Serum metalloproteinase 9 levels increase after generalized tonic-clonic seizures.

Metalloproteinase 9 (MMP9) is a member of a family of enzymes that mediate the degradation of extracellular matrix proteins, and is especially involved in blood-brain barrier maintenance. Increased levels of MMP9 have been observed in many neurological disorders, including epilepsy, suggesting it may be involved in the pathogenesis of seizures. We investigated changes in MMP9 serum levels after acute seizures in epilepsy patients. Concentrations of MMP9 in serum were measured by ELISA in 43 patients 1-3, 24, and 72h after generalized tonic-clonic seizure and once in participants of the control group. MMP9 levels were significantly increased 1-3 and 24h after seizure and decreased to control levels 72h after seizure. Our results suggest that MMP9 is released after or just before seizure; however, further studies are needed to resolve the consequences of the observed MMP9 increase.

Inhibition of adenylyl cyclase in amygdala blocks the effect of audiogenic seizure kindling in genetically epilepsy-prone rats.

Genetically epilepsy-prone rats of the severe seizure strain (GEPR-9s) exhibit audiogenic seizures (AGS) beginning with wild running and ending with tonic hind limb extension (TE). AGS kindling in GEPR-9s involves periodic repetition of >/=14 seizures over 7-21 days and results in prolonged seizures and an additional phase of generalized post-tonic clonus (PTC) that follows TE. AGS kindling behavior changes are long-lasting and involve expansion of the requisite seizure neuronal network from the brainstem to include the amygdala, mediated by neuroplasticity in lateral amygdala. Recent evidence indicates that focal activation of adenylyl cyclase (AC) in lateral amygdala leads to precipitous acquisition of AGS-kindled seizure behaviors, suggesting that activation of AC activity is important in development and maintenance of AGS kindling. The present study further examined the role of AC in AGS-kindled seizures in GEPR-9s by focally inhibiting AC in the amygdala. Bilateral microinjection of an AC inhibitor, SQ22,536 (0.25 and 0.50 nmol/side), in AGS-kindled GEPR-9s selectively blocked PTC during AGS at 1 h after microinjection, but the pre-kindled AGS behaviors remained intact. The incidence of PTC during AGS returned to pre-drug levels 12 h after the lower dose of SQ22,536 (0.25 nmol/side). However, after the higher dose of SQ22,536 (0.5 nmol/side), complete return to AGS with PTC was seen in all GEPR-9s at 120 h. These results indicate that maintenance of AGS kindling-mediated PTC in GEPR-9s may involve activation of AC. These data provide further evidence for the involvement of AC in the epileptogenic mechanisms subserving AGS kindling.

Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder?

This report describes the case of a 4 1/2-year-old female with developmental delay and tonic-clonic seizures, persistently elevated serum alkaline phosphatase activity, and low serum pyridoxal 5'-phosphate. Born at term to consanguineous parents, she was dysmorphic and delayed at 5 months. At 11 months, seizures and microcephaly were evident but skeletal and cerebral imaging, karyotyping, and genetic metabolic tests were unremarkable. Serum alkaline phosphatase activity, however, was elevated (1.3 +/- 0.6 times greater than the upper limit of normal) on seven occasions between 5 months and 4(1/2) years of age. Hyperphosphatasia with neurologic deficit (MIM #239300), a rare autosomal recessive disorder, was diagnosed. The low serum levels of pyridoxal 5'-phosphate (6 nmol/L; normal >20 nmol/L) prompted a pyridoxine challenge. A clinically significant but paradoxical response was observed. On electroencephalography, diffuse delta slow waves (1-2 Hz) were observed, suggestive of stage 3 or 4 slow-wave sleep. With daily administration of 100 mg pyridoxine and withdrawal of phenobarbital, seizures were not evident. We suggest that serum alkaline phosphatase should be measured in cases of seizures with paradoxical electroencephalographic response to pyridoxine. Conversely, pyridoxine challenge should be considered in cases of hyperphosphatasia with seizures and neurologic deficit.

Serum alanine aminotransferase in skeletal muscle diseases.

