bluuebunny/crossref_metadata_2025 huggingface dataset:
Frovatriptan: A Review of Drug‐Drug Interactions
Authors: Buchan P. , Wade A. , Ward C. , Oliver S.D. , Mfpm  , Stewart A.J. , Freestone S.
Published: March 2003

Objective.—To investigate the potential for interactions involving drugs likely to be coadministered with frovatriptan.

Background.—Frovatriptan is a new 5‐hydroxytryptamine (5‐HT)1B/1D agonist. Preclinical data suggest that the pharmacokinetic and pharmacological profile of frovatriptan may differ from that of the currently available triptans.

Methods.—The potential for interactions between frovatriptan and other drugs was investigated using in vitro methods, studies in healthy volunteers, and retrospective analysis of data from phase I trials.

Results.—In vitro, frovatriptan was principally metabolized by cytochrome P‐450 (CYP) 1A2 but was found not to be an inhibitor or inducer of this or other CYP isoenzymes. Frovatriptan was only a weak inhibitor of monoamine oxidase at very high concentrations in vitro and was not a substrate for this enzyme (unlike some other triptans). Coadministration with moclobemide, at doses known to inhibit monoamine oxidase‐A, did not affect the pharmacokinetics of frovatriptan. Binding to plasma proteins was low (15%), and binding to erythrocytes was moderate (60%) and unlikely to be a source of interaction with other drugs. The pharmacokinetics of frovatriptan were not affected by moderate alcohol intake. There were slight increases in area under the curve and maximum concentration on concomitant administration with the combined oral contraceptives, propranolol, and fluvoxamine; and slight decreases in these parameters on concomitant administration with ergotamine and in tobacco smokers; these findings were considered to have no clinical significance in view of frovatriptan's large therapeutic index (well tolerated at doses ranging from 2.5 to 40 mg). These effects can be attributed primarily to modification of CYP1A2 activity but their impact is limited, probably due to frovatriptan also undergoing renal clearance and the likely role of blood cell binding in controlling the amount of unbound drug available for elimination.

Conclusions.—Because it has no inhibitory or inducing effect on CYP isoenzymes and is only slightly bound to plasma proteins, it is unlikely that frovatriptan will alter the pharmacokinetics of concomitantly administered drugs. Frovatriptan, therefore, appears to have a low risk of interaction with other drugs, and adjustments of dose are unlikely to be required when it is coadministered with other agents.
Spectrum of Clinical and Histopathologic Responses to Intracranial Electrodes: From Multifocal Aseptic Meningitis to Multifocal Hypersensitivity‐type Meningovasculitis
Authors: Stephan Christina L. , Kepes John J. , SantaCruz Karen , Wilkinson Steven B. , Fegley Barbara , Osorio Ivan
Published: March 2003

Summary:  Purpose: We sought to characterize and compare the histopathologic and clinical changes elicited by subdural and depth electrodes in subjects undergoing epilepsy surgery evaluation.

Methods: A retrospective review of clinical records, imaging and histopathologic studies of epilepsy surgery cases requiring subdural strips and depth electrodes for localization of epileptogenic tissue was performed between 1993 and1999. Forty‐nine subjects had a combination of subdural and depth, whereas 10 had depth electrodes only. Histopathologic changes were classified as mild, moderate, or severe based on the density, extent, and composition of the inflammatory infiltrate.

Results: Subdural electrodes induced a clinical picture of transient aseptic meningitis; histopathologically, the infiltrates were moderate in degree in the majority (73%) and severe in the remainder (27%), with T cells and eosinophils infiltrating the cortex and arteriolar walls (hypersensitivity‐type response). Depth electrodes alone caused minimal or no symptoms of meningeal irritation; the cellular response elicited by these electrodes was mild in five and moderate in the remaining five cases; severe inflammation was not observed in this group. Although the proportion of small clinically silent hematomas was larger in cases with depth (five of 59) compared with subdural electrodes (one of 49), microhemorrhages were considerably more numerous with subdural than with depth electrodes.

