Robert S. Greenwood

Electrically elicited seizures from the inferior colliculus: A potential site for the genesis of epilepsy?

Most electrically induced seizures involve forebrain structures, such as the amygdala or frontal cortex, but the following studies characterized a specific anatomic site in the inferior colliculus which generated seizure-like behavior after a single, low current electrical stimulation. When a bipolar electrode was implanted into the dorsomedial aspect of the inferior colliculus, low stimulation currents (120 to 200 microA, 30 Hz) produced wild running behavior which outlasted the stimulation by 4 to 10 s. This wild running behavior was directly correlated with local afterdischarge in the inferior colliculus, while no changes were found in the EEG activity in the cortex or hippocampus. Though the threshold current necessary to invoke the wild running seizures remained stable for long periods of time, the presentation of two stimulations a day for 2 weeks caused a progressive increase in the duration of poststimulus wild running. In the last days of the chronic stimulations, some forelimb tonus or myoclonic jerks followed the wild running seizures. These latter behaviors were correlated with local afterdischarges at the electrode tips in the inferior colliculus and spiking EEG activity in the frontal cortex. Pharmacologically, haloperidol, phenobarbital, carbamazepine, and ethosuximide proved ineffective in attenuating the seizures, whereas phenytoin, sodium valproate, and chlordiazepoxide attenuated the seizures. These findings are discussed in relation to the genesis of epilepsy in humans.

l‐Carnitine Supplementation in Childhood Epilepsy: Current Perspectives

Summary: In November 1996, a panel of pediatric neurologists met to update the consensus statement issued in 1989 by a panel of neurologists and metabolic experts on L‐carnitine supplementation in childhood epilepsy. The panelists agreed that intravenous L‐carnitine supplementation is clearly indicated for valproate (VPA)‐induced hepatotoxicity, overdose, and other acute metabolic crises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L‐carnitine supplementation is strongly suggested for the following groups as well: patients with certain secondary carnitine‐deficiency syndromes, symptomatic VPA‐associated hyperammonemia, multiple risk factors for VPA hepatotoxicity, or renal‐associated syndromes; infants and young children taking VPA; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parenteral nutrition. The panel recommended an oral L‐carnitine dosage of 100 mg/kg/day, up to a maximum of 2 g/day. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage.

Quantitative mapping of glutamate presynaptic terminals in the supraoptic nucleus and surrounding hypothalamus

Although the hypothalamus is generally regarded to have low levels of glutamate receptors, anatomical and physiological studies have provided consistent evidence implicating glutamate as a potential transmitter for the control of neuroendocrine cell activity. To clarify the extent of the contribution of synapses utilizing glutamate for control of vasopressin/oxytocin neuroendocrine cells, we mapped the density and location of glutamate immunoreactive terminals in the supraoptic nucleus and surrounding hypothalamus. Colloidal gold particle densities in presynaptic terminals were measured from electron micrographs of: (1) the magnocellular neuroendocrine cell perikarya (main body of the supraoptic nucleus), (2) the dendritic field of the magnocellular neuroendocrine cells (ventral dendritic neuropil) and (3) the hypothalamic perinuclear zone dorsal to the supraoptic nucleus. In addition, serial sections were stained, alternatively, for glutamate or GABA to determine glutamate staining in GABA cells. Terminals with high glutamate immunoreactivity were clearly distinguished from the glutamate precursor staining found in GABA terminals and were abundant at all rostral-caudal levels within each region. The number of glutamate terminals identified in each region was similar but represented a very high proportion of all terminals in the ventral dendritic neuropil (38%) vs. the main body of the supraoptic nucleus and the perinuclear zone (20-22%). The regional variation in the relative proportion of glutamate terminals was determined largely by differences in the number of non-glutamate terminals within each region. Glutamate and GABA terminals together accounted for over two-thirds of the innervation of vasopressin/oxytocin neuroendocrine cells. No systematic relationship was observed between excitatory and inhibitory inputs on the same cell. These results suggest that glutamate is the predominant excitatory transmitter used for control of vasopressin/oxytocin cells. The relative contribution of glutamate neurotransmission to a particular region will depend, in part, on the number and type of competing non-glutamate terminals.

Adverse effects of antiepileptic drugs.

Summary: Because the efficacies of antiepileptic drugs (AEDs) are often equivalent, selection of an AED is often determined by adverse effects. Differences in methods for labeling adverse effects and in the adverse effect terms themselves, variations in the populations studied, and inconsistent classifications of adverse effects make it difficult to know how to use information on adverse effects to choose an AED. Effort is underway to develop more extensive and internationally acceptable descriptive terms for adverse effects. Comparison of adverse effects in patients taking AEDs with adverse events in control groups is helpful; however, data from controlled studies are often lacking for most AEDs. Because of these limitations, the clinician must adopt a preventative and early detection approach based on some general principles. This review outlines factors to consider for avoiding and detecting AED adverse effects. The occurrence of weight change with AEDs is reviewed extensively, serving to illustrate how the principle factors can be used to avoid and manage adverse effects and where there is need for better studies of the short‐ and long‐term adverse effects of AEDs.

