Quantitative analysis of EEG background activity in patients with rolandic spikes.

OBJECTIVE: The aim was to compare the background activity, through quantitative EEG analysis, of patients with rolandic spikes and normal age-matched controls. MATERIAL AND METHODS: Twenty-one channel EEG of 23 children with rolandic spikes and 39 normal children, with ages ranging from 7 to 12 years, were submitted to quantitative analysis (FFT) of discharge-free epochs. Patients and controls were divided in groups according to age (7-9 and 10-12 years old). Delta, theta, alpha and beta frequency ranges were compared between groups for all electrode positions. RESULTS: Comparing normals, the 7-9 years old group showed power reduction in the alpha and beta ranges. Comparing patients and normal age-matched groups, the patients showed power increase, at all frequency ranges in the 7-9 years old group and at delta and theta frequency ranges in the 10-12 years old group. CONCLUSIONS: Our findings agree with recent evidences that these children may differ from normal (besides the eventual occurrence of seizures); but they also suggest that these differences can be related to immaturity and not necessarily related to the epileptiform discharge.     

Computerized EEG analysis in migraine patients

Computerized analysis and topographical mapping were performed on the EEGs of 28 migraine patients (17 without and 11 with typical aura) and an age and sex-matched control group of 28 subjects.Traditional visual EEG analysis revealed only a slight diffuse slowing of theta band in eight patients (28.6%), and computerized analysis revealed significant changes in eleven (39.3%). The most frequently altered parameters were an increase in the relative power of the slow bands and/or a decrease in that of alpha band. These variations appeared to be particularly significant in the posterior regions. No significant inter-hemisphere asymmetry was revealed. Comparisons between the patient and control groups showed that the only statistically significant difference was a bilateral increase in theta power in the parieto-occipital regions of the patients.We conclude that the role of topographical EEG mapping in the clinical diagnosis of migraine is still limited.

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Sommario L'analisi computerizzata ed il mappaggio topografico dell'EEG sono stati eseguiti in 28 pazienti affetti da emicrania (17 con emicrania senz'aura e 11 con emicrania con aura tipica) e in 28 soggetti di controllo corrispondenti per età e sesso.L'analisi visiva tradizionale dell'EEG evidenziava unicamente dei modesti rallentamenti diffusi di banda theta in 8 pazienti (28.6%).L'analisi computerizzata mostrava alterazioni significative in 11 pazienti (39.3%): i parametri più frequentemente alterati consistevano in un aumento della potenza relativa della banda alpha. Tali variazioni apparivano particolarmente significative sulle regioni posteriori. Non si evidenziavano significative asimmetrie interemisferiche. Il confronto tra il gruppo dei pazienti e i controlli mostrava come unica differenza statisticamente significativa un aumento della potenza della banda theta nei soggetti emicranici sulle regioni parieto-occipitali bilateralmente.Si conclude per un ruolo tuttora limitato del mappaggio topografico dell'EEG nella diagnosi clinica di emicrania.

     

Intraindividual analysis of antiepileptic drug effects on EEG background rhythms

Antiepileptic drug (AED) therapy with either phenytoin or carbamazepine has been associated with generalized slowing of EEG background rhythms. These effects have been seen in groups of patients undergoing D manipulation, although the background slowing has been highly variable from patient to patient. Background slowing may represent an objective physiologic measure of drug impact on cerebral function and could be useful in monitoring for AED neurotoxicity in individual patients. This would require an intraindividual analysis of AED effects on EEG background rhythms. The present study was designed to develop a methodology for intraindividual analysis of EEG background changes and to apply this methodology to patients beginning or ending chronic AED therapy.EEG recordings were obtained under controlled conditions in 31 healthy subjects and were repeated after an interval of 12–16 weeks. EEG background rhythms from each record were analyzed using the fast Fourier transform, and test-retest differences for several quantitative measures were calculated from each subject's paired recordings. EEG recordings were also obtained in 6 patients beginning or ending chronic AED therapy. Test-retest differences for each patient's quantitative EEG measures were statistically compared with the distributions of test-retest measures obtained from the healthy controls.AED therapy was associated with an increase in absolute delta and/or theta power and a slowing of the dominant posterior rhythm; however, these EEG background changes varied widely in degree from patient to patient. Intraindividual analysis revealed that 5 patients had statistically significant slowing relative to the control group on at least 1 of the 9 target quantitative EEG measures, as well as a composite measure. Statistically significant slowing was also seen as a group effect. The results suggest that among patients undergoing chronic therapy with phenytoin or carbamazepine there are widely different degrees of EEG background slowing, often significantly beyond that expected on the basis of test-retest variability. Intraindividual analysis of the EEG background may be a practical objective measure of a patients unique response to chronic AED therapy.     