Conclusions: These results suggest that the spectrum of brain responses to foreign bodies is wide, ranging from self‐limited physiologic to hypersensitivity‐type reactions of varying severity. Subdural strips elicited more intense inflammation than did depth electrodes. The histopathologic extent of the reaction to either type of electrodes could not be precisely defined because of the retrospective nature of this study. History of allergy to latex or previous craniotomies are probable risk factors for the hypersensitivity‐type reaction. Surgical outcome, excellent in the majority, was independent of the severity or type of inflammation, and there have not been neurologic or systemic sequelae.
Transient Dystonias in Three Patients Treated with Tiagabine
Authors: Wolańczyk Tomasz , Grabowska–Grzyb Ałbena
Published: March 2003

Summary:  Purpose: Tiagabine (TGB) is a new antiepileptic drug (AED) with γ‐aminobutyric acid (GABA)ergic mechanism of action. GABAergic compounds may influence the extrapyramidal system, probably via modulation of dopaminergic nigrostriatal neurons. A well‐known side effect of TGB is probably dose‐related extrapyramidal tremor. To our knowledge, acute dystonias associated with TGB treatment have yet to be described.

Methods: Three patients with transient acute dystonic reactions while taking TGB as add‐on therapy with carbamazepine (CBZ) are presented. The focal limb dystonia in one case, an oromandibular dystonia in second, and writer's cramp in third one were observed.

Results: In all cases dystonic movements resolved spontaneously without discontinuation of TGB therapy and without any concomitant treatment.

Conclusions: Tiagabine may cause various mild extrapyramidal side effects. All three cases reported were diagnosed with transient possibly drug‐related dystonia after increase in TGB dose. It remain unclear whether dystonic movements are specific for patients treated with TGB/CBZ bitherapy.
The Management of Refractory Idiopathic Epilepsies
Authors: Perucca Emilio
Published: March 2003

Summary: Idiopathic epilepsies comprise a wide variety of partial and generalized syndromes that have in common a known or presumed genetic etiology and the lack of overt abnormalities other than the epilepsy itself. Most of these epilepsies have a benign natural history and/or show a favorable response to antiepileptic drug (AED) therapy, but pharmacoresistance does occur in some patients. In general, therapeutic algorithms in idiopathic partial epilepsies (IPEs) are similar to those used for symptomatic partial epilepsies, but aggressive pharmacologic therapy is rarely indicated in these patients. In self‐limited conditions such as benign epilepsy of childhood with centrotemporal spikes or some forms of benign epilepsy with occipital paroxysms, AED treatment may not even be indicated unless seizures interfere significantly with quality of life. Valproate (VPA) is usually regarded as the drug of choice in idiopathic generalized epilepsies (IGEs). Most patients become rapidly seizure free, and poor compliance or prescription of an inappropriate AED because of misdiagnosis are the most common causes of treatment failure in IGEs. In those patients who did not respond well to VPA (or in whom VPA is considered contraindicated), the choice of alternative AEDs is guided by syndromic diagnosis and associated possible coexistence of multiple seizure types. Lamotrigine is establishing itself as a useful agent for many refractory IGEs, and might be considered for first‐line use in selected patients. Topiramate (TPM) is another promising new agent in the management of refractory tonic–clonic seizures of nonfocal onset, but its potential efficacy against other primarily generalized seizure types has not been clearly established. Some of the older drugs, particularly ethosuximide (ESM), barbiturates, and benzodiazepines (BZDs), still have an important role in the management of refractory IGEs, especially in combination with VPA. Because carbamazepine (CBZ), phenytoin (PHT), tiagabine (TGB), vigabatrin (VGB), and gabapentin (GBP) may precipitate or aggravate absence and/or myoclonic jerks, their role in IGE syndromes associated with multiple seizure types is limited mostly to adjunctive use in patients unresponsive to first‐line therapy.
Tiagabine in Clinical Practice
Authors: Genton Pierre , Guerrini Renzo , Perucca Emilio
Published: March 2003

