Placebo-corrected efficacy of modern nonenzyme-inducing AEDs for refractory focal epilepsy: systematic review and meta-analysis.

PURPOSE: Given serious concerns over the adverse effects of enzyme induction, modern nonenzyme-inducing antiepileptic drugs (AEDs) may be preferable, provided they have similar efficacy as enzyme-inducing AEDs. This is currently unclear. METHODS: Therefore, we performed a meta-analysis of the evidence to determine the placebo-corrected efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs versus modern enzyme-inducing AEDs that are on the market for refractory focal epilepsy. KEY FINDINGS: Of 322 potentially eligible articles reviewed in full text, 129 (40%) fulfilled eligibility criteria. After excluding 92 publications, 37 studies dealing with a total of 9,860 patients with refractory focal epilepsy form the basis for the evidence. The overall weighted pooled-risk ratio (RR) in favor of enzyme-inducing AEDs over placebo was 2.37 (95% confidence interval [CI] 1.77-3.18, p < 0.001) for at least 50% seizure reduction and 4.45 (2.26-8.76, p < 0.001) for seizure freedom. The corresponding weighted pooled RR in favor of nonenzyme-inducing AEDs over placebo was 2.28 (95% CI 2.03-2.57, p < 0.001) for at least 50% seizure reduction and 3.23 (95% CI 2.23-4.67, p < 0.001) for seizure freedom. In a meta-regression analysis in the same sample with at least 50% seizure reduction as outcome, the ratio of RRs for enzyme-inducing AEDs (eight studies) versus nonenzyme-inducing AEDs (29 studies) was 1.01 (95% CI 0.77-1.34, p = 0.92)). Similarly, the ratio of RRs for a seizure-free outcome for enzyme-inducing AEDs (six studies) versus nonenzyme-inducing AEDs (19 studies) was 1.38 (95% CI 0.60-3.16, p = 0.43). SIGNIFICANCE: Although the presence of moderate heterogeneity may reduce the validity of the results and limit generalizations from the findings, we conclude that the efficacy of adjunctive treatment with modern nonenzyme-inducing AEDs is similar to that of enzyme-inducing AEDs. Given the negative consequences of enzyme induction, our data suggest that nonenzyme-inducing AEDs may be useful alternatives to enzyme-inducing AEDs for treatment of refractory focal epilepsy.

Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.

Febrile seizures (FS) and temporal lobe epilepsy (TLE) were found in four of the seven siblings born to healthy Moroccan consanguineous parents. We hypothesized autosomal recessive (AR) inheritance. Combined linkage analysis and autozygosity mapping of a genome-wide single nucleotide polymorphism genotyping identified a unique identical by descent (IBD) locus of 9.6 Mb on human chromosome 8q12.1-q13.2. Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6). Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients. Structural modeling of CPA6 indicated that both mutations are located near the enzyme's active site. In contrast to wild-type CPA6, which is secreted and binds to the extracellular matrix where it is enzymatically active, Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix. This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.

Alterations of phosphatidylinositol 3-kinase pathway components in epilepsy-associated glioneuronal lesions.

Low-grade glioneuronal lesions involving tumors such as gangliogliomas and focal cortical dysplasias (FCD) predispose individuals to pharmacoresistant epilepsy. A frequent variant of FCD is composed of dysplastic cytomegalic neurons and Taylor-type balloon cells (FCD(IIb)). Those are similar to cellular elements, which are present in cortical tubers in the autosomal dominant inherited tuberous sclerosis complex (TSC). This phacomatosis is caused by mutations in the TSC1 or TSC2 genes. Recent data have indicated accumulation of distinct allelic variants of TSC1 also in FCD(IIb). TSC1 represents a key factor in the phosphatidylinositol 3-kinase (PI3K) pathway. A variety of alterations in the PI3K-pathway have been recently reported in epilepsy-associated glioneuronal malformations. Here, we discuss pathogenetic similarities and differences between cortical dysplasias as well epilepsy-associated glioneuronal tumors and TSC-associated cortical tubers with a focus on PI3K-pathway components including ezrin, radixin and moesin (ERM), which represent downstream effectors involved in cytoskeleton-membrane interference. No evidence has been found for mutational events of ERM genes to play a major pathogenetic role in epilepsy-associated glioneuronal malformations. In contrast, aberrant expression of ERM proteins in FCDs and gangliogliomas was observed. These alterations may relate to compromised interactions of dysplastic cellular components in epilepsy-associated glioneuronal lesions and be involved in aberrant PI3K-pathway signaling in epilepsy-associated malformations. However, the underlying cause of PI3K-pathway activation and the functional relationship of PI3K-pathway activity to generation of seizures in epilepsy-associated glioneuronal lesions will need to be determined in the future.

