Hippocampal gene network analysis in an experimental model of posttraumatic epilepsy.

In the present study, we performed comprehensive gene expression and gene network analyses using a DNA microarray to elucidate the molecular events responsible for the pathology of posttraumatic epilepsy at the partial seizure stage. We used an experimental posttraumatic epilepsy model of amygdalar focal FeCl(3)-injected rats and compared gene expression profiles in the hippocampus at the partial seizure stage (less than stage 3 on Racine's convulsion scale) and that of sham-operated animals. At the partial seizure stage, upregulation of phospholipase A2 (PLA2) and lipid metabolism were observed, which have been reported to be caused by brain injury and seizures in previous studies. Furthermore, significant upregulation of genes related to inflammation and the immune system was observed. These molecular changes in PLA2 and lipid metabolism may be related to seizure propagation.

Chronic focal epileptiform discharges induced by injection of iron into rat and cat cortex.

A single injection of 5 or 10 microliters of ferrous or ferric chloride into rat or cat sensorimotor cortex resulted in chronic recurrent focal paroxysmal electroencephalographic discharges as well as behavioral convulsions and electrical seizures. Recurrent focal epileptiform discharge caused by cortical injection of iron salts suggests that the development of human posttraumatic epilepsy may depend, in part, on the neurochemical alterations induced by the principal metallic ions found in whole blood.

Posttraumatic epilepsy: hemorrhage, free radicals and the molecular regulation of glutamate.

Traumatic brain injury causes development of posttraumatic epilepsy. Bleeding within neuropil is followed by hemolysis and deposition of hemoglobin in neocortex. Iron from hemoglobin and transferring is deposited in brains of patients with posttraumatic epilepsy. Iron compounds form reactive free radical oxidants. Microinjection of ferric ions into rodent brain results in chronic recurrent seizures and liberation of glutamate into the neuropil, as is observed in humans with epilepsy. Termination of synaptic effects of glutamate is by removal via transporter proteins. EAAC-1 is within neurons while GLT-1 and GLAST are confined to glia. Persistent down regulation of GLAST production is present in hippocampal regions in chronic seizure models. Down regulation of GLAST may be fundamental to a sequence of free radical reactions initiated by brain injury with hemorrhage. Administration of antioxidants to animals causes interruption of the sequence of brain injury responses induced by hemorrhage, suggesting that such a strategy needs to be evaluated in patients with traumatic brain injury.

Predictive value of hippocampal MR imaging-based high-dimensional mapping in mesial temporal epilepsy: preliminary findings.

BACKGROUND AND PURPOSE: We objectively assessed surface structural changes of the hippocampus in mesial temporal sclerosis (MTS) and assessed the ability of large-deformation high-dimensional mapping (HDM-LD) to demonstrate hippocampal surface symmetry and predict group classification of MTS in right and left MTS groups compared with control subjects. METHODS: Using eigenvector field analysis of HDM-LD segmentations of the hippocampus, we compared the symmetry of changes in the right and left MTS groups with a group of 15 matched controls. To assess the ability of HDM-LD to predict group classification, eigenvectors were selected by a logistic regression procedure when comparing the MTS group with control subjects. RESULTS: Multivariate analysis of variance on the coefficients from the first 9 eigenvectors accounted for 75% of the total variance between groups. The first 3 eigenvectors showed the largest differences between the control group and each of the MTS groups, but with eigenvector 2 showing the greatest difference in the MTS groups. Reconstruction of the hippocampal deformation vector fields due solely to eigenvector 2 shows symmetrical patterns in the right and left MTS groups. A "leave-one-out" (jackknife) procedure correctly predicted group classification in 14 of 15 (93.3%) left MTS subjects and all 15 right MTS subjects. CONCLUSION: Analysis of principal dimensions of hippocampal shape change suggests that MTS, after accounting for normal right-left asymmetries, affects the right and left hippocampal surface structure very symmetrically. Preliminary analysis using HDM-LD shows it can predict group classification of MTS and control hippocampi in this well-defined population of patients with MTS and mesial temporal lobe epilepsy (MTLE).

Antiepileptic drug therapy in the elderly.