Summary: Among the newly introduced antiepileptic drugs (AEDs), tiagabine (TGB) stands out as a compound with a well‐understood and documented mechanism of action. It is a lipophilic derivative of nipecotic acid that blocks γ‐aminobutyric acid (GABA) reuptake by inhibition of the GAT‐1 transportation system, and that has no other significant pharmacodynamic effect. The relationship between intake and blood levels is linear. Usual daily maintenance doses range from 20 to 50 mg. It is completely absorbed by the gastrointestinal tract, and its half‐life is ∼7–9 h. TGB is sensitive to enzyme induction: when coprescribed with enzyme‐inducing AEDs, its half‐life is shortened to 2–3 h, whereas the daily dosage has to be increased into the upper range. It should be given 3 times per day. Placebo‐controlled, double‐blind, add‐on studies conducted in patients with drug‐resistant focal epilepsies have demonstrated its efficacy and overall safety. The clinical benefits appear to persist over time. Data on its use in monotherapy are scanty. The efficacy and tolerability of TGB in the pediatric age still remain to be investigated adequately. In daily practice, TGB appears to be a safe drug, but mild to moderate side effects are frequently seen, especially during titration: these include dizziness and fatigue, and are clearly abated when the drug is absorbed during meals. Titration should be especially slow, no faster than 5 mg weekly. Clinicians also should beware of the possible occurrence of confusion, which may be misdiagnosed as absence status, a short‐lasting, quickly reversible central nervous system–related side effect that appears to be correlated with the peak plasma concentrations of TGB. Particularly beneficial indications for TGB and/or AED associations including TGB have not been pointed out, but there is a hint that it works best in temporal lobe epilepsies.
Carnitine Levels and the Ketogenic Diet
Authors: Berry‐Kravis Elizabeth , Booth Gayle , Sanchez Ana Carolina , Woodbury‐Kolb Jean
Published: March 2003

Summary: Purpose:To determine the long‐term effect of the ketogenic diet (KD) on carnitine levels and whether carnitine depletion is a significant cause of clinical complications during KD initiation or treatment.

Methods:Carnitine levels at 0, 1, 6, 12, and 24 months of diet treatment, carnitine antiepileptic drug (AED) history, lowest blood glucose and time to achieve ketosis during diet initiation, and diet complications were analyzed for 38 consecutive patients who initiated the KD from May 1997 to March 2000. Carnitine levels at follow‐up were analyzed for eight patients started on the diet before to May 1997.

Results:Total carnitine (TC) at diet initiation correlated negatively with the number of AEDs at diet initiation but not with number of past AEDs, lowest blood glucose, or time to ketosis. TC decreased in the first months of diet treatment and then stabilized or increased slightly with long term treatment. Only 19% of patients were supplemented with carnitine for low TC. No patient showed clinical signs of carnitine deficiency.

Conclusions:Multiple AED exposure lowers TC, but actual TC deficiency in patients initiating the KD is not common, and TC levels do not appear to predict hypoglycemia or problems achieving ketosis. Mild carnitine depletion may occur early in KD treatment and occasionally TC decreases out of the normal range, without clinical symptoms. TC stabilizes or increases back toward baseline with long‐term treatment, and most patients do not require carnitine supplementation.
Alfentanil‐Induced Epileptiform Activity: A Simultaneous Surface and Depth Electroencephalographic Study in Complex Partial Epilepsy
Authors: Ross J. , Kearse L. A. , Barlow M. K. , Houghton K. J. , Cosgrove G. R.
Published: March 2003

Summary:  Purpose: Alfentanil is a high potency mu opiate receptor agonist commonly used during presurgical induction of anesthesia. This and other opiate receptor agonists have demonstrated proconvulsant effects in animals, but these properties have been less consistently demonstrated in humans. Most human scalp EEG studies have failed to demonstrate induction of epileptiform activity with these agents, which is inconsistent with findings using intracranial EEG. Simultaneous scalp and depth EEG recordings have yet to be performed in this setting. The relationship between opiate dose and proconvulsant activity is unclear.

Methods: Simultaneous scalp and depth electrode recordings were performed on five patients with complex partial epilepsy (CPE) who underwent alfentanil anesthesia induction before depth electrode removal. Consecutive equal bolus doses of alfentanil were administered to each patient according to strict time intervals so as to assess their correlation with any induced epileptiform activity.

Results: Epileptiform activity was induced by alfentanil in three of five patients. Two of these patients had electrographic seizures. Epileptiform activity was only detected from the depth electrodes, occurring within 2 min of the first bolus dose in all three cases. Further increase or spread of epileptiform activity did not occur despite cumulative bolus doses of alfentanil.

Conclusions: Alfentanil is proconvulsant in patients with CPE. Induced seizures may be subclinical and lack a scalp EEG correlate. There is a complex dose–response relationship. Alfentanil induction of anesthesia should be approached with caution in patients with CPE.
Impaired Motor Function in Patients with Psychogenic Pseudoseizures
Authors: Sackellares Dalma Kalogjera , Sackellares J. Chris
Published: March 2003

Summary:  Purpose: To evaluate motor speed and grip strength in patients with well‐documented psychogenic pseudoseizures.