Serum neuron-specific enolase, prolactin, and creatine kinase after epileptic and psychogenic non-epileptic seizures.

PURPOSE: To evaluate the discriminative power of serial, simultaneous determinations of serum neuron-specific enolase (NSE), prolactin (PRL) and creatine kinase (CK) in differentiating psychogenic non-epileptic seizures (PNES) from epileptic seizures (ES). METHODS: Prospective measurement of the three markers after 44 single seizures (32 ES and 12 PNES) during continuous video-EEG monitoring at seven different sampling points. RESULTS: Patients with ES had a significantly greater increase in PRL at 10, 20, 30 min, 1 and 6 h. The sensitivity for elevated NSE and CK was low. PRL showed a higher sensitivity. However, the corresponding positive predictive value was lower than in CK and NSE. Additionally, PRL had the lowest specificity of all parameters. CONCLUSIONS: The limited discriminative power of PRL, CK, and NSE calls into question if these markers are helpful in differentiating PNES and ES.

Valproic acid blood genomic expression patterns in children with epilepsy - a pilot study.

OBJECTIVE: Valproic acid (VPA) is a commonly used anticonvulsant with multiple systemic effects. The purpose of this pilot study is to examine the blood genomic expression pattern associated with VPA therapy in general and secondly VPA efficacy in children with epilepsy. MATERIALS AND METHODS: Using oligonucleotide microarrays, gene expression in whole blood was assessed in pediatric epilepsy patients following treatment with VPA compared with children with epilepsy prior to initiation of anticonvulsant therapy (drug free patients). RESULTS: The expression of 461 genes was altered in VPA patients (n = 11) compared with drug free patients (n = 7), among which a significant number of serine threonine kinases were down-regulated. Expression patterns in children seizure free on VPA therapy (n = 8) demonstrated 434 up-regulated genes, many in mitochondria, compared with VPA children with continuing seizures (n = 3) and drug free seizure patients (n = 7). CONCLUSION: VPA therapy is associated with two significant and unique blood gene expression patterns: chronic VPA monotherapy in general and a separate blood genomic profile correlated with seizure freedom. These expression patterns provide new insight into previously undetected mechanisms of VPA anticonvulsant activity.

Kinetics of serum neuron-specific enolase and prolactin in patients after single epileptic seizures.

PURPOSE: To investigate and compare the temporal profile of serial levels of neuron-specific enolase (NSE) and prolactin in serum from patients after single epileptic seizures. METHODS: Measurement of NSE and prolactin by sensitive immunoassays in 21 patients with complex partial seizure (CPSs: n = 11) and secondarily generalized tonic-clonic seizures (SGTCSs; n = 10) during continuous video-EEG monitoring at four different time points (1, 3, 6, and 24 h after ictal event). Statistical analysis was performed by using a repeated-measures analysis of variance (ANOVA) model. RESULTS: Mean+/-SD values for NSE levels (ng/ml) were 12.5 +/-4.4 (1 h), 10.8+/-3.8 (3 h), 11.1+/-4.9 (6 h), and 8.2+/-1.9 (24 h). The corresponding prolactin levels (mU/L) were 1,311+/-1,034, 232+/-158, 237+/-175, and 251+/-98. There was a significant decrease of NSE and prolactin levels over time (p < 0.001). The pair-wise comparison of NSE levels showed significant differences between the time points 1 vs. 24 h (p < 0.001), 3 vs. 24 h (p = 0.007), and 6 vs. 24 h (p = 0.009). In contrast, serum prolactin levels showed a significant difference between 1 vs. 3 h (p < 0.001) only. Most of the NSE levels remained normal after CPSs and SGTCSs. At 1 h after the seizure, only 33% of the subjects had increased NSE, whereas abnormal prolactin levels occurred with a sensitivity of 80%. CONCLUSIONS: In contrast to prolactin, serum NSE is not a sensitive marker of individual seizures. Only some individuals showed an increase of NSE beyond the prolactin-sensitive time frame after a single seizure, and mean NSE levels were not significantly increased compared with those of normal controls.

GABAA alpha 2 mRNA levels are decreased following induction of spontaneous epileptiform discharges in hippocampal-entorhinal cortical slices.

