Comparison of human eosinophils from normals and patients with eosinophilia.

Previous studies of the biochemistry and physiology of eosinophils have relied upon cells obtained from patients with eosinophilia (EE). It is unknown whether such cells might have been activated or partially exhausted by the pathological state causing eosinophilia. We examined cell surface charge, membrane transport of deoxyglucose, activation of lyso-somal acid phosphatase, and oxidative metabolism to provide a profile to compare EE with purified normal eosinophils (NE) and normal neutrophils. Eosinophils or neutrophils were obtained in >95% purity from normal individuals and patients with eosinophilia of diverse etiologies. Cell surface charge was determined by electrophoretic mobility in micromoles per second per volt per centimeter. Normal eosinophils demonstrated a surface charge of 2.46+/-0.03. Stimulation of the cells by zymosan-activated serum (ZAS) reduced the surface charge to 1.82+/-0.02. In contrast, the charge of "resting" EE was already reduced (1.89+/-0.05) and was not altered by ZAS. Resting and stimulated neutrophils had a charge of 1.98+/-0.01 and 1.69+/-0.02, respectively. Uptake of [(3)H]2-deoxyglucose has been shown to reflect carrier-facilitated hexose transport in granulocytes. Deoxyglucose uptake by resting NE and NE stimulated by ZAS was 2.40+/-0.40 and 5.44+/-0.39 (cpm x 10(-3)/2 x 10(5) eosinophils), respectively. Resting and stimulated EE demonstrated deoxyglucose uptake of 7.55+/-0.58 and 15.3+/-0.6, respectively.Lysosomal acid phosphatase was determined by an electron microscopic cytochemical technique. In normal eosinophils and neutrophils, lysosomal acid phosphatase in mature cells is held in a latent form. Normal eosinophils demonstrated weakly positive acid phosphatase activity in 7.8+/-1.2% of the specific granules. Normal eosinophils, stimulated by opsonized staphylococci or the calcium ionophore A23187, develop rapid activation of acid phosphatase in approximately 80% of the granules throughout the cells. Resting EE were usually already activated and demonstrated acid phosphatase in 48.6+/-8.6% of the granules (range, 2-95% granules positive; significant activation was observed in preparations in EE from 11 of 15 patients). Oxidative metabolism was monitored by measurement of the hexose monophosphate shunt (HMPS) (metabolism of 1-[(14)C]glucose to (14)CO(2)). Previous studies demonstrated that resting EE have an HMPS activity which is nearly that of stimulated neutrophils, yet EE remain capable of further 7-10-fold increase when stimulated by opsonized zymosan. In contrast, the HMPS of NE (resting and stimulated) was not significantly different from that of neutrophils. Thus eosinophils obtained from patients with eosinophilia appear significantly activated when compared with normal eosinophils by the criteria of surface charge, activation of lysosomal acid phosphatase, membrane hexose transport, and hexose monophosphate shunt activities.

Agenesis of the corpus callosum and limbic malformation in Apert syndrome (type I acrocephalosyndactyly).

Agenesis of the corpus callosum and malformation of limbic structures are described in a patient with Apert syndrome, a disorder characterized by acrocephaly, severe syndactyly, and often, mental retardation. Including the present case, malformation of the corpus callosum and/or limbic structures apparently has been reported in a total of ten patients with the syndrome. Complete or partial agenesis of the corpus callosum was found in six patients, septal defects in three, and arhinencephaly and ammonic hypoplasia in one. Since malformation or limbic structures are, to our knowledge, a consistent feature of agenesis of the corpus callosum, it seems that limbic abnormalities could be important for the pathogenesis of mental retardation not only in Apert syndrome, but also in other acallosal patients.

Encephalopathy in infants and children with chronic renal disease.

The examination of five pediatric patients with encephalopathy secondary to chronic renal failure has indicated a stereotyped sequence of neurologic signs and symptoms including ataxia, loss of motor abilities, myoclonus, seizures, dementia, and bulbar dysfunction. Both the patients with CNS dysfunction and a control group selected for a similar degree of renal failure had increased levels of serum phosphate, alkaline phosphatase, and parathyroid hormone. Serial EEGs in the affected group revealed progressive slowing and an increase in paroxysmal features. No specific neuropathologic findings were noted in one patient.

Neonatal rhabdomyolysis as a presentation of muscular dystrophy.

