In vivo 1H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (NKH) is an autosomal recessive disorder of glycine metabolism. Defective glycine cleavage causes elevated concentrations of glycine in plasma, urine, and cerebrospinal fluid. A longitudinal study using magnetic resonance imaging (MRI) and single-voxel 1H magnetic resonance spectroscopy (MRS) was performed on an infant with the typical clinical picture of NKH. He was examined twice during the course of treatment with sodium benzoate and dextromethorphan. At the age of 10 months, MRI showed normal brain structure, while MRS detected a prominent glycine peak in the brain. Repeat MRS at the age of 13 months showed a small increase in glycine peak and a prominent glutamate/glutamine peak not previously detected. The MRS measurements were consistent with the slight increase in blood glycine level and the elevation in glutamine level, indicating that 1HMRS can be a valuable tool in the diagnosis and monitoring of treatment effects in patients with NKH.

Symptoms of depression and anxiety in pediatric epilepsy patients.

PURPOSE: We assessed rates of symptoms of anxiety and depression among pediatric patients with epilepsy. METHODS: We administered the Revised Child Manifest Anxiety Scale (RCMAS), and Child Depression Inventory (CDI) to 44 epilepsy patients aged 7-18 years (mean age 12.4 years). Demographic, socioeconomic, and epilepsy-related information was examined in relation to depression and anxiety scores. RESULTS: No patients had been previously identified to have depression or anxiety. However, 26% had significantly increased depression scores and 16% met criteria for significant anxiety symptomatology. CONCLUSIONS: Symptoms of depression and anxiety are common among pediatric patients with epilepsy and appear to be overlooked by care providers.

Differential spatiotemporal expression of K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro.

Hippocampal neurons are highly plastic in their excitable properties, both during development and in the adult brain. As voltage-sensitive K+ channels are major determinants of membrane excitability, one mechanism for generating plasticity is through regulation of K+ channel activity. To gain insights into the regulation of K+ channels in the hippocampus, we have analyzed the spatiotemporal expression patterns of five K+ channel polypeptides in rat hippocampal neurons developing in situ and in vitro. Delayed rectifier-type channels (Kv1.5, Kv2.1, and Kv2.2) are expressed on all neuronal somata and proximal dendrites, while A-type channels (Kv1.4 and Kv4.2) are present distally on distinct subpopulations of neurons. The development of these patterns in situ is monotonic; that is, while the time and spatial development varies among the channels, each K+ channel subtype initially appears in its adult pattern, suggesting that the mechanisms underlying spatial patterning operate through development. Immunoblots confirm the differential temporal expression of K+ channels in the developing hippocampus, and demonstrate developmentally regulated changes in the microheterogeneity of some K+ channel polypeptide species. Temporal expression patterns of all five K+ channels observed in situ are retained in vitro, while certain aspects of cellular and subcellular localization are altered for some of the K+ channel polypeptides studied. Similarities in K+ channel polypeptide expression in situ and in vitro indicate that the same regulatory mechanisms are controlling spatiotemporal patterning in both situations. However, differences between levels of expression for all subtypes studied except Kv2.1 indicate additional mechanisms operating in situ but absent in vitro that are important in determining polypeptide abundance.

TrkA expression in the CNS: evidence for the existence of several novel NGF-responsive CNS neurons.

NGF acts as a neurotrophic factor by binding and activating its receptor on certain neuronal populations in the CNS and PNS. TrkA is a receptor for NGF. Recent findings in vitro indicate that this NGF-activated receptor tyrosine kinase transduces the NGF signal. To further define NGF actions in the CNS, we examined trkA expression in the adult rat brain. We found that trkA mRNA and immunoreactivity (IR) coincided in specific, defined neuronal populations in the forebrain and brainstem. In addition to cholinergic neurons in the basal forebrain and neostriatum, trkA expression was found in noncholinergic neurons in (1) the paraventricular anterior and reuniens thalamic nuclei, (2) the rostral and intermediate subnuclei of the interpeduncular nucleus (IPN), (3) scattered neurons in the ventrolateral and paramedian medulla, (4) the prepositus hypoglossal nucleus, and (5) the area postrema. NGF responsiveness was demonstrated for each of these populations. In contrast to trkA, p75NGFR was found only in a minority of NGF-responsive populations. Our data provide further evidence that expression of trkA marks NGF-responsive CNS neurons and suggests novel roles for NGF in the brain.

Dopaminergic regulation of a transfected preproenkephalin promoter in primary rat astrocytes in vitro and in vivo.