Methods: We analyzed manual motor speed and grip strength in a group of 40 patients with confirmed psychogenic pseudoseizures (without evidence of concomitant epilepsy) and a group of 40 normal controls matched for handedness and gender, and of comparable age. The two groups were compared with respect to manual motor performance with the dominant hand, nondominant hand, and asymmetry between the dominant and nondominant hands. For the patient sample, we reviewed the neurologic history.

Results: Patients with pseudoseizures performed more poorly than controls with both dominant and nondominant hands. In addition, pseudoseizure patients failed to demonstrate the dominant‐hand advantage observed in the normal control subjects on both tasks. The patient group had a high incidence of head trauma and other antecedent neurologic risk factors, and the proportion of left‐handers was 3 times higher than expected.

Conclusions: Bilaterally reduced motor speed and grip strength, reduced intermanual performance asymmetry, the high percentage of left‐handers, and historical evidence of antecedent insults to the brain indicate that frontal lobe impairment may be common in patients with psychogenic pseudoseizures.
Vagus Nerve Stimulation in Children with Refractory Seizures Associated with Lennox–Gastaut Syndrome
Authors: Frost Michael , Gates John , Helmers Sandra L. , Wheless James W. , Levisohn Paul , Tardo Carmelo , Conry Joan A.
Published: March 2003

Summary:  Purpose: Vagus nerve stimulation (VNS) is approved for use for refractory partial seizures. Nevertheless, information regarding VNS therapy for special populations, including Lennox–Gastaut syndrome (LGS) is limited. We discuss the effectiveness, tolerability, and safety of VNS therapy in patients with LGS.

Methods: A six‐center, retrospective study evaluated the effectiveness of VNS therapy in patients with LGS at 3 and 6 months and compared preimplant and postimplant seizure frequency. Adverse effects and quality of life (QOL) were included as secondary measures.

Results: Fifty patients, median age 13 years, with medically refractory epilepsy, were implanted. Median age at onset of seizures was 1.4 years, and a median of nine anticonvulsants (AEDs) had been tried before implantation. Data‐collection forms were designed for retrospectively gathering data on each patient's preimplant history, seizures, implants, device settings, QOL, and adverse events. Median reductions in total seizures were 42% at 1 month, 58.2% at 3 months, and 57.9% at 6 months. The most common adverse events reported were voice alteration and coughing during stimulation. Other uncommon adverse events included increased drooling and behavioral changes. Investigators noted that QOL had improved for some patients in the study.

Conclusions: VNS is an effective treatment for medically refractory epilepsy in LGS. This treatment is well tolerated, safe, and may improve QOL.
Levetiracetam Psychosis in Children with Epilepsy
Authors: Kossoff Eric H. , Bergey Gregory K. , Freeman John M. , Vining Eileen P. G.
Published: March 2003

Summary: Purpose:Levetiracetam is a new anticonvulsant (AED) with a novel mechanism of action. Although it is generally well tolerated with a good cognitive profile, irritability and hostility have been reported in some adults taking levetiracetam. Observations in children are limited; levetiracetam is not yet approved by the Food and Drug Administration for use in children.

Methods:In four young patients, acute psychosis developed within days to months of initiation of levetiracetam for seizures.

Results:A 5‐year‐old girl began having visual hallucinations of spiders in her room 14 days after starting levetiracetam. A 13‐year‐old boy began having auditory hallucinations, insomnia, and screaming behavior 3 months after initiation of levetiracetam. A 16‐year‐old girl became acutely agitated, hyperreligious, and had persecutory delusions within 7 days of starting levetiracetam. A 17‐year‐old girl had auditory hallucinations telling her to sing and yell after 30 days of taking the drug. All four children had dramatic improvement within days of either discontinuing or decreasing the dose of levetiracetam. The three adolescents had historical findings consistent with mild behavioral problems before initiating levetiracetam, and all four patients had prior cognitive deficits.

Conclusions:Reversible treatment‐emergent psychosis associated with levetiracetam therapy was observed in four children and adolescents. Whether rapid initiation or prior neurobehavioral problems predispose to this side effect is not established.
Induction of Hypersensitivity to a Previously Tolerated Antiepileptic Drug by a Second Antiepileptic Drug
Authors: Klassen B. D. , Sadler R. M.
Published: March 2003

Summary: Purpose:To describe the induction of hypersensitivity to one antiepileptic drug (AED) by a second AED.