We report a unique presentation of X-linked recessive dystrophy as neonatal rhabdomyolysis. There was induration of the proximal musculature in an otherwise well neonate and striking CK elevation, without myoglobinuria. Muscle biopsy at age 1 year showed dystrophic alterations, and X chromosome analysis showed a deletion within or adjacent to the Duchenne/Becker locus.

Neuropathologic changes in ataxia-telangiectasia.

The neuropathologic findings in a 17-year-old boy with ataxia-telangiectasia are described. In agreement with previous reports, pathologic changes were present in the cerebellum, spinal cord, dorsal root ganglia, and straited muscle. The lesions in the spinal cord and dorsal root ganglia were more severe than previously described. Abnormalities were also seen in several brain stem nuclei, including the mesencephalic nucleus of the trigeminus and the substantia nigra. In addition, a small hamartomatous tumor was found in that thalamus.

Maternal muscle biopsy in X-linked recessive centronuclear (myotubular) myopathy.

Muscle biopsy was used to attempt determination of carrier status in mothers and maternal relatives of patients with severe neonatal centronuclear (myotubular) myopathy, an X-linked recessive disorder. We report findings from muscle biopsies of 3 mothers, one an obligate carrier. All biopsies showed abnormalities of nonspecific character. Whether such abnormalities assist in defining carrier status is uncertain. A more specific tissue marker for this disorder is required before muscle biopsy will facilitate carrier identification.

Mental retardation, hypotonia, and generalized seizures associated with astrocytic "residual" bodies. An ultrastructural study.

Two siblings suffering since birth from convulsions, hypotonia, and mental retardation are presented. In the older sibling (eight and one-half years of age) frontal lobe biopsy revealed abnormal cytosomes with lamellar profiles in astrocytes, macrophages, and to a lesser degree in neurons. Similar cytosomes have not yet been reported in cases of sphingolipidoses or in late infantile-juvenile amaurotic idiocy. These cytosomes stained intensely with silver proteinate, an ultrastructural cytochemical stain for carbohydrate moieties. In contrast, lipofuscin did not stain with silver proteinate. Multilamellar (crescentic curvilinear) cytosomes from a reported case of late infantile amaurotic idocy (Batten-Vogt-Spielmeyer disease) did not stain with silver proteinate. Abnormal cytosomes were not found in blood cells, liver, and peripheral nerve. In the younger sibling (14 months old) postmortem ultrastructural studies of cerebral tissue showed very few abnormal cytosomes. On the basis of the clinical and ultrastructural findings, we conclude that these two cases can be distinguished from those with multilamellar (crescentic-curvilinear) inclusions and from cases of the so-called "neuronal ceroid-lipofuscinosis" syndrome.

Cholecystokinin potentiates morphine anticonvulsant action through both CCK-A and CCK-B receptors.

Recent studies have suggested that cholecystokinin may have a role in modulating the effects of the endogenous opioid system in physiological functions such as thermoregulation and pain control. However, the possible interaction of cholecystokinin and morphine in epileptogenesis is unknown. We studied the effect of subcutaneous morphine and intracerebroventricularly administered cholecystokinin octapeptide sulphate ester and receptor antagonists CCK-A (MK 329) and CCK-B (L 365,260) on seizures provoked by maximal electroshock in male Sprague-Dawley rats. Seizures were induced through electrode-gel-coated ear clip electrodes by a high voltage, high internal resistance constant current generator, 30 minutes after morphine administration and 10 minutes after cholecystokinin-8-SE, CCK-A and CCK-B infusion. Morphine decreased the length of the tonic component of the seizure and cholecystokinin potentiated this decrease. Cholecystokinin antagonists blocked the effects of both cholecystokinin and morphine. The results suggest that cholecystokinin acts as an endogenous agonist with opioids in the regulation of seizure susceptibility through both CCK-A and B receptors and may be responsible for part of the anticonvulsant action of morphine.

Case study: corticosteroid treatment of language regression in pervasive developmental disorder.

The authors describe a child whose language and behavior regressed at 22 months and in whom pervasive developmental disorder was later diagnosed. At 6 years, he displayed a profound receptive-expressive aphasia accompanied by behavioral disturbances characterized by hyperactivity, impaired social interactions, tantrums, gestural stereotypies, and echolalia. A single-photon emission computed tomography scan and steady-state auditory evoked potentials suggested bitemporal and left frontal pathophysiology. The overall profile resembled Landau-Kleffner syndrome, but no electroencephalographic disturbance was evident. Corticosteroid treatment resulted in amelioration of language abilities and behavior. These findings suggest that the factors underlying language regression in pervasive developmental disorder can, in special circumstances, be amenable to pharmacological treatment.