Interactions between antiepileptic drugs,and between antiepileptic drugs and other drugs

Interactions between antiepileptic drugs, or between antiepileptic drugs and other drugs, can be pharmacokinetic or pharmacodynamic in nature. Pharmacokinetic interactions involve changes in absorption, distribution or elimination, whereas pharmacodynamic interactions involve synergism and antagonism at the site of action. Most clinically important interactions of antiepileptic drugs result from induction or inhibition of drug metabolism. Carbamazepine, phenytoin, phenobarbital and primidone are strong inducers of cytochrome P450 and glucuronizing enzymes (as well as P‐glycoprotein) and can reduce the efficacy of co‐administered medications such as oral anticoagulants, calcium antagonists, steroids, antimicrobial and antineoplastic drugs through this mechanism. Oxcarbazepine, eslicarbazepine acetate, felbamate, rufinamide, topiramate (at doses ≥200 mg/day) and perampanel (at doses ≥8 mg/day) have weaker inducing properties, and a lower propensity to cause interactions mediated by enzyme induction. Unlike enzyme induction, enzyme inhibition results in decreased metabolic clearance of the affected drug, the serum concentration of which may increase leading to toxic effects. Examples of important interactions mediated by enzyme inhibition include the increase in the serum concentration of phenobarbital and lamotrigine caused by valproic acid. There are also interactions whereby other drugs induce or inhibit the metabolism of antiepileptic drugs, examples being the increase in serum carbamazepine concentration by erythromycin, and the decrease in serum lamotrigine concentration by oestrogen‐containing contraceptives. Pharmacodynamic interactions between antiepileptic drugs may also be clinically important. These interactions can have potentially beneficial effects, such as the therapeutic synergism of valproic acid combined with lamotrigine, or adverse effects, such as the reciprocal potentiation of neurotoxicity observed in patients treated with a combination of sodium channel blocking antiepileptic drugs.     

Analysis of background EEG activity in patients with juvenile myoclonic epilepsy

PURPOSE: To analyze background EEG activity of patients with juvenile myoclonic epilepsy (JME) with and without antiepileptic drugs. METHODS: We studied the background EEG activity in 18 patients with JME. The qEEG analysis included absolute power (AP), relative power (RP) and mean frequency (MF) of delta, theta, alpha and beta bands. The Z scores were calculated by comparison with population parameters based on the age-dependent regression function. Seven patients were unmedicated (UM) and eleven medicated (M). RESULTS: The UM group presented 69 (4.32%) abnormal Z scores and 227 (9.05%) in the M group (P<0.001). In the UM group, AP delta abnormal Z scores were identified in frontotemporal and occipital leads. In AP alpha and beta bands an increase in Z scores was encountered in frontoparietal leads in three patients. In addition, in three patients, the AP theta Z scores were below -1.96 and distributed in all regions. In the M group, AP beta Z scores were above 1.96 in frontoparietal leads in 7 of 11 patients. The AP delta increased above 1.96 in frontotemporal and occipital leads in 6 patients of 11. The AP alpha showed an abnormal decrease in Z scores in 5 of 11 patients, whereas other 5 patients presented normal scores. The AP theta presented 7 normal Z scores out of 11; this band exhibited the lowest number of abnormalities of the 4. CONCLUSION: Patients with JME have an increase in AP delta, alpha and beta bands, which is more evident in frontoparietal regions.     