Exposure of hippocampal slices to Mg2+ free media (0 Mg) has been shown to trigger full production of stimulus-induced seizure activity after restoration of physiological conditions [1]. In the present study employing hippocampal entorhinal cortical slices (HEC), spontaneous epileptiform discharges (SEDs) were induced using 0 Mg treatment following the return of the slices to physiological conditions. To evaluate the effect of sustained epileptiform activity on gene expression in this HEC slice preparation, changes in mRNA levels of the GABAA alpha 1 and alpha 2 and beta CaM Kinase II subunits were measured using in situ hybridization. HEC slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) in the presence or absence of Mg2+ for 3 h, then placed in oxygenated ACSF containing Mg2+ for up to 3 h. Control slices were maintained in Mg2+ containing ACSF for up to 6 h. Recurrent SEDs were observed in 0 Mg pre-treated slices while no epileptiform discharges were seen in control slices. Following induction of SEDs by 0 Mg pre-treatment, a significant decrease in mRNA encoding GABAA alpha 2 was found in the CA1, CA2, CA3 and dentate gyrus (DG) regions of the hippocampus for up to 3 h after treatment. Levels of mRNA for GABAA alpha 1 and beta CaM Kinase II were not affected. The results document a decrease in GABAA alpha 2 gene expression following the induction of SEDs in the HEC slice preparation and suggest that rapid changes in neuronal gene expression may contribute to long lasting excitability changes associated with the induction of epilepsy.

A comparative study of serum F protein and other liver function tests as an index of hepatocellular damage in epileptic patients.

Gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) may not be sensitive indicators of hepatocellular damage in patients taking anticonvulsant drugs as raised levels may only reflect enzyme induction. Aspartate aminotransferase (AST) is a specific, but relatively insensitive marker of liver damage and has a poor correlation with liver histology. Serum F protein is found in high concentration in the liver and levels are not influenced by enzyme induction. We measured serum F protein levels in patients taking carbamazepine (CBZ) and phenytoin (PHT) as monotherapy and in patients receiving multiple drugs. We compared the results with patients taking sodium valproate (VPA). Serum F protein levels were elevated in 6%, 22% and 13% of patients receiving CBZ, PHT and VPA, respectively. Raised GGT levels were reported for both the CBZ (26%) and PHT (78%) groups. Raised ALP levels were observed in 16%, 25% and 4% of the CBZ, PHT and VPA groups, respectively. Raised levels of serum F protein in the VPA group and the absence of any associated increases in either GGT or AST may further support the suggestion that serum F protein is an indicator of hepatocellular dysfunction associated with anticonvulsant therapy. However, further correlation with liver histology is required.

Contribution of Na+,K(+)-ATPase to focal epilepsy: a brief review.

The authors review some of their experimental data on the contribution of Na(+)- and K(+)-dependent adenosine triphosphatase (Na+,K(+)-ATPase) to focal epilepsy. It has been previously demonstrated that high extracellular K+ concentration increases glial Na+,K(+)-ATPase specific activities in normal conditions while this was not observed in neuronal preparations. At this time, it was hypothesized that this molecular mechanism could play a role in removing K+ released in the extracellular space during neuronal firing. These results have therefore been investigated in acute and chronic epileptogenic lesions of cats with freeze lesion. It was demonstrated that within the primary (F) and the secondary or 'mirror' (M) focus the K+ activation of the glial Na+,K(+)-ATPase dramatically decreased compared to both control animals (C) and the perifocal (PF) non epileptogenic area. Similar results were observed in man when using specimens of anterolateral temporal neocortex obtained during temporal lobectomies in patients with intractable temporal lobe epilepsy, compared with postmortem human specimens or control brain tissues. The modifications of the level of phosphorylation of partially purified Na+,K(+)-ATPase was also investigated in the epileptic cortex in these two experimental conditions. The catalytic subunits were resolved by sodium dodecylsulfate (SDS) gel electrophoresis and their phosphorylation levels were measured in the presence of various concentrations of K+ ions which dephosphorylate the catalytic subunit. K(+)-induced dephosphorylation was decreased in primary and secondary foci of acutely lesioned cats. Those alterations, due to a decreased affinity for K+, were limited to the alpha (-) subunit. In cats with chronic lesions, the dephosphorylating step of the Na+,K+-ATPase catalytic subunit recovered to normal affinity for K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphorylation of brain (Na+,K+)-ATPase alpha catalytic subunits in normal and epileptic cerebral cortex: II. Partial seizures in human epilepsy.