Cytochrome c oxidase-associated Leigh syndrome: phenotypic features and pathogenetic speculations.

Fourteen new cases of cytochrome oxidase (COX)-associated Leigh syndrome (LS) are combined with 20 reported cases to describe the clinical, laboratory, and radiological features of this devastating metabolic condition. Three clinical stages are identified. Most patients have normal neurological development during the first 8-12 months (stage I). Somatic complaints are common, including chronic diarrhea, recurrent vomiting, anorexia, and decelerating body and head growth. The second stage evolves during late infancy and early childhood when motor regression becomes evident. Eye signs, altered breathing patterns, pyramidal, extrapyramidal, and cerebellar signs emerge and sudden clinical deterioration occurs during intercurrent infectious or metabolic stress. The last stage may extend from 2 to 10 years and is manifested by extreme hypotonia, swallowing difficulties and undernutrition. Feeding assistance is necessary and seizures may occur. The CSF lactate concentration is consistently elevated and MRI abnormalities are seen in the subcortical structures. COX deficiency affects most tissues, but is not always generalized. For example, 3 patients with a cardiomyopathy had normal COX activity in cultured skin fibroblasts. Nearly normal amounts of cross-reacting material are present by ELISA and immunoblot analyses. Parental consanguinity has been found in several families, the hereditary pattern is recessive and males are affected more commonly (2:1). The biomolecular abnormality causing COX deficiency in LS is unknown, but the available evidence implicates a nuclear-encoded protein that affects the structure or the stability of the holoenzyme complex.

Long-term computer-assisted outpatient electroencephalogram monitoring in children and adolescents.

The aims of this study were (1) to define the role of long-term computer-assisted outpatient electroencephalographic monitoring (COEEG) in children and adolescents with known or suspected epilepsy, and (2) to compare COEEG data with routine interictal electroencephalograms (EEG). We performed 18-channel COEEG in 84 children and adolescents with diagnosed (group 1, n = 49) or suspected (group 2, n = 35) epilepsy. Mean recording time was 1.4 days. Overall, COEEG was useful in 87% of patients. In group 1, events were recorded in 73% of patients and were electrographic seizures in 45%. In group 2, events were detected in 86% of patients and were electrographic seizures in 17%. Nocturnal and partial seizures predominated. Seizure diagnosis and classification by COEEG was concordant with interictal EEG findings in 19% and discordant in 63% of patients. COEEG is a useful technique for the diagnosis of epileptic and nonepileptic events among selected children and adolescents. When compared to routine interictal EEG, COEEG could offer additional accuracy in the classification of seizures in pediatric patients.

Technetium 99mTc-HMPAO SPECT in children and adolescents with neurologic disorders.

We evaluated regional cerebral blood flow with technetium 99mTc hexamethylpropyleneamineoxime single photon emission computed tomography (SPECT) in 20 children and adolescents with neurologic dysfunction of varied etiology and abnormal electroencephalograms (EEGs). All patients were also examined with computed tomography (CT) and magnetic resonance imaging (MRI). Abnormal perfusion was found in 17 (85%) of 20 SPECT scans. Abnormal CT or MRI scans were noted in nine (45%) and in 10 (50%) of 20 cases, respectively. In eight (73%) of 11 cases with normal CT scans and in seven (70%) of 10 with normal MRI scans, the SPECT scan was abnormal. Abnormal regional cerebral blood flow on SPECT scans correlated better with EEG abnormalities than with neurologic examination or CT or MRI scan findings. We conclude that in children and adolescents with a spectrum of neurologic diseases and abnormal EEGs, abnormalities of brain structure or function are more likely to be documented by SPECT than by CT or MRI scans. SPECT findings correlate well with the location and type of EEG abnormality.

Tuberous sclerosis complex and epilepsy: prognostic significance of electroencephalography and magnetic resonance imaging.