Methods:Case report and review of the relevant literature.

Results:A patient is reported who was treated with phenytoin (PHT) for 6 months without adverse effect, but developed a hypersensitivity reaction with rash, fever, elevated liver enzymes, lymphadenopathy, and colitis 6 weeks after the introduction of carbamazepine (CBZ). PHT and CBZ were discontinued. Seizures continued despite treatment with valproic acid and clobazam. A decision was made to cautiously reintroduce PHT. Diffuse skin rash and pharyngitis appeared after two doses of PHT.

Conclusions:The AED hypersensitivity syndrome has been thought to occur as a consequence of preexisting pharmacogenetic and immunologic abnormalities. Our case demonstrates induction of hypersensitivity to an AED that had been formerly well tolerated, after a hypersensitivity reaction to another AED. This is distinct from simple cross‐reactivity between one or more drugs. Such induction of hypersensitivity with AEDs has not been previously described.
Functional MRI of Language Processing: Dependence on Input Modality and Temporal Lobe Epilepsy
Authors: Carpentier A. , Pugh K. R. , Westerveld M. , Studholme C. , Skrinjar O. , Thompson J. L. , Spencer D. D. , Constable R. T.
Published: March 2003

Summary:  Purpose: Functional magnetic resonance imaging (MRI) using two language‐comprehension tasks was evaluated to determine its ability to lateralize language processing and identify regions that must be spared in surgery.

Methods: Two parallel cognitive language tasks, one using auditory input and the other visual input, were tested in a group of control subjects and in temporal lobe epilepsy patients who were candidates for surgical intervention. The patient studies provide an opportunity to compare functional MRI language localization with that obtained using Wada testing and electrocorticography. All of the patients in this study underwent all three procedures and a battery of neuropsychological testing. Such studies provide an opportunity not only to validate the fMRI findings but also, by comparing the patient results with those obtained in control subjects, to provide insight into the impact of a pathology such as epilepsy on cortical organization or functional patterns of activation.

Results: The results reveal both modality‐dependent and modality‐independent language‐processing patterns for visual versus auditory task presentation. The visual language task activated distinct sites in Broca's area, BA (Brodmann area) 44 that were not activated in the auditory language task. The auditory language task strongly activated contralateral right BA22‐21 area (homologous to Wernicke's area on the left). Language lateralization scores were significantly stronger for visual than for auditory task presentation. The conjunction of activation from the two different input modalities (modality‐independent areas) likely highlights regions that perform more abstract computations (e.g., syntactic or pragmatic processing) in language processing. Modality‐specific areas (e.g., right Wernicke, left fusiform gyrus, Broca BA44, supramarginal gyrus), appear to cope with the computations relevant to making contact with these more abstract dimensions. Patients showed recruitment of contralateral homologous language areas (p < 0.005) that was significantly above that found in a normal control group. Extra‐ and intraoperative cortical stimulations were concordant with the fMRI data in eight of 10 cases. The fMRI lateralization scores were also consistent with the Wada testing in 8/10 patients.

Conclusions: The fMRI results demonstrate that the epileptic brain may be a progressive model for cortical plasticity.
Myoclonus in Epilepsy Patients with Anticonvulsive Add‐On Therapy with Pregabalin
Authors: Huppertz Hans‐Jürgen , Feuerstein Thomas J. , Schulze‐Bonhage Andreas
Published: March 2003

Summary:  Purpose: To report on the occurrence of myoclonus in patients receiving pregabalin (PGB) for the treatment of focal epilepsy.

Methods: Clinic records of 19 patients who were consecutively enrolled at a tertial referral epilepsy center in a randomized, double‐blind and/or open add‐on study with PGB were reviewed.

Results: In four patients treated with PGB, focal myoclonus newly developed. The side effect appeared with PGB doses of 50–600 mg/day; the intensity showed some dose dependency. All patients had medically refractory focal epilepsy and received other antiepileptic drugs (AEDs) besides the study medication. One patient showed focal myoclonic jerks of the left arm, whereas the other patients developed multifocal myoclonus. Polygraphic studies including electromyogram (EMG)‐triggered back‐averaging of the EEG in the patient with the highest frequency of myoclonic jerks showed no visible correlate of the myoclonus. In this patient, frequency and intensity of myoclonic jerks significantly decreased after dose reduction of PGB. In the other cases, myoclonus was only subtle and did not significantly interfere with daily activities, so that a dose reduction of PGB was not considered necessary.