Although elevation of the levels of serum alanine aminotransferase (ALT) following liver injury is well known, confusion exists concerning skeletal muscle injury as the cause of this rise. We reviewed the records of 16 patients who had muscle necrosis without evidence of liver disease. The patients were divided into three groups: extreme exercise, polymyositis, and seizures. All patients exhibited markedly elevated creatine kinase and lactate dehydrogenase levels consistent with muscle injury. In acute cases, aspartate aminotransferase (AST) and ALT were both elevated, and the AST/ALT ratio was greater than 3, but this ratio approached 1 after a few days because of a faster decline in AST. In conclusion, this difference in half-life accounts for the comparable AST and ALT levels in our cases with chronic muscle injury.

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.

Pentylenetetrazol-induced seizures and kindling: changes in free fatty acids, superoxide dismutase, and glutathione peroxidase activity.

The whole brain free fatty acid (FFA) level, as well as the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPX) were determined in the frontal cortex, cerebellum, hippocampus, and pons-medulla region of the single pentylenetetrazol (PZT)-treated and PZT-kindled Hannover-Wistar rats. PZT administration in the convulsive dose caused significant increase of the brain FFA content. Decreased SOD activity was detected in the frontal cortex of PZT-kindled rats, whereas decreased GPX activity was found in the frontal cortex and cerebellum of all treated rats, as well as in the hippocampus and pons-medulla of PZT-kindled rats. Kindling caused distinctive change of antioxidative defense in the frontal cortex, hippocampus, and pons-medulla region.

Influence of cytochrome P450 induction on the pharmacokinetics and pharmacodynamics of remacemide hydrochloride.

Remacemide hydrochloride (RMD) is a putative anticonvulsant agent with an active metabolite, desglycinyl-remacemide (DGR) and a broad spectrum of activity in experimental seizure models. In clinical trials, however, the efficacy of RMD is questionable. In the case of add-on studies, the inconclusive findings may be related to pharmacokinetic interactions between RMD and established antiepileptic drugs. We have investigated the influence of cytochrome P450 (CYP(450)) induction following repeated treatment with phenobarbital (PB) on the pharmacokinetics and pharmacodynamics of RMD in mice. Pre-treatment with PB (80 mg/kg; once daily for 4 days) significantly increased CYP(450) content and activity in mouse liver. This was associated with a consistent reduction in the brain concentrations of both RMD and DGR and attenuation of the anticonvulsant effects of RMD in the maximal electroshock model. Pharmacokinetic analysis suggested that DGR was proportionately more susceptible to CYP(450) induction than the parent compound. As the principal active moiety, the selectively enhanced metabolism of DGR under induced conditions may underlie the debatable findings of add-on trials with RMD in refractory epilepsy. However, this hypothesis does not explain the similarly questionable efficacy of RMD monotherapy in newly diagnosed epilepsy, an observation that may have wider pharmacological implications.

Serum levels of neuron-specific enolase and s-100 protein after single tonic-clonic seizures.

Serum neuron-specific enolase (s-NSE) and s-100 protein (s-100) are sensitive markers of various brain diseases. We investigated both of these markers in nine patients within 5 min, 6 h, 12 h, and 48 h after a single tonic-clonic seizure. The mean peak s-NSE level was significantly higher after 5 min (11.97 +/- 8.56 microg/l) and 48 h (10.31 +/- 8.92 microg/l, P < 0.05) than the levels of seizure-free, age-matched controls. Five patients had increased s-NSE levels regarding the upper limit of normal as mean + 3 SD. s-100 was not detected either in controls or epileptic patients. These data indicate that s-NSE in contrast to s-100 may be an in vivo marker after generalized seizures in some patients.

Sequential serum creatine kinase determination differentiates vaso-vagal syncope from generalized tonic-clonic seizures.