We examined the activity and phosphorylation level of (Na+,K+)-ATPase (E.C. 3.6.1.3) partially purified from normal and epileptic human cortices. Control patients (n = 11) were operated on for a non-epileptogenic deep brain lesion, while epileptic patients (n = 10) were operated on for temporal or frontal originating partial seizures, resistant to medications or secondary to evolutive brain tumors. No differences in the specific activity of microsomal (Na+,K+)-ATPase were observed between the two groups of patients. After partial purification of the enzyme followed by SDS-polyacrylamide gel electrophoresis, (Na+,K+)-ATPase catalytic subunit had a decreased affinity for K+ in human epileptic cortex and lost its sensitivity to phenytoin dephosphorylation. Indirect evidence suggests that those abnormalities of (Na+,K+)-ATPase in human epileptic cortex hold preferentially true for the alpha(-) enzymatic subunit. Those results indicate that, in human epileptic cortex, (Na+,K+)-ATPase and most probably its glial subtype is altered in its K+ regulation and phenytoin sensitivity and could be responsible for ictal transformation and seizure spread.

Synaptosomal ATPase activities in temporal cortex and hippocampal formation of humans with focal epilepsy.

Intact nerve endings (synaptosomes) have been isolated from spiking and non-spiking temporal cortex and hippocampus samples from 14 patients immediately after temporal lobectomy for intractable epilepsy. Synaptosomes were also prepared from frozen brain samples of humans with no known neurological diseases. Four adenosine triphosphatase (ATP)-metabolizing enzymes (ecto-ATPase, ecto-adenylate kinase, Na+,K(+)-ATPase and Ca2+,Mg2(+)-ATPase) were assayed in the synaptosomal fractions from the most spiking temporal cortex area (including focus) as well as from various regions of the hippocampus, and compared with enzyme activities of the least spiking or non-spiking temporal cortex of the same patient. Enzyme activities of the epileptic brain samples were also compared with values measured in the corresponding regions of normal brains. Ecto-ATPase activities of epileptic temporal cortex were decreased (approximately 30%) in both comparisons. In contrast to these findings, a substantially increased (in some cases 300%) ecto-ATPase activity was observed in the posterior part of epileptic hippocampus. We suggest that the higher than normal ecto-ATPase activity in this particular hippocampal region is related to the presence of granule cells and their efferent (or afferent) synaptic connections. The synaptosomal ecto-adenylate kinase showed alterations opposite to the changes found for the ecto-ATPase. The intrasynaptosomal ATPase (Na+,K(+)- and Ca2+,Mg2(+)-) were decreased in the epileptic hippocampus-, but not in the temporal cortex samples, in relation to the corresponding normal enzyme activity values. These complex alterations in synaptosomal ATP-metabolizing enzyme activities may be important elements of seizure development and maintenance in human temporal lobe epilepsy.

Time course of the reduction of GABA terminals in a model of focal epilepsy: a glutamic acid decarboxylase immunocytochemical study.

Immunocytochemical localization of glutamic acid decarboxylase (GAD), the synthesizing enzyme for the neurotransmitter gamma-aminobutyric acid (GABA), has been used to study the time course of the decrease in putative GABAergic synaptic terminals that occurs in an alumina gel-induced model of focal epilepsy. Monkeys were studied at progressive intervals following unilateral application of alumina gel to sensorimotor cerebral cortex, and were categorized into 3 different experimental groups depending upon their clinical status. These groups respectively exhibited: (1) no abnormal bioelectrical (EEG and ECoG) activity; (2) abnormal bioelectrical activity, but no clinical seizures; and (3) both abnormal bioelectrical activity and clinical seizures. Normal and sham-operated monkeys were also studied. The amounts of GAD-positive terminal-like structures were determined on control and experimental sides of motor cortex (layer V) of all specimens with an image analysis system. This quantitative study revealed that monkeys from the 3 experimental groups showed reductions of GAD-positive terminals on the experimental cortical side, with greater losses occurring at progressively longer times following alumina gel implants. Statistical tests showed that there were no significant cortical side differences for the normal and sham groups, but that cortical side variations were significantly different for each of the 3 experimental groups. Conventional electron microscopy of an early experimental stage revealed degenerating axon terminals in layer V of motor cortex, as well as phagocytosis of degenerating material and astrogliosis. Similar findings were obtained from a chronically epileptic specimen, except that degenerating terminals were observed less often and fibrous astrocytic scarring was more prevalent, especially surrounding the somata of pyramidal neurons. The main conclusion drawn from the results of this investigation is that significant decreases of GAD-positive terminals occur prior to the onset of clinical seizures, and this is consistent with a causal role for a loss of GABAergic innervation in the development of seizure activity in this primate model of focal epilepsy.