The clinical benefit of transplantation therapies utilizing genetically modified cells could be enhanced if expression of engineered genes was regulated by clinically useful pharmacological agents. Toward this end, we examined pharmacologic effects on the expression of hybrid gene constructs transfected into primary rat striatal astrocytes. These astrocytes are known to express receptors for the neurotransmitter dopamine (DA). In vitro, we found that expression of a transiently transfected human ppEnk promoter-driven chloramphenicol acetyltransferase (CAT) reporter construct was induced by DAergic agonists, as much as 20-fold. This induction was blocked by a DA receptor antagonist. The same concentration of DA also increased the endogenous rat ppEnk mRNA, by > 2-fold. In vivo, regulation of CAT expression by DA was tested by implanting the genetically modified astrocytes into the normal striatum and the contralateral striatum which had > 95% DA depletion induced by a previous 6-hydroxy-DA lesion of the substantia nigra. As hypothesized on the basis of the in vitro data, CAT activity on the lesioned side, where the stimulating effect of endogenous DA was lacking, was 30% lower than on the control side where the normal DA content was present. The data suggest that control of the enkephalin gene in astrocytes may involve second messenger pathways activated by DA receptors. Moreover, the evidence that clinically applicable drugs can regulate inducible genes introduced into the brain by astrocyte implantation is of potential importance in development of therapeutic strategies.

Chronic paroxysmal hemicrania in a young child: possible relation to ipsilateral occipital infarction.

We report a child with chronic paroxysmal hemicrania beginning at 3 years of age with more than 2 years of daily episodes. Indomethacin produced total relief. An ipsilateral, occipital hemorrhagic infarction, probably predating the headaches, may have contributed to their pathogenesis. This is an unusually early onset and persistent chronic paroxysmal hemicrania of possible symptomatic type.

Clinical utility of unbound antiepileptic drug blood levels in the management of epilepsy.

We tabulated all unbound and total antiepileptic blood levels collected in 13 months. According to strict criteria, 24% of phenytoin and 15% of valproate unbound blood levels but none of the carbamazepine unbound levels had clinical significance in the management of seizures or side effects. These data support frequent use of unbound phenytoin or valproate blood levels in the management of epilepsy.

Fatal hepatocerebral syndrome in siblings discordant for exposure to valproate.

Occurrence of a progressive encephalopathy with seizures in siblings was associated with hepatic pathology. One of these patients was exposed to valproate (VPA) and developed hepatic necrosis, confirmed at autopsy. The other had not been exposed to VPA, and her hepatic lesions at autopsy were less severe. The liver pathology in both was within the range described in previous cases of liver disease attributed to VPA. These facts and the otherwise similar course of their disease suggests that in these patients, and probably in other cases of fatal liver failure attributed to VPA, the drug actually either had no effect or acted only to increase the severity of the preexisting hepatic component of the hepatocerebral disorder.

Regulation of the redox potential of general acyl-CoA dehydrogenase by substrate binding.

Significant thermodynamic changes have been observed for general acyl-CoA dehydrogenase (GAD) upon substrate binding. Spectroelectrochemical studies of GAD and several of its substrates have revealed that these substrates are essentially isopotential for chain lengths of C-4 to C-16 (E 0' =-0.038 to -0.045 V vs SHE). When GAD is bound by these substrates, a dramatic shift in the midpoint potential of the enzyme is observed (E 0' = -0.136 V for ligand-free GAD and -0.026 V for acyl-CoA-bound GAD), thus allowing a thermodynamically favorable transfer of electrons from substrate to enzyme. This contrasts with values reported elsewhere. From these data an isopotential scheme of electron delivery into the electron-transport chain is proposed.

Hemicholinium-3 binding sites in subnuclei of the rat interpeduncular nucleus: quantitative in vitro autoradiography.

The interpeduncular nucleus (IPN) receives dense cholinergic input from the medial habenulae (MH) via the fasciculus retroflexus (FR). This projection is known to terminate in the rostral, central and intermediate subnuclei. Correspondingly, the concentration of hemicholinium-3 (HC-3) binding sites in these subnuclei was equal to or greater than that reported in any other brain areas. Moderate values in the distal FR and in the lateral subnuclei indicate that choline uptake sites are located on nonterminal portions of MH afferent axons as well. Possible relationships of HC-3 binding to the unusual metabolic properties of FR and IPN, and to the distribution of choline acetyltransferase-containing axons and terminals in FR and IPN are suggested.

The hippocampus in experimental chronic epilepsy: a morphometric analysis.