Conclusions: These data indicate a relatively high incidence (four of 19) of myoclonus associated with PGB therapy. The rate seems to be at least as high as reported in patients receiving the structurally similar anticonvulsant gabapentin.
Effect of Vagal Nerve Stimulation on Interictal Epileptiform Discharges: A Scalp EEG Study
Authors: Kuba Robert , Guzaninová Markéta , Brázdil Milan , Novák Zdenĕk , Chrastina Jan , Rektor Ivan
Published: March 2003

Summary:  Purpose: To investigate the effects of acute vagal nerve stimulation (VNS) on interictal epileptiform discharges (IEDs).

Methods: Fifteen epilepsy patients, all of whom had been treated with VNS for ≥6 months, entered the study. In each subject, the absolute number of IEDs was counted at the baseline period (BP), the stimulation period (SP), six interstimulation periods (IPs), and the prestimulation period (PP), by using an original paradigm. The number of IEDs at the BP and the PP was compared with the number of IEDs at the SP and IPs. The results were correlated with other variables (the duration of VNS, the value of the output current, the duration of epilepsy, the type of epilepsy, the effect of VNS, and the effect of extrastimulation).

Results: We observed a significantly higher reduction in the number of IEDs in the SP and all the IPs as compared with the BP. We noticed a significantly higher reduction in the number of IEDs in the SP and in the first IP as compared with the PP. The reduction of IEDs was greater in patients who responded to VNS (>50% reduction of all seizures) and in patients who responded positively to magnetic extrastimulation. There were no other significant results in the reduction of IEDs when comparing other variables.

Conclusions: Short‐term VNS reduces IEDs significantly. The reduction is most prominent during the SP (i.e., when the pulse generator is active). The value of reduction of IEDs is higher in patients who respond to VNS and in patients with positive experiences with magnetic extrastimulation. These results can be useful in predicting the effect of VNS.
Reduced Extrahippocampal NAA in Mesial Temporal Lobe Epilepsy
Authors: Mueller Susanne G. , Suhy Joyce , Laxer Kenneth D. , Flenniken Derek L. , Axelrad Jana , Capizzano Andres A. , Weiner Michael W.
Published: March 2003

Summary:  Purpose: Structural and metabolic abnormalities in the hippocampal region in medial temporal lobe epilepsy (mTLE) are well described; less is known about extrahippocampal changes. This study was designed to characterize extrahippocampal metabolic abnormalities in mTLE with magnetic resonance spectroscopy in combination with tissue segmentation and volumetry of gray and white matter.

Methods: Multislice magnetic resonance spectroscopic imaging (1H‐MRSI) in combination with tissue segmentation was performed on 16 patients with mTLE and 12 age‐matched healthy volunteers. The data were analyzed by using a regression‐analysis model that estimated the metabolite concentrations in 100% cortical gray and 100% white matter in the frontal lobe and nonfrontal brain. The segmented image was used to calculate the fraction of gray and white matter in these regions.

Results: mTLE had significantly lower N‐acetyl aspartate (NAA) in ipsi‐ and contralateral frontal gray (p = 0.03) and in ipsi‐ and contralateral nonfrontal white matter (p = 0.008) compared with controls. Although there were no associated volumetric deficits in frontal gray and white matter, ipsilateral nonfrontal gray matter (p = 0.003) was significantly smaller than that in controls.

Conclusions: mTLE is associated with extrahippocampal metabolic abnormalities and volumetric deficits, but these do not necessarily affect the same regions.
Early‐onset Absence Epilepsy and Paroxysmal Dyskinesia
Authors: Guerrini Renzo , Sanchez‐Carpintero Rocio , Deonna Thierry , Santucci Margherita , Bhatia Kailash P. , Moreno Teresa , Parmeggiani Lucio , Bernardina Bernardo Dalla
Published: March 2003

Summary: Purpose:To report on the association of childhood absence epilepsy and paroxysmal dyskinesia (PD).

Methods:We describe six patients aged 6 to 27 years (mean, 14 years) who were identified in five centers participating in a European study group. Patients had been followed up clinically from the first symptoms and had been studied with video‐EEG recordings of absence seizures, videotaping of dyskinetic attacks, and brain magnetic resonance imaging (MRI).