Tuberous sclerosis complex is a disease that affects many organs, including the central nervous system. Nervous system involvement in the form of hamartomas often results in seizures. In this study we wanted to determine the outcome of epilepsy in tuberous sclerosis complex and determine whether interictal electroencephalograms (EEGs) and hamartoma burden as seen with magnetic resonance imaging (MRI) are predictive of degree of seizure control. The study population consisted of 30 patients. For each patient two sets of EEG and MRI data, separated by at least 12 months, and information on seizure frequency at time of data collection were obtained. Sensitivity, specificity, and positive and negative predictive values of various EEG and MRI findings were determined. Seizure control improved in 20 and worsened in 10 patients. In relation to seizure control, the specificity of an abnormal sleep EEG and the positive predictive value of normal sleep EEG were 100%. MRI and EEG background were neither sensitive nor specific for predicting seizure control. A majority of children with tuberous sclerosis complex can achieve good seizure control. The sleep EEG is helpful in predicting eventual seizure control.

Diagnostic value of pediatric outpatient video-EEG.

Outpatient video-electroencephalography (OVEEG) was performed in 100 infants, children, and adolescents with diagnosed (group I, n = 64) or suspected (group II, n = 36) epilepsy. Median monitoring duration was 4 hours. Indications for OVEEG in group I were classification of seizures, reported seizure exacerbation, or onset of new signs. OVEEG indications in group II were repetitive paroxysmal and stereotyped signs of myoclonic movements, fixed gaze, abnormal behavior, or nonmyoclonic motor activity. In group I patients, symptomatic events were recorded in 89%, half of which were seizures. Among group II patients, events were recorded in 67% and were seizures in 22%. Overall, OVEEG was successful in 83% of patients. Compared to a 24-hour inpatient admission for video-EEG monitoring, OVEEG represented cost reductions of 55-80% per patient. We conclude that OVEEG is a cost-effective, useful alternative to continuous inpatient video-EEG monitoring in the investigation of selected infants, children, and adolescents with diagnosed or suspected epilepsy.

Efficacy of primidone for seizure control in neonates and young infants.

Primidone can be used for seizures refractory to standard antiepileptic drugs. We administered primidone, 25 mg/kg/day in 3 divided doses, to 10 patients and obtained serum levels of primidone, phenobarbital, and phenylethylmalonic acid at 1, 2, 4, 6, and 8 hours on day 1, alternate days until discharge, and after 6 weeks. Other antiepileptic drugs were discontinued in 8 of 10 patients with refractory seizures. Mean primidone levels were 10.6 +/- 4.4 micrograms/ml by day 3 and remained stable until discharge. Phenylethylmalonic acid was detected by 6 hours and increased to 11.1 +/- 4.0 micrograms/ml by day 7. Phenobarbital levels in 3 of 10 patients not previously treated with phenobarbital ranged from 0.6-3.4 micrograms/ml by day 5. The mean initial phenobarbital level was 30.1 +/- 10.5 micrograms/ml and had decreased to less than 15 micrograms/ml by day 7. Seizure control occurred within 5 days in 8 of 10 patients and was achieved by day 3 in 6 of 8 patients, coinciding with primidone levels greater than 10 micrograms/ml. No toxic effects of primidone were observed. All levels decreased during subsequent examinations suggesting auto-induction of metabolic systems. Our data indicate that seizure control is best correlated with primidone and phenylethylmalonic acid levels and unrelated to phenobarbital levels in this age group.

Timing of maintenance phenytoin therapy after intravenous loading dose.

The specific timing of maintenance phenytoin therapy in children has not been addressed. Prevention of a subtherapeutic phenytoin level is important for seizure control. We devised a protocol using an 18 mg/kg loading dose of phenytoin with serial levels (obtained after 2,6,12 hours) and analyzed the results in 20 consecutive patients. A therapeutic level (greater than 10 micrograms/ml) was present in all patients at 2 hours, in 16 of 20 at 6 hours, and in 10 of 20 at 12 hours. The patients were divided into 2 groups by the 12-hour levels: group I: therapeutic level; and group II: subtherapeutic level. The mean 2-hour level in group I was 22.7 micrograms/ml versus 15.6 micrograms/ml in group II (P less than 0.001). The mean decline in plasma concentration in individual patients was 0.7 micrograms/ml/hr in group I versus 1.02 micrograms/ml/hr in group II (P less than 0.05). We now use the 2-hour level to decide the timing of maintenance phenytoin therapy and have devised an equation to estimate the duration of the therapeutic range. Phenytoin can be administered at 12 hours when the 2-hour level is satisfactory or earlier when the 2-hour level indicates that a subtherapeutic level will occur.

Hypoxemia and hemodynamic changes during the hypercarbia stimulation test.