Screening and characterization of antiepileptic drugs with rapidly recurring hippocampal seizures in rats

A method to efficiently screen antiepileptic drugs (AED) for their actions against complex partial and secondarily generalized seizures is presented. The procedure relies on rapidly recurring hippocampal seizures (RRHS) in rats which are first used to bring epileptic responses to a stable, fully kindled state and then to test 3 parameters--behavioral seizures, electrographic seizures, and afterdischarge thresholds--before and after drug administration. With the methods described, the effects of a given drug treatment can be thoroughly determined in a single study period. Quantitative determinations of dose-response, time-action and relative potency characteristics are readily ascertained. A battery of known AED, encompassing those in common clinical use, was studied with this system. Kindled motor seizures (classes 4 and 5) were more readily suppressed than limbic behavioral seizures (classes 1-3). Electrographic seizures were usually, but not always, shortened concurrently with suppression of behavioral seizures. Under the conditions of this study, afterdischarge thresholds were not elevated, indicating that a critical role of AED is to counteract seizure spread and prolongation. The overall behavior of the RRHS test system with AED was identical to that with traditional amygdala kindled seizures and results were in good agreement with the clinical responsiveness of the kinds of seizures that these experimental systems model. The features of RRHS make it a useful system for screening new agents for antiepileptic effects, even in circumstances where little or no information about the drug under study is available.     

Interactions between tiagabine and conventional antiepileptic drugs in the rat model of complex partial seizures

This study evaluated the interactions between tiagabine (TGB) and three conventional antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB) in amygdala-kindled rats, a reliable model of complex partial seizures in humans. Isobolographic analysis of interactions revealed that TGB interacted additively with all tested conventional AEDs for the fixed-ratio combinations of 1:3, 1:1, and 3:1. Evaluation of pharmacokinetic interactions between AEDs revealed that the observed additivity was pharmacodynamic in nature. TGB did not affect the plasma and brain concentrations of VPA, CBZ and PB. Similarly, none of the studied conventional AEDs changed the plasma or brain levels of TGB. Also, TGB, VPA, CBZ, and PB administered alone (at their median effective doses) and in combinations at the fixed-ratio of 1:1 did not impair motor performance evaluated in the chimney test. In conclusion, additivity between TGB and conventional AEDs in amygdala-kindled rats and lack of bidirectional pharmacokinetic interactions suggest that TGB appears to be a valuable drug for an add-on therapy of refractory complex partial seizures in humans.     

Computerized EEG in schizophrenic patients

We undertook a study of electroencephalograms (EEGs) in 30 right-handed, untreated patients (27.3 +/- 10.0 years; hebephrenic, 16; paranoid, 12; residual, 2) who fulfilled ICD-9 criteria for schizophrenia and compared them with sex- and age-matched controls by using the percentage of power in six EEG frequency bands calculated as a fraction of total power. T-statistic significance probability mapping (t-SPM) showed that, compared with normal controls, schizophrenics had more slow activity (delta, theta, and alpha 1) in the parieto-occipital regions, and more fast activity (beta 1) in the occipital regions. In contrast, alpha 2 activity decreased strikingly in the occipital regions and this decreased activity extended over much of the head. These findings were thought to indicate both cerebral hypofunction and excitability in acute untreated schizophrenia.     

7-nitroindazole differentially affects the anticonvulsant activity of antiepileptic drugs against amygdala-kindled seizures in rats

PURPOSE: The objective of this study was to evaluate the interaction of the preferential brain nitric oxide synthase (NOS) inhibitor, 7-nitroindazole (7-NI), with conventional antiepileptic drugs (AEDs) against amygdala-kindled seizures in rats. METHODS: Experiments were performed on fully kindled rats. Adverse effects were evaluated with the rotorod test, which assesses motor coordination, and the passive-avoidance task, which assesses memory. Plasma levels of AEDs were measured by immunofluorescence. RESULTS: 7-NI (up to 100 mg/kg) failed to modify seizure parameters. However, it reduced the severity and duration of kindled seizures when coadministered with otherwise ineffective doses of carbamazepine (CBZ) (10-20 mg/kg) or phenobarbital (PB) (20 mg/kg). Combinations of 7-NI with valproate (VPA), diphenylhydantoin (DPH), or clonazepam (CLO) were not protective. L-Arginine (500 mg/kg) did not reverse the seizure-suppressing interactions between 7-NI and the conventional AEDs. The combinations of 7-NI and CBZ or PB did not impair performance in the rotorod test. Coadministration of 7-NI with CBZ did not affect long-term memory, and 7-NI given with PB didn't affect the mnemonic effect of PB. Finally, 7-NI did not affect the free plasma levels of CBZ or PB. CONCLUSIONS: Pharmacokinetic interactions do not seem to account for the anticonvulsant effects of 7-NI combined with CBZ or PB. Central nitric oxide (NO) is possibly not involved in the synergism between 7-NI and these AEDs.     