Populations are aging, and the incidence of epilepsy is increased in the elderly population. These demographic facts emphasize the importance of understanding the use of antiepileptic drugs in older patients. Healthy elderly have expected alterations in renal blood flow, hepatic volume and function, and alterations in fat-to-lean ratio of body composition. All of these changes make elderly patients vulnerable to dose-related adverse effects of the standard antiepileptic drugs. Newly developed compounds without enzyme induction effects and renal routes of excretion may be more favorable for use in elderly patients.

Steady-state kinetics of valproic acid in epileptic patients.

Pharmacokinetic evaluation and prediction were carried out in 20 epileptic patients. Using conventional pharmacokinetic techniques and a one-compartment model, predicted and observed valproic acid plasma concentrations were compared. Valproic acid assay was performed by gas-liquid chromatography. There was good agreement between predicted and observed plasma concentrations. Most patients had predicted half-lives (t1/2s) of 6 to 8 hr, independent of the plasma concentration of valproic acid. Five patients had predicted t1/2s of 12 hr. The correlation between dose and plasma level was poor. Most patients had valproic acid plasma levels between 55 and 100 microgram/ml. Administration of valproic acid three times a day with determination of individual plasma concentrations offers a reliable method of monitoring. Constant levels are maintained in individual patients, but there is substantial intersubject variation.

Valproate-induced coma with ketosis and carnitine insufficiency.

We observed two patients who developed coma following administration of valproate in dosages of 32 to 40 mg/kg per day. Valproate levels were within the therapeutic range, and results of liver function studies were normal. Both patients had ketosis and adipic aciduria. Plasma free carnitine levels were decreased during coma and after recovery. One patient excreted ethylmalonic acid, butyrylcarnitine, and glutarylcarnitine during and after resolution of coma, suggesting a multiple acyl coenzyme A dehydrogenation defect. Low serum carnitine levels may predispose patients to development of altered consciousness when treated with valproate.

Quality of life perception in patients with intractable epilepsy or pseudoseizures.

OBJECTIVES: To contrast and compare self-reported quality of life in patients with intractable epilepsy and pseudoseizures and to examine the relationship between self-reports and objective measures of cognitive functioning in both of these groups. DESIGN: Case series using profile analysis and analysis of covariance. SETTING: University epilepsy surgery program. PARTICIPANTS: Forty-three patients with intractable complex partial seizures of unilateral temporal lobe origin and 25 patients with pseudoseizures. MEASURES: Quality of Life in Epilepsy Inventory-89; neuropsychological tests assessing verbal memory, nonverbal memory, naming, and attention; and the Depression Scale (2) of the MMPI-2 (Minnesota Multiphasic Personality Inventory). RESULTS: Patients with pseudoseizures described themselves as more limited in the physical health domain than patients with complex partial seizures. Self-perceptions of cognitive functioning were similar between groups, despite the superior performance of patients with pseudoseizures on objective measures. Self-perception of cognitive dysfunction was related to mood disorder in the pseudoseizure group only, and there were no relationships between subjective and objective measurements of cognitive status within this group independent of mood disorder. For the complex partial seizures group, relationships between subjective and objective measures of cognitive function were dependent on the side of seizure onset. CONCLUSIONS: Results are consistent with hypotheses that suggest that patients with pseudoseizures focus on physical rather than psychological explanations for stress, and that this focus is related, at least in a subgroup of patients, to mood disorder. Results also provide support for the validity of the Quality of Life in Epilepsy Inventory-89 in populations with intractable seizure disorder, although there is evidence for a possible floor effect on some of the subscales.

Clinical pharmacology of new antiepileptic drugs.

Advances in neurobiology, molecular biology, and pharmaceutical science have led to the development of a number of new antiepileptic drugs (AEDs). The investigational AEDs described in this review include ganaxolone, levetiracetam, losigamone, pregabalin, remacemide, rufinamide, stiripentol, and zonisamide. They have shown efficacy in a variety of seizure types and offer hope for improved therapeutic efficacy, beneficial pharmacokinetics, and a decrease in the incidence of drug interactions and adverse events. As the results of ongoing clinical trials of these drugs become available, these medications may be considered for rational drug therapy of epilepsy, either singly or in combination with currently available AEDs.

Epilepsy emergencies: the first seizure and status epilepticus.