The hypercarbia stimulation test is a valuable technique to document the absence of brainstem responsiveness to elevated levels of carbon dioxide (PCO2); however, its application has been limited by concern that hypoxemia may induce cardiovascular instability. We investigated hemodynamic and oxygen (PO2) changes in 19 patients: group 1 (17 patients) had no spontaneous ventilations at PCO2 values ranging from 37-129 torr; group 2 (2 patients) had spontaneous ventilations at less than 38 torr. Group 1 was separated into 2 subgroups: A (10 patients) with PO2 greater than 153 torr and B (7 patients) with PO2 less than 80 torr. Hemodynamic changes (less than 10% variation in baseline pulse and blood pressure) occurred in 9 of 10 patients in group 1A and all patients in Group 1B. Mean differences in pulse and blood pressure changes between these groups were not significant; therefore, pulse and blood pressure changes are not predictive of hypoxemia and hypercarbia is not necessary to induce spontaneous ventilation in patients with intact medullary function.

Mitochondrial activity in Pompe's disease.

Mitochondrial oxidative metabolism was examined in two infants with Pompe's disease. The clinical diagnosis was confirmed by the demonstration of intralysosomal glycogen accumulation and a deficiency of acid alpha-D-glucosidase in muscle biopsies. Light and electron microscopy studies demonstrated a normal number of mitochondria with normal ultrastructure. Spectrophotometric measurements revealed that the specific activities of citrate synthase and the partial reactions of electron transport were markedly elevated in the skeletal muscle homogenates prepared from both infants with Pompe's disease when calculated as micromoles per minute per gram wet weight of tissue. However, when respiratory chain enzyme activities were expressed relative to citrate synthase as a marker mitochondrial enzyme, a different pattern emerged, in which all Pompe muscle respiratory enzymes, except complex IV, were decreased relative to control subjects. These observations demonstrate that caution should be exercised when analyzing and interpreting data obtained from tissue homogenates in general and, in particular, in those prepared from tissues in which the wet weight of tissue may be altered, for example, by pathologic accumulation of carbohydrate or lipid.

Comparison of MRI and MRA findings in children with a variety of neurologic conditions.

The role of MRA in the evaluation of children is evolving. We compared MRA and MRI in children with a variety of neurologic conditions to determine when MRA provides positive, cost-beneficial information. A total of 114 patients were retrospectively studied. MRA and MRI were performed and compared. MRA was abnormal in 34 (30%) of 114 patients: five (83%) of six with Menkes' disease, four (33%) of 12 with sickle cell disease, 12 (38%) of 32 with vascular malformations, one (6%) of 17 with headaches, seven (24%) of 24 with new focal deficits, one (10%) of 10 with seizures, and four (31%) of 13 with miscellaneous diagnoses. MRA and MRI were concordant in 73 (64%) of 114. Maximum concordance was in patients with Menkes' disease (100%) and minimum in those with new focal deficits (50%). The best MRA cost/benefit ratios were obtained in patients with Menkes' disease, vascular malformations, and sickle cell disease. A normal MRI usually forecasted a normal MRA. However, abnormal MRI findings did not always predict MRA abnormalities. Positive, cost-beneficial information is provided by MRA mostly in conditions known to involve the cerebral vasculature. Indications to perform MRA should be based on the neurologic diagnosis and MRI findings.

West syndrome in tuberous sclerosis complex.

West syndrome occurs commonly in children with tuberous sclerosis complex and is associated with a grave prognosis for cognitive and seizure outcomes. We sought to determine the epilepsy outcome of children with tuberous sclerosis complex and West syndrome and whether EEG, MRI, or steroid therapy duration were different in those whose epilepsy improved compared with those with intractable seizures. Seventeen patients with tuberous sclerosis complex and West syndrome were identified. For each patient, two sets of clinical evaluations, EEG and MRI data, and treatment information separated by at least 12 months were obtained. The patients were divided into two seizure outcome groups. EEG, MRI, and treatment data were compared between the groups. The intellectual deficiency was either severe (76%) or moderate (24%). Seizure control improved in 10 and worsened in seven, without mortality (follow-up range = 12-216 months). No significant differences in EEG background, MRI findings, or steroid treatment duration were evident between the groups. The difference in EEG-sleep approached statistical significance (P = 0.06). Our findings did not confirm reports of high mortality and poor epilepsy outcome in intellectually deficient children with West syndrome and tuberous sclerosis complex. EEG sleep was the best indicator of seizure control and approached statistical significance. The duration of steroid therapy had no influence on seizure control.