Computerized EEG frequency analysis: sensitivity and specificity in patients with focal lesions

We performed computerized EEG frequency analysis (C-EEGFA) in 69 controls and 20 patients with focal brain lesions and focally abnormal conventional EEGs. Individual channel EEG frequency analysis variables that were helpful in differentiating the 2 groups were absolute delta and theta band power, relative delta, theta, and alpha band powers, and median-power frequency. High-frequency beta band power (20 to 32 Hz) was not useful. Changes in EEG with age were seen only after age 50 and generally consisted of an increase in anterior alpha power, with no significant increase in slowing. Correlations of C-EEGFA variables with posterior alpha power were more significant than correlations with age. Calculating normative C-EEGFA data for 5 subsets of controls, each with a different amount of posterior alpha power, increased the sensitivity of the EEG frequency analysis test without altering the specificity. Even with this correction 2 of 20 patients with focal lesions and focally abnormal conventional EEGs had normal C-EEGFA studies. If these obvious focal lesions produced normal results, more subtle diseases might not be detected. A significant clinical utility of C-EEGFA remains to be proven.     

Effect of antiepileptic drugs on spontaneous seizures in epileptic rats

The present study investigated whether spontaneously seizing animals are a valid model for evaluating antiepileptic compounds in the treatment of human epilepsy. We examined whether clinically effective antiepileptic drugs (AEDs), including carbamazepine (CBZ), valproic acid (VPA), ethosuximide (ESM), lamotrigine (LTG), or vigabatrin (VGB) suppress spontaneous seizures in a rat model of human temporal lobe epilepsy, in which epilepsy is triggered by status epilepticus induced by electrical stimulation of the amygdala. Eight adult male rats with newly diagnosed epilepsy and focal onset seizures were included in the study. Baseline seizure frequency was determined by continuous video-electroencephalography (EEG) monitoring during a 7 days baseline period. This was followed by a 2-3 days titration period, a 5-7 days treatment period, and a 2-3 days wash-out period. During the 5-7 days treatment period, animals were treated successively with CBZ (120 mg/kg/day), VPA (600 mg/kg/day), ESM (400 mg/kg/day), LTG (20 mg/kg/day), and VGB (250 mg/kg/day). VPA, LTG, and VGB were the most efficient of the compounds investigated, decreasing the mean seizure frequency by 83, 84, and 60%, respectively. In the VPA group, the percentage of rats with a greater than 50% decrease in seizure frequency was 100%, in the LTG group 88%, in the VGB group 83%, in the CBZ group 29%, and in the ESM group 38%. During the 7 day treatment period, 20% of the VPA-treated animals and 14% of the CBZ-treated animals became seizure-free. These findings indicate that rats with focal onset spontaneous seizures respond to the same AEDs as patients with focal onset seizures. Like in humans, the response to AEDs can vary substantially between animals. These observations support the idea that spontaneously seizing animals are a useful tool for testing novel compounds for the treatment of human epilepsy.     

B-vitamin deficiency in patients treated with antiepileptic drugs

Enzyme-inducing antiepileptic drugs (AEDs) produce many alterations in metabolism, including vitamin levels. Whether they produce clinically relevant deficiency of B vitamins has rarely been assessed. We obtained B-vitamin levels in patients who were being converted from an inducing AED (phenytoin or carbamazepine) to a non-inducing AED (levetiracetam, lamotrigine, or topiramate), with measurements both before and ≥ 6 weeks after the switch. A group of normal subjects underwent the same studies. Neither folate nor B12 deficiency was seen in any patient. Vitamin B6 deficiency was found in 16/33 patients (48%) taking inducers, compared to 1/11 controls (9%; p=0.031). After switch to non-inducers, only 7 patients (21%) were B6 deficient (p=0.027). The incidence of deficiency was similar regardless of which inducing or non-inducing AED was being taken. Our findings demonstrate that treatment with inducing AEDs commonly causes pyridoxine deficiency, often severe. This could conceivably contribute to the polyneuropathy sometimes attributed to older AEDs, as well as other chronic heath difficulties.     