Discontinuing Antiepileptic Drugs in Children with Epilepsy: A Comparison of a Six-Week and a Nine-Month Taper Period

BACKGROUND The optimal regimen for discontinuing antiepileptic medications in children with epilepsy is unknown. METHODS We randomly assigned 149 children to either a six-week or a nine-month period of drug tapering, after which therapy was discontinued. Each group was composed of patients who had been seizure-free for either two or four years before drug tapering was begun. Most patients were receiving one antiepileptic drug; none were taking more than two. The children were evaluated periodically during and after the taper period. Sixteen patients were lost to follow-up before the beginning of the taper period. Proportional-hazards regression analysis was used to assess the risk of seizure recurrence among the remaining 133 patients. RESULTS Seizures recurred in 53 patients (40 percent). The mean duration of follow-up was 39 months (range, 11 to 105) for the patients who did not have a recurrence of seizures. Neither the length of the taper period (six weeks vs. nine months, P = 0.38) nor the length of time the patients were free of seizures before the taper period was begun (two years vs. four years, P = 0.20) significantly influenced the risk of seizure recurrence. The presence of mental retardation (relative risk, 3.1, 95 percent confidence interval, 1.5 to 6.2) or spikes in the electroencephalogram at the time of tapering (relative risk, 1.9, 95 percent confidence interval, 1.0 to 3.4) increased the risk of seizure recurrence. CONCLUSIONS The risk of seizure recurrence during drug tapering and after the discontinuation of antiepileptic drug therapy in children with epilepsy is not different whether the medications are tapered over a six-week or a nine-month period.

Movement disorder after withdrawal of fentanyl infusion

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Outcome in children with fetal mild ventriculomegaly : a case series

Mild enlargement of the lateral ventricles is associated with schizophrenia and other neurodevelopmental disorders. While it has been hypothesized that ventricle abnormalities associated with neurodevelopmental disorders arise during fetal brain development, there is little direct evidence to support this hypothesis. Using ultrasound, it is possible to image the fetal ventricles in utero. Fetal mild ventriculomegaly (MVM) has been associated with developmental delays in early childhood, though longer-term neurodevelopmental outcome has not been studied. Follow-up of five children (aged 4--9 years) with mild enlargement of the lateral ventricles on prenatal ultrasound and two unaffected co-twins is reported: one child had attention deficit hyperactivity disorder (ADHD), one had autism, and two had evidence of learning disorders. These cases suggest that the mild enlargement of the lateral ventricles associated with these neurodevelopmental disorders arises during fetal brain development and can be detected with prenatal ultrasound. In addition, the presence of mildly enlarged, asymmetric ventricles in two children on prenatal ultrasound and on follow-up MRI at age 6 years indicates that ventricle structure present in utero can persist well into childhood brain development. The study of fetal ventricle development with ultrasound may provide important insights into neurodevelopmental disorders and allow the identification of children at high risk.

Inferior Collicular Interactions with Limbic Seizure Activity

Summary: : Because under certain conditions, seizure activity electrically elicited from layers III and IV of the inferior collicular cortex can spread into forebrain regions, potential inferior collicular interactions with the amygdala were studied. Following acute electrical initiation of seizure activity from the inferior colliculus, no changes in amygdala EEG activity were noted. Following repetitive stimulation of the inferior colliculus, however, postictal spiking activity was noted in the amygdala, similar to interictal spiking reported for amygdala kindling, but this abnormal EEG activity did not coincide with any observable behavioral change. Conversely, the course of amygdala kindling in animals previously stimulated in the inferior colliculus progressed quite differently in comparison to control animals. Those animals repetitively stimulated in the inferior colliculus required a significantly greater number of amygdala kindling stimulations to reach class 5 seizure activity than did animals that received no inferior collicular stimulation and, unlike the controls, the chronic inferior collicular stimulation group usually regressed to class 2 or 3 seizure activity after the first class 5 seizure. Furthermore, the chronic inferior collicular stimulation group all exhibited wet‐dog shakes during the amygdaloid kindling stimulation, whereas at no time did controls exhibit wet‐dog shake behaviors. Finally, the seizure generalization from the inferior colliculus appears to be mediated by a mechanism distinct from the acute seizure activity, because a dose of diazepam (0.4 mg/kg), or carbamazepine (10 mg/kg), which had no effect on the wild running seizure, blocked behaviors indicative of seizure generalization. The significance of these results to epilepsy is discussed.

MRI morphometric analysis and neuropsychological function in patients with neurofibromatosis.

Volumes of cerebral gray and white matter were measured in 22 children with neurofibromatosis type 1 (NF1) and in 20 controls. Judgment of Line Orientation (JLO) and the Developmental Test of Visual-Motor Integration (DTVMI) were administered to 16 of the NF1 patients. General linear models analysis of covariance revealed significantly larger brain volumes in NF1 children than in controls, particularly in white matter, and particularly in girls. JLO and DTVMI performance were positively related to right-hemisphere gray-matter volume. The results implicate a failure of growth control in NF1, leading to aberrant neurodevelopment. Our findings also suggest a basis for refined understanding of learning disabilities, which are a prominent feature of NF1.

Möbius syndrome in infant exposed to cocaine in utero

The pathophysiology of Möbius syndrome has been debated for decades. A vascular etiology is currently favored because it explains the wide clinical spectrum of this syndrome. An infant is reported who was born with Möbius syndrome after a pregnancy complicated by heavy maternal use of cocaine and alcohol. We speculate that cocaine-induced vasoconstriction at a critical time of cerebrovascular development produced a vascular disruption sequence leading to the Möbius syndrome.