Patients experiencing a first seizure need a careful history and examination to confirm that the presenting seizure is truly the initial event and to identify other possible risk factors for recurrence. The decision of whether to start therapy should be made by the clinician and a fully informed patient. Status epilepticus presents in several forms, with generalized convulsive status epilepticus (GCSE) being the most dramatic. Management of GCSE requires life support and monitoring measures as well as timely administration of antiepileptic drugs (AEDs) to terminate the seizure and reduce the risks for morbidity and mortality. Benzodiazepines, phenytoin, and phenobarbital can all be used to treat GCSE. Clinicians need to be familiar with the dosage and administration, adverse events, time to onset, and duration of action of these drugs. Should seizures continue or recur despite AED administration, induction of coma with pentobarbital may be considered. This must be done with continuous EEG and other physiologic monitoring in an intensive care unit. Additional assessment of the patient who has experienced GCSE focuses on identification of the underlying cause.

Antiperoxidant pretreatment and iron-induced epileptiform discharges in the rat: EEG and histopathologic studies.

Iron causes formation of superoxide radicals resulting in peroxidation of membranous components of tissue. Hemosiderin deposition in human brain often accompanies chronic posttraumatic seizures induced by trauma. We injected an aqueous solution of iron salts, the principal metallic iron of whole blood, into rat isocortex. Serial electroencephalographic recording showed than 94% of untreated animals developed epileptiform discharges. Pretreatment with alpha-tocopherol and with 2 ppm selenium prevented development of iron-induced epileptiform activity in 72% of animals. Histopathologic assessment of serial sections stained with Nissl, hematoxylin and eosin, and prussian blue showed cavitation, neuronal pyknosis and loss, and astrogliosis in untreated animals. The site of iron injection in animals treated with antiperoxidants contained only an area of neuronal pyknosis. The efficacy of antioxidants in preventing development of iron-induced cavitation, gliosis, and epileptiform discharges suggests that peroxidative injury may be important in the development of experimental epilepsy induced by isocortical injection of ferrous chloride.

Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. The M88-194 Study Group.

We studied the efficacy of divalproex sodium in patients with complex partial seizures taking concomitant carbamazepine or phenytoin as monotherapy. Patients were selected because of inadequate seizure control by current therapy. The primary efficacy measure was median reduction of seizure frequency during add-on treatment compared with baseline. A secondary measure was the percentage of patients achieving > or = 50% reduction in seizure frequency. In the intent-to-treat analysis (137 patients), divalproex-treated patients experienced a median reduction of 7.9 complex partial seizures per 8 weeks compared with 2.5 in the placebo group (p = 0.001). Also, 38% of divalproex-treated patients completed the study with a seizure reduction of > or = 50% compared with 19% receiving placebo (p = 0.011). Six divalproex- and one placebo-treated patient became free of complex partial seizures. We conclude that divalproex sodium is an effective drug for treating patients with complex partial seizures.

Valproic acid and plasma levels of phenytoin.

Eight patients were treated concurrently with a constant dose of phenytoin and valproic acid for 1 year. During initial therapy with valproic acid, total plasma phenytoin levels decreased. The interaction was transient and was not observed at the end of 1 year. Total plasma phenytoin levels returned to pre-valproic-acid levels in seven patients.

Clinical efficacy and long-term effects of valproic acid therapy on spike-and-wave discharges.

Twenty-two patients with absence seizures and other seizure types were treated with valproic acid and followed up for 1 year. Results were excellent with more than 75% improvement in 80% of patients with absence seizures, in 40% of those with tonic-clonic seizures, in all of those with myoclonic seizures, and in 43% of those with partial seizures. Fifty-seven percent of the patients had more than a 75% reduction in the total number of paroxysmal spike-wave discharges, and 62% had more than a 75% reduction in the number of spike-wave discharges lasting longer than 3 seconds. Photosensitivity and activation by hyperventilation decreased. More patients achieved good EEG control in 1 year than in 10 weeks.

Valproic acid: interaction with other anticonvulsant drugs.