Nitric oxide, epileptic seizures, and action of antiepileptic drugs

Nitric oxide (NO) plays a variety of physiological and pathological roles in mammalian cells. In the central nervous system NO may behave as a second messenger, neuromodulator, and neurotransmitter, which may suggest an essential role of this gaseous molecule in epilepsy and epileptogenesis. The aim of this review is to survey the current literature in terms of experimental and clinical evidence of anti- or proconvulsive properties of NO and its implications in the anticonvulsive action of antiepileptic drugs. Up-to-date multiple NO synthase (NOS) inhibitors and donors of NO were used in a plethora of seizure models (e.g. electrically and pharmacologically-evoked convulsions, amygdala-kindled seizures). Reported results vary depending on the seizure model, kind and doses of pharmacological tools used in experiments, and route of drug administration. The most thoroughly tested NOS inhibitor was 7- nitroindazole (7-NI), which presented anticonvulsive properties in most known models of seizures. The clear-cut proconvulsant action of 7-NI was observed only in kainate-, nicotine-, and soman-induced convulsions in rodents. This NOS inhibitor enhanced the anticonvulsant action of almost all available classic and second-generation antiepileptic drugs except tiagabine, felbamate, and topiramate. The effect of NG-nitro-L-arginine methyl ester was not so unambiguous. In pentylenetetrazole, pictotoxin, and N-methyl-Daspartate seizure models the inhibitor exhibited dose-dependent bidirectional action. NG-nitro-L-arginine methyl ester potentiated the efficacy of diazepam and clonazepam, diminished that of valproate and phenobarbital, but did not affect the anticonvulsant action of phenytoin and ethosuximide. On the other hand, NG-nitro-L-arginine, was anticonvulsant in nicotine-, glutamate-, and hyperbaric O2- evoked seizures, and proconvulsant in pilocarpine-, kainate-, bicuculline-, aminophylline-, and 4-aminopyridine-induced convulsions. NG-nitro-L-arginine remained without effect on the anticonvulsant action of both classic (valproate, phenobarbital, diazepam) and new generation (oxcarbazepine, felbamate, and ethosuximide) antiepileptic drugs. The action of ethosuximide was even impaired. Summing up, in the present state of knowledge the only reasonable conclusion is that NO behaves as a neuromodulator with dual - proconvulsive or anticonvulsive - action.     

Interactions between antiepileptic and chemotherapeutic drugs

Cancer and epilepsy commonly co-occur, and concomitant administration of antiepileptic (AEDS) and chemotherapeutic drugs (CTDs) is necessary in many cases. Many drugs are metabolised by the hepatic cytochrome P450 (CYP) isoenzyme system, and coadministration of AEDs and CTDs can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. These interactions can cause insufficient tumour and seizure control or lead to unforeseen toxicity. Enzyme-inducing AEDs reduce the effects of taxanes, vinca alkaloids, methotrexate, teniposide, and camptothecin analogues. Inhibition of the metabolism of nitrosoureas or etoposide by valproic acid can lead to CTD toxicity. Poor seizure control may result from the combinations of phenytoin with cisplatin or corticosteroids, and valproic acid with methotrexate. Increased toxicity of AEDs can occur when phenytoin is combined with 5-fluorouracil. Use of enzyme-inducing AEDs should be avoided in patients with cancer, particularly in association with chemotherapy. Generally, valproic acid-although not free from interactions-would be the agent of first choice. Some of the newer AEDs not metabolised by the P450 system may prove to be good alternatives.     

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy

PurposeA study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy.MethodFrom the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000–2013 (n = 529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011–2012 as monotherapy (n = 1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX–PHARAO database, were analysed.ResultsHypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3–5 (OR 4.22; p = 0.05) or over six (OR 8.86; p = 0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs.ConclusionsElderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions.