Leif Gjerstad

Two different responses of hippocampal pyramidal cells to application of gamma-amino butyric acid.

1. Extra‐ and intracellular recordings were made from CA1 cells in hippocampal slices in vitro. The effects of ionophoretically applied GABA on somatic and dendritic regions were studied. 2. Ionophoresis of GABA at dendritic sites gave a reciprocal effect by inhibiting the effect of excitatory synapses close to the dendritic application, while facilitating those lying further away. For example, GABA delivered to the mid‐radiatum dendritic region reduced the population spike generated by a radiatum volley, while facilitating the population spike evoked by oriens fibre stimulation. Similarly, when single cells were recorded from, mid‐apical dendritic delivery of GABA abolished the synaptically driven discharges evoked by fibres terminating at this part of the dendritic tree, but facilitated the responses to input from fibres terminating on the basal dendrites of the same cell. 3. With intracellular recording two effects were observed. Applied near the soma, GABA induced a hyperpolarization associated with an increased membrane conductance. When applied to dendrites, GABA caused a depolarization also associated with an increased membrane conductance. Both types of GABA applications could inhibit cell discharges, although in some cases the depolarizing response could facilitate other excitatory influences or cause cell firing by itself. 4. Both the hyperpolarizing and depolarizing GABA responses persisted after blockade of synaptic transmission by applying a low calcium high magnesium solution, indicating mediation via a direct effect upon the cell membrane. 5. The reversal potential for the hyperpolarizing GABA effect was similar to the equilibrium potential for the i.p.s.p. evoked from alveus or orthodromically, and was 10‐12 mV more negative than the resting potential. The size of the depolarizing response was also dependent upon the membrane potential. By extrapolation an estimated equilibrium potential was calculated as about ‐40 mV. 6. Our results support the idea that the hyperpolarizing basket cell inhibition at the soma is mediated by the release of GABA. This hyperpolarizing response causes a general inhibition of firing. The dendritic effects of GABA, however, seem to represent another type of inhibition, which by shunting synaptic currents makes possible a selective inhibitory influence on afferents synapsing locally while facilitating more remotely placed excitatory synapses. We propose the term discriminative inhibition for this postulated new type of control of pyramidal cell discharges.

Reduced inhibition during epileptiform activity in the in vitro hippocampal slice.

1. Intracellular recordings were made from CA1 pyramidal cells in the hippocampal slice in vitro. The responses to orthodromic and antidromic activation and to ionophoretically applied GABA were studied. 2. The epileptogenic agent sodium benzyl penicillin reduced the recurrent i.p.s.p. evoked by subthreshold antidromic stimulation. Reversal potential studies of the i.p.s.p. and resistance measurements showed that this reduction was mainly due to a decrease in i.p.s.p. conductance. 3. Penicillin also reduced the conductance and associated membrane potential changes induced by ejecting GABA near the soma or into the apical dendritic region. 4. The mixed e.p.s.p.‐i.p.s.p. evoked by orthodromic stimulation was converted to a pure depolarizing potential as the i.p.s.p. was blocked. Concurrently the probability of discharge to a constant orthodromic stimulus was increased. Similar changes were seen in a low chloride solution. 5. The time course of the reduction of inhibition was similar to that of the enhanced orthodromic response seen after penicillin treatment. 6. We conclude that reduction of postsynaptic inhibition is partly responsible for the increased probability of orthodromic discharge caused by penicillin. The longer latency all‐or‐nothing burst seen in some cells, however, seems to require an additional mechanism, although reduced inhibition may facilitate the triggering of this burst.

An International Multicenter Randomized Double‐Blind Controlled Trial of Lamotrigine and Sustained‐Release Carbamazepine in the Treatment of Newly Diagnosed Epilepsy in the Elderly

Summary:  Purpose: To assess the comparative effectiveness, efficacy, and tolerability of lamotrigine (LTG) and sustained‐release carbamazepine (CBZ) in the treatment of newly diagnosed epilepsy in the elderly.

Altered ovarian function and cardiovascular risk factors in valproate-treated women.

PURPOSE Polycystic ovaries and menstrual disturbances seem to be common among women taking valproate for epilepsy. The purpose of the present study was to assess the frequency of valproate-related metabolic and endocrine disorders in different groups of women with epilepsy. SUBJECTS AND METHODS Seventy-two women with epilepsy and 52 control subjects from centers in three European countries (Finland, Norway, and the Netherlands) participated in the study. Thirty-seven of the women with epilepsy were taking valproate monotherapy and 35 carbamazepine monotherapy. RESULTS The frequency of polycystic ovaries or hyperandrogenism, or both, among valproate-treated women with epilepsy was 70% (26 of 37) compared with 19% (10 of 52) among control subjects (P <0.001). They were found in 79% (11 of 14) of obese and 65% (15 of 23) of lean women on valproate, and in 20% (7 of 35) of carbamazepine-treated women. The obese valproate-treated women with polycystic ovaries or hyperandrogenism, or both, had hyperinsulinemia and associated unfavorable changes in serum lipid levels consistent with insulin resistance. CONCLUSIONS Polycystic ovaries and related hyperandrogenism are frequently encountered in both obese and lean women taking valproate for epilepsy. The use of valproate is associated with risk factors for cardiovascular disease in obese women.

Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study

Partial epilepsies have a substantial heritability. However, the actual genetic causes are largely unknown. In contrast to many other common diseases for which genetic association-studies have successfully revealed common variants associated with disease risk, the role of common variation in partial epilepsies has not yet been explored in a well-powered study. We undertook a genome-wide association-study to identify common variants which influence risk for epilepsy shared amongst partial epilepsy syndromes, in 3445 patients and 6935 controls of European ancestry. We did not identify any genome-wide significant association. A few single nucleotide polymorphisms may warrant further investigation. We exclude common genetic variants with effect sizes above a modest 1.3 odds ratio for a single variant as contributors to genetic susceptibility shared across the partial epilepsies. We show that, at best, common genetic variation can only have a modest role in predisposition to the partial epilepsies when considered across syndromes in Europeans. The genetic architecture of the partial epilepsies is likely to be very complex, reflecting genotypic and phenotypic heterogeneity. Larger meta-analyses are required to identify variants of smaller effect sizes (odds ratio <1.3) or syndrome-specific variants. Further, our results suggest research efforts should also be directed towards identifying the multiple rare variants likely to account for at least part of the heritability of the partial epilepsies. Data emerging from genome-wide association-studies will be valuable during the next serious challenge of interpreting all the genetic variation emerging from whole-genome sequencing studies.

Consequences of antiepileptic drug withdrawal : A randomized, double-blind study (Akershus Study)

Objective: Despite side effects associated with the use of antiepileptic drugs (AEDs), withdrawal of AEDs remains controversial, even after prolonged seizure freedom. The main objective of this study was to assess the effects of AED withdrawal on cognitive functions, seizure relapse, health‐related quality of life (HRQOL), and EEG results. Additionally, potential predictors for freedom from seizures after AED withdrawal were studied.

Penicillin blocks hippocampal IPSPs, unmasking prolonged EPSPs.

The possible role of reduced synaptic inhibition in epilepsy has received increased attention recently from studies in invertebrates, where it has been demonstrated that the epileptogenic agent, penicillin, reduces inhibitory synaptic chloride conductance10,14,19. These findings complement extracellular observations made in the cat spinal cord, showing that penicillin attenuates both presynaptic inhibitionZ and postsynaptic recurrent inhibition onto motoneurons 12. Penicillin has also been shown to reduce the cortical field potentials thought to be generated by recurrent inhibitory synapses is. However, there is as yet no detailed study of the effect of penicillin on cortical inhibition, and little effort has been made to determine the importance of reduced inhibition for the development of epileptic burst discharges. We report here that in hippocampal pyramidal cells penicillin blocks the conductance increase associated with recurrent IPSPs. Concurrent with IPSP reduction, the mixed EPSP/ IPSP elicited by weak afferent stimulation is converted to a larger and prolonged depolarizing potential. In this way the firing probability to a constant orthodromic stimulus is elevated, raising the excitability of the pyramidal cell population. Abstracts of this work have been published 7,s. In addition, Wong and Prince 2° have also recently reported that penicillin blocks hippocampal IPSPs. Intracellular recordings were obtained from CA1 pyramidal cells in transverse slices of the guinea pig hippocampus maintained at 32-35 °C in vitro 17. Recording electrodes, filled with 4 M potassium acetate and having a resistance of 100-200 M[~, were visually positioned in the cell body layer. Electrolytically sharpened tungsten stimulating electrodes were placed in the stratum radiatum and in the alveus to activate neurons orthodromically and antidromically. A coarse pipette was used to apply a droplet (about one nl) of sodium benzyl penicillin (17 mM; i.e. 104 I.U./ml) to the surface of the slice. Weak electrical stimulation of the alveus could elicit a pure recurrent IPSP 2, while a slightly stronger stimulus evoked an antidromic spike. By such criteria all cells studied were judged to be pyramidal neurons 11, Stimulation of the stratum radiatum evoked synaptically driven action potentials of 55-85 mV. The

Psychiatric comorbidity and hostility in patients with psychogenic nonepileptic seizures compared with somatoform disorders and healthy controls.

Summary:  Purpose: To investigate the prevalence of psychiatric comorbidity and level of anxiety, depression, and aggression in patients with psychogenic nonepileptic seizures compared with those in patients with somatoform disorders and healthy controls.

Poststroke Epilepsy: Occurrence and Predictors—A Long‐term Prospective Controlled Study (Akershus Stroke Study)

Summary:  Purpose: The aims of the study were to assess the occurrence of poststroke epilepsy (PSE) in patients with ischemic strokes, to identify predictors, and to investigate whether treatment in a stroke unit (SU) influenced the long‐term outcomes of epilepsy.

New SCN5A mutation in a SUDEP victim with idiopathic epilepsy

Many idiopathic epilepsies have been shown to be caused by ion channel dysfunction. Channelopathies also cause the long QT syndrome (LQTS) which is associated with syncopes and sudden cardiac death. It has been postulated that the same channelopathy may be associated with both epilepsy and LQTS. We report a patient with idiopathic epilepsy who died in sudden unexpected death in epilepsy (SUDEP) at the age of 25. A post mortem DNA sequencing of the LQTS-associated genes revealed a novel missense mutation in the SCN5A gene coding for the cardiac sodium channel, voltage gated, type V, alpha subunit. The possibility that the mutation may explain both the epilepsy and the sudden death is discussed. However, the patient was treated with lamotrigine which may interfere with cardiac ion channels and may also have played a part in inducing a terminal cardiac arrhythmia.