MATERIALS AND METHODS: In a prospective study we evaluated patients with first generalized tonic-clonic seizure (GTCS) (n = 16, age: 31 +/- 11 years, 8 women) and patients with vaso-vagal syncope (VVS) (n = 17, age: 32 +/- 13 years, 8 women), diagnosed on the basis of past history and clinical presentation who had serum creatine kinase (CK) levels assessed at admission to the emergency room and 24-26 h later. Patients with physical injuries were excluded. RESULTS: On admission, CK levels were > 130 mU/ml (2.16 microkat/l) in 25% (4/16) GTCS vs 6% (1/17) VVS patients; 24 h later, the figures were 56% (9/16) vs 12% (2/17) respectively. For GTCSD patients CK level > 200 mU/ml (3.33 microkat/l) had a sensitivity and specificity of 0.12 and 0.94 on the first day, and 0.25 and 1.0 respectively on the second day. The change in the CK level from the first to the second day was 155 +/- 266 mU/ml (2.58 +/- 4.43 microkat/l) for GTCS group and -2 +/- 37 mU/ml (-0.03 +/- 0.61 microkat/l) in VVS. An increase of more than 15 mU/ml (0.25 microkat/l) was observed in 11/16 GTCS patients and only in 1/17 VVS patients. Taking an increase of > 15 mU/ml (0.25 microkat/l) as a cut-off value, the sensitivity of this figure is 0.69 and specificity 0.94. An increase of > 15 mU/ml (0.25 microkat/l) in CK level among the patients with normal CK on both days was seen in 50% of GTCS but in none with VVS. Using the criteria of CK levels > 200 mU/ml (3.33 microkat/l) (on either day) and/or elevation from the first to the second day of > 15 mU/ml (0.25 microkat/l), there were only 12% false negatives and 12% false positives. CONCLUSIONS: We conclude that a higher increase in CK levels from the first to the second day occurs in GTCS as compared to VVS, and even when both sequential tests are within the normal range, an increase of at least 15 mU/ml (0.25 microkat/l) is highly indicative of an epileptic event. CK levels above 200 mU/ml (3.33 microkat/l) are unlikely to be the result of VVS.

Medium chain acyl-CoA dehydrogenase deficiency and fatal valproate toxicity.

A boy with delayed psychomotor development, attention deficit disorder, and therapy-resistant epilepsy was treated with valproate. The patient died of liver failure after 4 months of valproate treatment. Postmortem investigation of cultured fibroblasts suggested medium chain acyl-CoA dehydrogenase deficiency, an unexpected finding since the boy had not presented typical manifestations of this disease. Because medium chain acyl-CoA dehydrogenase is an important enzyme in the beta-oxidation of fatty acids, our patient probably had a genetically reduced tolerance to valproate. This drug should be omitted in the treatment of seizures in patients with possible medium chain acyl-CoA dehydrogenase deficiency.

Neuron-specific enolase is increased after single seizures during inpatient video/EEG monitoring.

Neuron-specific enolase (NSE) is a marker of brain injury after acute neurologic insults. We report changes in serum NSE (s-NSE) in 25 patients (15 with epilepsy and 10 patients with nonepileptic events) during continuous inpatient video/EEG monitoring. s-NSE was significantly increased as compared with baseline and normal controls after the first ictal event in the epileptic group, especially in patients with secondarily generalized tonic-clonic seizures (p = 0.01), but s-NSE was not increased in patients with nonepileptic events. These preliminary data indicate that s-NSE may be increased after complex partial seizures--and generalized tonic-clonic seizures (GTCS).

Selective liver enzyme induction by carbamazepine and phenytoin in Chinese epileptics.

OBJECTIVE: Anticonvulsant drugs are known inducers of cytochrome P450 liver enzymes and it has been suggested that this induction increases susceptibility to paracetamol-induced hepatotoxicity. METHODS: We measured the percentage urinary recovery of paracetamol and its metabolites after a dose of 20 mg kg-1, and the excretion of 6 beta-hydroxycortisol as a ratio to urinary free cortisol (6 beta OHF/F) in Chinese epileptic patients maintained on long-term therapy with carbamazepine (n = 6) or phenytoin (n = 6). RESULTS: Compared to the healthy controls (n = 20), patients on phenytoin had significantly lower recoveries of mercapturic acid, cysteine and sulphate metabolites, but a higher recovery of glucuronide metabolites of paracetamol. The recoveries of paracetamol metabolites in patients on carbamazepine were not different from controls. In contrast, the 6 beta OHF/F was significantly higher in patients on carbamazepine (3-fold) or phenytoin (2-fold) compared to controls. Healthy control Chinese subjects metabolised paracetamol in a similar way to that reported in Caucasians, indicating that the risk for hepatotoxicity would be the same. Our findings in a group of Chinese patients on phenytoin were also similar to those previously reported in Caucasians on this drug. The apparent differences in the pattern of isoenzyme induction between the groups on phenytoin and carbamazepine require verification in larger studies. The data do not suggest an increased risk of paracetamol-induced hepatotoxicity in Chinese patients on anticonvulsants.