A decrease in the number of GABAergic somata is associated with the preferential loss of GABAergic terminals at epileptic foci.

Previous studies have indicated that a loss of GABAergic terminals occurs at epileptic foci. The present study was undertaken to investigate if this loss is associated with a loss of GABAergic neuronal somata. Seven juvenile monkeys (M. mulatta) received alumina gel injections to the pre-central gyrus of the left cerebral hemisphere to produce epileptic foci. Four of these monkeys were chosen for further quantitative study. One was sacrificed prior to seizure onset ('pre-seizure'), one had seizures for 3 days ('acute'), and two had a seizure record of one month ('chronic'). Sections of tissue from the epileptic cortex and from the contralateral, non-epileptic cortex were processed for glutamate decarboxylase (GAD) immunocytochemistry at the light microscopic level. Quantitative analysis revealed that a loss of GAD-positive neuronal somata ranging from 24 to 52% occurred at epileptic foci for all monkeys. This decrease was significant (P less than 0.01) for the two chronic monkeys. There was also a slight decrease in GAD-positive neurons 1 cm distal to the focus ('parafocus') in the chronic monkeys, but not in the acute or pre-seizure animals. In addition, small GAD-positive somata (50-150 micron2) were more severely decreased in number at epileptic foci than larger ones (200-250 micron2). As an experimental control, an additional monkey was given a surgical lesion in area 4 of one cerebral hemisphere. It did not display seizure activity prior to sacrifice and did not show a loss of GAD-positive neurons proximal to the control lesions. The results of this study indicate that a loss of GABAergic neuronal somata is associated with a loss of GABAergic terminals at epileptic foci, and that this loss may be more specific for the small GABAergic neurons.

Amino acid and catecholamine markers of metabolic abnormalities in human focal epilepsy.

Studies of various parameters of amino acid and catecholamine metabolism in human cerebral cortex have provided a number of biochemical markers that appear to delineate areas of focal epileptic activity. These observations have been consolidated further by investigations of a number of experimental models of epilepsy in animals. In appraising this data, it is important to take into consideration whether the tissue samples were obtained during an actual seizure state or in an interictal period. It is also important when possible to assess the extent of astrogliosis and neuronal loss. Sites of spontaneously active epileptic spiking in the cerebral neocortex have a somewhat different amino acid profile when compared to gray matter obtained from surrounding nonspiking gyri several centimeters away. There is an elevation in glycine content, a relative diminution in taurine, and a trend towards lowered glutamic acid levels. However, the concentrations of the eight amino acids measured appear in both the foci and surround to still be within the general range for normal tissue. Measurements of key enzymes involved in the synthesis and regulation of neurotransmitters provide a complementary method of evaluating functional changes in epileptic brain as they are generally less labile than their substrates. There is a moderate increase in the activity of glutamic acid dehydrogenase, an enzyme that plays an important role in the synthesis of glutamic acid from glucose. In some patients a decrease in glutamic acid decarboxylase has also been reported: this enzyme forms gamma-aminobutyric acid (GABA) from glutamic acid and is thus important for inhibition in the central nervous system. Moreover, there is a striking increase in the activity of tyrosine hydroxylase, the rate-limiting enzyme responsible for catecholamine synthesis. The possibility of a focal abnormality in catecholamine metabolism is reinforced by the simultaneous finding of a relative decrease in the number of alpha-1 postsynaptic receptor sites. An important marker of energy metabolism in neural tissue, Na+,K+-ATPase activity, has also been found to be decreased in actively spiking human cerebral cortex. Data from experimental animal foci produced by topical application of convulsant agents show a consistent drop in glutamic acid tissue content. This can be matched to an efflux of glutamic acid from the cortical surface, which in turn is proportional to the electrographic activity of the spike focus. In addition, there is often also a decrease in taurine and GABA in such foci, as well as an increase in the levels of a number of neutral amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)

Cathepsins B and D in rat brain glia during experimentally induced neuropathological defects. An immunocytochemical approach.

The lysosome-associated cathepsins B and D were localized by means of immunocytochemistry (peroxidase-antiperoxidase technique) in glial cells of rat brain. A specific reaction pattern of hippocampal neuroglia could be observed after intracerebroventricular application of the neurotoxin kainic acid. After the induction of a focal epilepsy in rats by the implantation of cobalt pellets there was a pronounced immunoreaction of glia near the primary focus as well as the mirror focus. It is concluded that both cathepsins are useful immunocytochemical markers to trace functionally activated glia.

