 52 of 318 (16.4%), unaffected by investigational drug. The resulting preoperative risk model contained 4 variables: (1) cardiac anatomy (two-ventricle vs single ventricle surgery, with/without arch obstruction), (2) 1-minute Apgar score (5), (3) presence of genetic syndrome, and (4) age at hospital admission for surgery (5 days). Mortality for two-ventricle repair was 3.2% (4/130). Mortality for single ventricle palliation was 25.5% (48/188) and was significantly influenced by Apgar score, genetic diagnosis, and admission age. The preoperative model had a prediction accuracy of 80%. The operative risk model included duration of deep hypothermic circulatory arrest, which significantly (P =.03) increased risk of death, with a prediction accuracy of 82%. CONCLUSIONS: In this selected population, postoperative mortality risk is significantly affected by preoperative conditions. Identification of infants with varying mortality risks may affect family counseling, therapeutic intervention, and risk stratification for future study designs.

CHOP Infant Coma Scale ("Infant Face Scale"): a novel coma scale for children less than two years of age.

The Glasgow Coma Scale (GCS) is the most frequently used tool worldwide for assessing the severity of neurologic injury after brain trauma, although applying this scale to infants and younger children can be problematic. The CHOP Infant Coma Scale, or Infant Face Scale (IFS), is a novel scale for children under 2 years of age which differs from other pediatric coma scales in the following ways: (1) it relies on objective behavioral observations; (2) it assesses cortical as well as brainstem function; (3) it parallels the GCS in scoring but is based on infant-appropriate behaviors; and (4) it can be applied to intubated patients. We report the results of a prospective study designed to compare interrater reliability between the IFS and GCS in children less than 2 years of age. Seventy-five hospitalized children less than 2 years of age were assessed simultaneously by a pair of observers, representing a spectrum of health care professionals, who scored the children using both the IFS and GCS. Interrater reliability for each pair of observers for each scale was assessed using the kappa statistic. A second series of 10 infants in the intensive care unit with specific diagnoses of acute traumatic or hypoxic/ischemic brain injury were similarly assessed. In the 75 hospitalized infants with a variety of diagnoses, interrater reliability for the GCS was in the "almost perfect," "slight," and "fair" range for the eye-opening, motor, and verbal subtests, respectively. In contrast, the IFS showed interrater reliability in the "almost perfect," "substantial," and "almost perfect" ranges for the three subtests. When applied to infants in an intensive care unit with acute traumatic brain injury or hypoxia/ischemia, the GCS interrater reliability scores were in the "fair" range, while the IFS scores were in the "almost perfect" range. The IFS demonstrates improved interrater reliability in direct comparison to the GCS, particularly in the "verbal/face" component where most pediatric coma scales are deficient. The IFS may prove to be a simple and practical bedside index of brain injury severity in children less than two years of age.

Horner syndrome associated with implantation of a vagus nerve stimulator.

PURPOSE: To report a case of Horner syndrome that occurred after implantation of a vagus nerve stimulator. METHODS: Case report. RESULTS: A 6-year-old female with cerebral dysgenesis and intractable partial seizures presented with Horner syndrome after vagus nerve stimulator implantation. CONCLUSION: Horner syndrome can occur as a result of the vagus nerve stimulator implant procedure and should be included as one of its possible surgical complications.

Clinical variability in congenital fiber type disproportion.

Congenital Fiber Type Disproportion (CFTD) has recently been described as a consistent and stereotyped clinicopathological entity, including congenital nonprogressive hypotonia and weakness, contractures, kyphoscoliosis, high arched palate, dislocated hips, short stature, and feet deformities. Our personal experience with this condition suggests a wider disparity in the physical appearance and associated abnormalities of affected individuals than the well-defined clinical syndrome previously described. We are presenting 5 cases, including 2 siblings, whose muscle biopsies satisfy the major histological and statistical criteria for the diagnosis. Although each child clearly had hypotonia and weakness consistent with a congenital myopathy, only 3 had a sufficient number of other similarities to establish the diagnosis clinically. The clinical spectrum of the other cases ranged from one infant whose only abnormality was mild hypotonia in the legs to another whose problems included severe motor impairment, marked mental retardation, growth failure, frontal bossing, abnormal hair, and scoliosis. Even in retrospect, the diagnosis of CFTD could not have been supported on clinical grounds alone. Therefore, CFTD is a congenital myopathy whose diagnosis can be made only by muscle biopsy, rather than a distinct syndrome whose diagnosis can be assumed on the basis of clinical characteristics alone.