Effect of sodium valproate on serum amylase in epileptics.

Thirty-eight patients of generalised tonic-clonic seizures of epileptics in the age group of 15-30 years were included in this study. Of these 20 were started sodium valproate afresh and 18 already taking it for more than one year prior to inclusion. Serum amylase and serum valproic acid levels were measured in all of them, initially and at every 3 months interval for 9 months. Though no clinical evidence was present, there was significant increase in serum amylase levels in both the groups which has no correlation with dose or serum valproic acid levels.

[Induction of liver microsomal enzymes in epileptics under treatment with carbamazepine]. / Induzione degli enzimi microsomiali epatici in epilettici in trattamento con carbamazepina.

Serum gamma-GT activity was significantly (0.01 greater than P greater than 0.001) elevated in 18 out of 30 epileptics receiving carbamazepine (CBZ), i.e. in 60%. The incidence of abnormal gamma-GT levels in the control group (25 neurotic patients taking minor tranquilizers) was lower (12%). The possible relationships between the enzyme induction or chronic hepatic toxicity and the elevation of serum gamma-GT activity in epileptics taking CBZ are discussed.

Creatine kinase in serum after grand mal seizures.

Total creatine kinase (CK) activity in serum was increased post-ictally in 14 out of 17 patients (82%) admitted to the hospital after one or more generalized seizures. No correlation was found between increased CK levels and cerebral or extracerebral ictal injuries. A highly significant negative correlation exists between regular anti-epileptic treatment and elevated levels of the enzyme (p less than 0.01). The maximum value of CK activity was found on the 3rd or 4th post-ictal day in 10 out of 14 patients. Correspondingly, late CK-activity increases on the 2nd-4th post-ictal day were found in 6 out of 9 experiments with unrestrained cats. In cats immobilized by relaxant drugs, only an initial rise of the enzyme within 24 h after the electrographic seizures was observed. These findings suggest that sources other than the skeletal muscle alone contribute to the increased CK activity after grand mal seizures.

[Ceruloplasmine in schizophrenic and in epileptic patients (author's transl)]. / Valoración inmunológica y oxidásica de ceruloplasmina. I. Determinación en esquizofrénicos y epilépticos

Ceruloplasmine was measured in serum of normal, schizophrenic and epileptic patients through the use of oxidase and immunological methods. The measurements were correlated to find: the reliability of oxidase method as an index of ceruloplasmine concentration and the immunological identity of this protein in the three groups of individuals. The results showed that the oxidase method served as a good index of ceruloplasmine concentration in the sera and that an immunological identity among the three groups exised. A significant correlation between the serum oxidase activity and the ceruloplasmine immunological determination was, further, observed.

Grand mal seizures and acute intermittent porphyria. The problem of differential diagnosis and treatment.

A 36-year-old white man had both acute intermittent porphyria and long-standing idiopathic grand mal seizures. Diphenylhydantoin apparently adversely affected both the clinical and biochemical parameters of the acute intermittent porphyria. Comparison of urinary levels of the porphyrin precursors, delta aminolevulinic acid and porphobilinogen, under controlled diet conditions before and after withdrawal of diphenylhydantoin, showed that this drug accounted for approximately one-half of the porphyrin precursor excretion. Significant clinical improvement of the porphyria followed withdrawal of the diphenylhydantoin. Bromides appeared to be approximately as effective as diphenylhydantoin for seizure control in this patient.

Cyclic amp concentration and enzyme activities of cerebrospinal fluid in patients with epilepsy or central nervous system damage.

Cyclic adenosine-3',5'-monophosphate (cAMP) concentration in cerebrospinal fluid (CSF) was measured by the protein binding method of Gilman from 62 neurological patients, 46 of them were epileptics and 16 with a central nervous system (CNS) damage. In epileptic patients the CSF concentration of cAMP was significantly elevated (p smaller than 0.02) for 3 days after an attack when compared with those free from attacks for at least 2 weeks. The causality relationship between the rise of cAMP in CSF and an epileptic discharge is discussed. In patient with an active or rapidly progressing CNS damage the cAMP levels in the CSF were significantly higher (p smaller than 0.001) than in those with an old CNS damage. Also some enzyme activities in CSF were measured but no uniform alterations could be found. In damaging processes of the CNS, the cAMP values in the CSF seem to correlate to the activity of the disease.