[Changes in the spectrum of LDH isoenzymes in foci of epileptic activity induced by penicillin in the cerebral cortex of rats]. / Izmeneiia spektra izofermentov LDG v ochagakh épilepticheskoi aktivnosti, vyzvannykh penitsillinom v kore golovnogo mozga krys.

The correlation between electrophysiological changes and isozymes of LDH of the rat brain cortex was studied in seizure foci induced by application of sodium penicillin. It was discovered that activity of LDH1 was suppressed, and that of LDH5 fraction was elevated in the determinant focus, which indicates the enhanced glucose anaerobic transformation. The spectrum of LDH isozymes did not practically differ from the indicators in control animals in a homotopic region of the contralateral hemisphere prior to creation of the mirror focus. The anaerobic processes were found to be increased in the mirror focus and in the determinant one as well. Similar pattern of changes in electrophysiological and neurochemical characteristics in the determinant and dependent mirror foci attests to the formation of a pathological system out of the two epileptic foci.

[Decreased acetylcholinesterase activity in the area of epileptogenic foci created by met-enkephalin in the hippocampus of rats]. / Snizhenie aktivnosti atsetilkholinesterazy v oblasti épileptogennykh ochagov, sozdannykh met-énkefalinom v gippokampe krys.

Experiments on rats with electrochemotrodes implanted in the left and right hippocamp have shown that in epileptogenic foci created by microinjections of met-enkephalin or D-ala-2-met-enkephalin into the hippocamp, acetylcholinesterase activity (AChE) was diminished. It is assumed that reduction in AChE activity is an adaptive mechanism by which the excitability of hippocampal inhibitory basket cells, which are sensitive to acetylcholine, is increased.

[Endogenous phospholipase hydrolysis in the cerebral cortex during the development of epileptic activity]. / Endogennyi fosfolipaznyi gidroliz v kore golovnogo mozga pri razvitii épilepticheskoi aktivnosti.

The development of epileptic activity in the rat brain cortex is attended by activation of endogenous phospholipase hydrolysis. The development of primary-generalized epileptic activity induced by intramuscular injection of bemegride increased the content of free fatty acids in the brain tissue from 14 +/- 3 micrograms per mg protein in the control to 35 +/- 4 micrograms/mg. The appearance of focal cortical epileptic activity after penicillin application also provoked an increase in the content of free fatty acids in the brain tissue withdrawn from the hyperactive focus (from 40 +/- 5 micrograms/mg in the control to 75 +/- 10 micrograms/mg). Analysis of the free fatty acid spectrum in the brain tissue by gas-liquid chromatography has shown that the development of epileptic activity induced primary stearic acid accumulation by the brain cortex, a decrease in the relative content of short-chain fatty acids, a tendency towards arachidonic acid accumulation. It is assumed that endogenous phospholipase hydrolysis may be involved in the mechanisms of the development of epileptic activity.

Neuraminidase deficiency and accumulation of sialic acid in lymphocytes in adult type sialidosis with partial beta-galactosidase deficiency.

Neuraminidase deficiency has been demonstrated in cultured skin fibroblasts of patients who have adult type sialidosis with partial beta-galactosidase deficiency. A substantial amount of residual enzyme activity has been observed in leukocytes, however. To explain this discrepancy, the nature and distribution of the enzyme were studied. Neuraminidase activity was higher in lymphocytes than in granulocytes of normal controls. In patients' lymphocytes, neuraminidase activity was profoundly decreased and total sialic acid contents were increased 2.3-fold. Two neuraminidases, one sonication-labile and the other sonication-stable, were found in lymphocytes; the former was predominant in cultured skin fibroblasts. The defective enzyme in this disorder was found to be the sonication-labile neuraminidase in both cultured skin fibroblasts and lymphocytes.

[The activity of cytochrome oxidase in the normal cerebral cortex and after destructive and irritating lesions. Histochemical research]. / Activité de la cytochrome oxydase dans le cortex cérébral normal et après lésions destructives et irritatives (recherches histochimiques).

Production of an epileptogenic focus by cobalt-gelatin implantation in the cerebral cortex of the rat determines a local increase of cytochrome oxidase activity in neurones and probably a decrease of its activity in neuroglia. This variation of oxidative metabolism is not characteristic of the "epileptic neuron" since it takes also place after non irritative lesions, though remaining less conspicuous and less extensive.