Using age-appropriate prolactin levels to diagnose children with seizures in the emergency department.

OBJECTIVE: To assess the utility of serum and cerebrospinal fluid (CSF) prolactin levels for identifying children who have experienced seizures. METHODS: A prospective cohort study was performed in a pediatric ED at an urban children's hospital. A convenience sample of children underwent blood and CSF analyses in the ED over a 2-year period. RESULTS: Thirty-five children (aged 3 months-15 years) with generalized tonic-clonic seizures and 48 ill control patients were studied. Both groups included febrile and afebrile patients. The patient characteristics in the seizure and control groups were similar with respect to age, fever, current medications, and blood, urine, and CSF cultures. When serum prolactin levels were assigned age-adjusted dichotomous values of "elevated" or "normal," the rates of elevation between the seizure and control patients were different (p < 0.001). The positive and negative predictive values of these age-adjusted levels were 68% (95% CI 47-85%) and 76% (95% CI 61-87%), respectively. The mean CSF prolactin levels of the seizure and control groups were not significantly different. In addition, there was no single threshold CSF prolactin level that could delineate seizure patients from control patients. CONCLUSIONS: Age-adjusted serum prolactin levels are useful only as an adjunct in the prospective evaluation of the individual pediatric patient for epileptic seizure activity. CSF prolactin levels are not useful in the diagnosis of generalized seizures in children in the acute care setting.

Interictal sharp EEG transients in neonatal seizures.

This study describes the differences between several quantifiable variables that characterize interictal sharp EEG transients (SETS) recorded from neurologically ill neonates with proven electrographic seizures and a comparison group of apparently neurologically well babies with no known seizures. The abundance (number of sharp EEG transients per ten minutes), waveform morphology, repetitive behavior, and spatial distribution of SETS provide interpretive guidelines that help discriminate between these two patient populations.

Midline foci of epileptiform activity in children and neonates.

We report the clinical and electroencephalographic (EEG) correlates of focal potentially epileptogenic discharge arising from midline sagittal vertices (Fz, Cz, Pz) in 21 children prospectively identified from among 7,051 consecutive EEGs recorded during a 27-month period. The patients range in age from neonates to 13 years. EEGs were obtained during evaluations for solitary or recurrent seizures (17/21), attention deficit disorder (2/21), psychomotor retardation (1/21), and headache (1/21). Clinical seizure types were diverse and included simple partial (5/17), complex partial (2/17), generalized tonic-clonic (4/17), mixed (2/17), and neonatal (4/17). The majority (13/21) of patients had an identifiable etiology for their disorder; CT scans verified mass lesions in two patients. Midline epileptogenic foci were present during wakefulness in 14 of 17 older children and restricted to sleep in the others. Sleep states were indeterminate in the four neonates. Midline foci were exquisitely confined to Fz, Cz, and/or Pz in 6 of 17 older children and would have been entirely missed by a recording montage that did not include vertex electrodes. In five other children, midline foci spread preferentially to the adjacent central-parietal regions and closely resembled the appearance of benign rolandic foci in the longitudinal EEG montages, a potentially serious cause of EEG misinterpretation in view of the high incidence of neuropathology in this patient group.

Adequacy of routine EEG examinations in neonates with clinically suspected seizures.

This study identified the clinical and electroencephalographic (EEG) characteristics that distinguished neonates with EEG-confirmed seizures from those without, in order to assess the adequacy of routine short-term EEG examinations in neonates with clinically suspected seizures. Two different subgroups of tracings were analyzed: EEGs performed on therapeutically paralyzed (TP+) neonates and EEGs performed on non-therapeutically paralyzed (TP-) neonates. The rate of electrographic seizures, abnormal EEG background activity, and excessive sharp EEG transients (SETs) was significantly more common in the tracings performed on TP- neonates. In lethargic/comatose TP- neonates with clinically suspected seizures and abnormal EEG background activity, the rate of EEGs with excessive SETs (implying a "lowered seizure threshold") occurred equally in tracings with or without documented electrographic seizures. Consequently, we suspect that routine EEGs may be inadequate to electrographically confirm suspected seizures in some TP- neonates due to a large sampling error. In contrast, routine 40-minute EEGs are probably adequate to seek evidence of electrographic seizure activity in TP+ neonates because their seizure rate is low and most do not display background abnormalities or excessive SETs.

Lissencephaly-pachygyria associated with congenital cytomegalovirus infection.

We report the presence of major cerebral migrational defects in five severely, multiply handicapped children with congenital cytomegalovirus (CMV) infection. These patients had both computed tomographic (CT) scan and magnetic resonance imaging (MRI) evidence of marked migrational central nervous system defects consistent anatomically with the spectrum of lissencephaly-pachygyria, a disorder commonly idiopathic or associated with chromosomal abnormalities or with unknown early gestational insults. Neuroradiologic features included broad, flat gyri, shallow sulci, incomplete opercularization, ventriculomegaly, periventricular calcifications, and white-matter hypodensity on CT scans or increased signal intensity on long-TR MRI scans. Evidence for congenital CMV infection included prenatal onset of microcephaly, periventricular calcifications, neonatal jaundice, hepatomegaly, elevated CMV-specific immunoglobulin M, or viral isolation from urine. Previous reports of the neurologic sequelae of CMV have emphasized varying degrees of psychomotor retardation, cerebral palsy and epilepsy due to polymicrogyria, periventricular calcification, microcephaly, or rarely, hydrocephalus. Our patients appear to represent extremely severe examples of the effects of CMV on neurologic growth, maturation, and development. Recognition of these severe migrational abnormalities was improved by use of MRI, a technique that affords superior definition of the nature and extent of gyral and white-matter abnormalities. We suggest that these abnormalities may be more common than has previously been recognized.

Paradoxical precipitation of tonic seizures by lorazepam in a child with atypical absence seizures.

A 10-year-old girl with Lennox-Gastaut syndrome who received intravenous lorazepam for atypical absence status seizures is reported. Tonic seizures occurred immediately and appeared to represent a paradoxical seizure exacerbation. We also review other patients with paradoxical seizure exacerbation by benzodiazepines.

Recent advances in the diagnosis, treatment, and prognosis of neonatal seizures.

Current knowledge about the diagnosis, treatment, and prognosis of neonatal seizures is reviewed. The pitfalls in establishing the diagnosis are emphasized and the usefulness of new electrodiagnostic techniques is discussed. A protocol for treating neonatal seizures is suggested. Finally, the clinical and electroencephalographic variables which are relevant in determining neurologic outcome are discussed.

Cerebral venous thrombosis in neonates and children.

Twenty-five patients (10 neonates, 15 children) with cerebral venous thromboses diagnosed by magnetic resonance imaging or computed tomography over a 10-year period were reviewed retrospectively. Two groups were analyzed separately because of their differing modes of presentation and outcome. Eighty percent of neonates presented with seizures and the outcomes were unfavorable in more than 50%. Thrombosis usually was associated with an acute systemic illness, such as shock or dehydration. In comparison, headache was the most common mode of presentation in the older children (excluding infants) and their outcomes generally were favorable. Thrombosis in this group usually occurred in the setting of a hypercoagulable state or an infectious process. In both groups, global or focal neurologic findings on initial examination unrelated to increased intracranial pressure correlated with the presence of an infarction on computed tomography or magnetic resonance imaging. Infants and children with infarction due to a deep venous thrombosis often had persistent neurologic disability at subsequent examination. No sequelae were observed in those children and neonates only with thrombosis or with superficial venous infarction. Treatment for both groups was conservative. No patient was anticoagulated specifically for the thrombosis. The good outcomes in most patients suggest that acute anticoagulation may not be indicated.