The effect of intermittent seizures on the pyramidal neurons of the hippocampus is largely unknown. To determine whether recurrent seizures centered in the hippocampus can produce neuronal loss in this region, a morphometric analysis was performed from standardized sections of hippocampus using 5 groups of animals: (1) surgical control subjects, (2) rats kindled by the rapidly recurring hippocampal seizure (RRHS) paradigm, (3) kindled rats with a few additional limbic seizures (528 +/- 66 seizures), (4) kindled rats with many limbic seizures (1,523 +/- 130 seizures), and (5) rats experiencing limbic status epilepticus (SE) induced by "continuous" hippocampal stimulation. The RRHS and SE protocols induced significant neuronal loss in the CA1 region, but no evidence was found for additional cell loss with increasing numbers of intermittent seizures. These intermittent seizures were, however, associated with a significant thickening of the basal and apical dendritic fields of the CA1 region. These findings indicate that intermittent seizures produce no significant hippocampal neuronal loss and may result in a hypertrophy of CA1 dendritic fields.

Facial sparing as a feature of prenatal-onset hemiparesis.

The presence of facial weakness was prospectively correlated with age of onset of hemiparesis. Facial weakness was not associated with prenatal-onset hemiparesis, but sometimes occurred with onset of hemiparesis during the first year of life. In contrast, facial weakness was generally present when all patients with postnatal-onset hemiparesis were considered as a group. With double hemiparesis, facial weakness was common, regardless of age at onset. These findings suggest that facial sparing results from plasticity of the developing corticobulbar tract, the critical period ending during the first year of life. Decreased synapse elimination of uninjured, ipsilateral terminals is suggested as the mechanism of facial sparing. Facial weakness accompanying double hemiparesis thus would be a reflection of absence of an uninjured pathway.

Postinfectious encephalomyelitis with localized basal ganglia involvement.

The diagnosis of postinfectious encephalomyelitis with symmetric lesions in the basal ganglia was confirmed by magnetic resonance imaging in 2 patients. A 7-year-old patient experienced severe dystonia and hyperreflexia; magnetic resonance imaging demonstrated bilateral lesions in the putamina and basis pontes. The other patient, a 2-year-old female, manifested hypotonia, facial grimacing, and athetosis. Symmetric lesions in the globus pallidus and substantia nigra were demonstrated by imaging studies. The nature and monophasic course of illness in these 2 patients, as well as the symmetric involvement of specific regions of the basal ganglia, may result from an immune-mediated postinfectious demyelinating process.

Plasmapheresis associated with a relapsing course in Guillain-Barré syndrome.

An 11-year-old boy with severe Guillain-Barré syndrome underwent 2 courses of 5 plasmaphereses. During each course his strength and respiratory function improved. Within 3 days of completing each course, his deficits worsened. After a prolonged plateau following the second course of plasmapheresis, he spontaneously improved and continues to recover gradually 11 months following the onset of symptoms. Plasmapheresis appeared to produce a fluctuating course in our patient. Prior to the availability of effective therapeutic intervention for Guillain-Barré syndrome, a natural course, characterized by recurrence of symptoms, predicted poorer recovery. Fluctuations related to plasmapheresis may not carry similar implications; the clinician should consider this phenomenon in assessing prognosis.

Modification of left-right pairing during the development of individual crest synapses in the rat interpeduncular nucleus.

The synaptic organization of the rat interpeduncular nucleus is highly ordered in the normal adult. By 90 days of age, 90% of crest synapses in its intermediate subnuclei are formed by two cholinergic endings, one from each medial habenula. Stereological calculation of the number of crest synapses per intermediate subnucleus, based on total samples of crest synapses in 3-4 sections through the subnucleus, allows comparisons of afferent pairing among ages without interference by other developmental changes. Between 21 and 90 days of age, the total number of crest synapses per intermediate subnucleus increases tenfold (p less than 10(-8], from 90,000 at 21 days of age, through 130,000 at 28 days, 440,000 at 45 days, to 1,000,000 at 90 days. The volume of the intermediate subnucleus increases fivefold during the same interval. Electron microscopic degeneration was used to estimate the pairing of left and right habenula afferents at crest synapses at the same ages. Through 21 days of age, only one-third of crest synapses are formed with pairing of one left and one right medial habenula afferent, whereas two-third have both afferent endings arising from the same medial habenula. At 28 days of age left-right pairing has increased to 43%, and at 45 days of age 53%, or 240,000, are so paired. The number of same-side paired crest synapses at 45 days, 210,000, is 3.5 times the number so paired at 21 days (p = .003). This indicates continued formation of considerable numbers of crest synapses with this transient mode of airing as late as 45 days of age.(ABSTRACT TRUNCATED AT 250 WORDS)