The interaction of valproic acid and other antiepileptic drugs was studied in 25 patients for 5 to 9 months. Clinical evaluations, seizure records, and antiepileptic drug levels were followed regularly. Eleven of the 13 patients required a reduced phenobarbital dose when concurrently treated with valproic acid. This reduction was prompted by sedation. An average dose reduction of 46 percent resulted in an average serum phenobarbital decrease of 15 percent. Ten of 15 patients had decreased phenytoin concentrations during concurrent administration with valproic acid. No definitive conclusion was reached about other antiepileptic drugs. Decreased phenobarbital excretion because of urine acidification and displacement of phenytoin from protein binding sites may account for the observations. Careful monitoring of anticonvulsant levels is required in anticipation of the documented interactions.

Effect of valproic acid on hepatic function.

Altered hepatic function tests occurred in four of 25 patients treated with valproic acid. An average dose reduction in three patients of 10 mg per kilogram per day resulted in reversion of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) to normal. The drug was discontinued in one patient. Careful monitoring of hepatic function is required of patients being treated with valproic acid, but our experience suggests that dose reduction alone may be effective in preventing untoward hepatic side effects.

Status epilepticus in pregnancy: effect of phenytoin malabsorption on seizure control.

In the second trimester of pregnancy in a 26-year-old woman, marked exacerbation of epileptic seizures occurred with somatomotor status epilepticus. The oral requirement of phenytoin varied, and up to 1,200 mg per day were needed to maintain a therapeutic plasma concentration during the second trimester. Intestinal malabsorption was shown to be a causal factor; 56 percent of the daily oral dose of phenytoin was found in the stool. Late in pregnancy and postpartum, therapeutic plasma concentrations of phenytoin were maintained with decreased daily oral doses. Intestinal absorption improved postpartum.

Effects of duration of epilepsy on the uncoupling of metabolism and blood flow in complex partial seizures.

We derived interhemispheric asymmetry indices (AIs) in interictal glucose uptake and blood flow in the temporal lobes of patients with intractable complex partial seizures from 18F and 15O positron emission tomograms. All patients subsequently underwent either left (n = 16) and right (n = 18) temporal lobectomy. We determined the effects on AIs of clinical seizure variables, including duration of seizure disorder, age at seizure onset, frequency of complex partial seizures, history of secondary generalization, history of febrile seizures, and magnetic resonance imaging evidence for mesial temporal sclerosis. Duration of seizure disorder produced the only significant effects. Degree of interhemispheric asymmetry in both glucose uptake and blood flow increased with duration of seizure disorder. However, the rate of increase in asymmetry was significantly greater for glucose uptake than for blood flow. These results indicate that uncoupling of metabolism and blood flow is a progressive process that results from the differential response of glucose metabolism and blood flow to chronic seizure activity. The results also suggest that duration of seizure disorder may be an important variable to consider in the interpretation of PET studies for evaluation of seizure surgery candidates.

Language dominance determined by magnetic source imaging: a comparison with the Wada procedure.

OBJECTIVE: To evaluate the validity of data derived from magnetic source imaging (MSI) regarding cerebral dominance for language in patients with intractable seizure disorder. METHOD: The authors performed functional imaging of the receptive language cortex using a whole-head neuromagnetometer in 26 consecutive epilepsy patients who also underwent the intracarotid amobarbital (Wada) procedure. During MSI recordings, patients engaged in a word recognition task. This task was shown previously to activate language areas in normal adults as well as in patients who undergo intraoperative language mapping, allowing confirmation of MSI findings. Language laterality indices were formed for both the Wada and the MSI procedures. In addition, clinical judgments regarding cerebral dominance for language were made using the two methods by independent raters. RESULTS: Cluster analysis indicated excellent agreement between the quantitative MSI and Wada indices. Rater judgments showed almost complete agreement as well. CONCLUSION: MSI is a promising method for determining cerebral dominance for language.

Effect of valproic acid on spike and wave discharges in patients with absence seizures.

Twenty-five patients with absence seizures were treated with valproic acid in doses from 17 to 62.5 mg per kilogram per day. Nineteen patients experienced reduction of spike and wave discharges; in 11 it was greater than 75 percent. Twenty-one patients had a reduction of the total time of spike and wave discharge. Four patients had increase of spike and wave discharges. Nineteen patients had fewer absence seizures. There was no correlation between plasma concentration of valproic acid and EEG change, but clinical improvement occurred when plasma levels of valproic acid reached 50 to 60 microgram per milliliter.