Results:Four patients were sporadic, and two were siblings. Age at onset of absence seizures was unusually early (range, 3 months to 3 years 6 months; mean, 16 months), with four children having their first episodes within the first year of life, and the remaining two by age 3 years 6 months. Resistance to multiple appropriate drugs was seen in five children, in four of whom absences improved remarkably when ethosuximide was added. Absences remitted between age 8 and 13 years in the three patients in whom follow‐up was long enough. Different types of PD were seen including paroxysmal kinesigenic dyskinesia (one patient), paroxysmal exercise‐induced dystonia (three patients), and paroxysmal tonic upgaze (two siblings). In most patients, PD appeared at a later age than, co‐occurred with, and outlasted absence seizures. Only in the two siblings with tonic upgaze, dyskinetic attacks had an earlier onset. PD improved with increasing age and did not usually produce severe disability.

Conclusions:There is a widening spectrum of epilepsy and PD syndromes, within which epilepsy has the characteristics of the common idiopathic syndromes, with some atypical features.
Maternal Deprivation Stress Exacerbates Cognitive Deficits in Immature Rats with Recurrent Seizures
Authors: Huang Li‐Tung , Holmes Gregory L. , Lai Ming‐Chi , Hung Pi‐Lien , Wang Chih‐Lu , Wang Tzu‐Jou , Yang Chin‐Hwa , Liou Chia‐Wei , Yang San Nan
Published: March 2003

Summary:  Purpose: Maternal deprivation is stressful for the neonate. The aim of this study was to investigate the short‐ and long‐term effects of maternal separation on recurrent seizures in the developing brain.

Methods: Rats were divided into four groups according to whether the rat pups were treated with maternal deprivation from postnatal day 2 (P2) to P9 or neonatal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazol (PTZ) from P10 to P14. Rats in the control group received saline i.p. injection from P10 to P14; rats in the isolation group underwent daily separation from their dams from P2 to P9; rats in the PTZ‐treated group were subjected to PTZ‐induced recurrent seizures from P10 to P14; rats in the isolation plus PTZ–treated group were subjected to maternal deprivation from P2 to P7 followed by serial seizures from P10 to P14. In addition, subsets of rats at P15 were killed and the brains assessed for acute neuronal degeneration. Visual–spatial memory test using the Morris water maze task was performed at P80. After testing, the hippocampus was evaluated for histologic lesions and cyclic adenosine monophosphate (cAMP)‐responsive element‐binding protein phosphorylation at serine‐133 (pCREBSer‐133), an important transcription factor underlying learning and memory.

Results: All rats given PTZ developed recurrent seizures. After PTZ administration, rats with a history of maternal deprivation had more intense impairment than did rats with maternal deprivation and neonatal seizures than those without deprivation. Neuronal degeneration was most prominent in the rats exposed to maternal deprivation plus recurrent seizures. Rats receiving maternal deprivation or PTZ‐induced recurrent seizures exhibited only spatial deficits, but no morphologic changes in the hippocampus. However, rats with maternal deprivation plus PTZ‐induced recurrent seizures exhibited worse visual–spatial learning compared with rats with either isolation or PTZ‐induced recurrent seizures alone. The levels of pCREBSer‐133 may play a role in the decrease in the hippocampus from the rats subjected to maternal deprivation and/or PTZ‐induced recurrent seizures, as compared with rats exposed to vehicle‐control saline. These results indicate that repeated maternal deprivation can exacerbate long‐term cognitive deficits resulting from neonatal seizures. In addition, impaired phosphorylation of CREBSer‐133.

Conclusions: Repeated maternal deprivation stress has synergistic effects with recurrent seizures in inducing neurologic damage in the developing brain.
Effects of the Novel Antiepileptic Drug Levetiracetam on Spontaneous Recurrent Seizures in the Rat Pilocarpine Model of Temporal Lobe Epilepsy
Authors: Glien Maike , Brandt Claudia , Potschka Heidrun , Löscher Wolfgang
Published: March 2003

Summary:  Purpose: Animal models in which seizures are elicited by chemical or electrical means are commonly used for identification and preclinical testing of novel antiepileptic drugs (AEDs). Such models have been successful in discovering all the new AEDs. However, despite the high efficacy of AEDs against elicited seizures in rodent models, a significant proportion of epilepsy patients with spontaneous recurrent seizures is resistant to these drugs. It is not known whether drug testing in rodent models with spontaneous recurrent seizures would yield a more predictive result with respect to AED efficacy in the clinic. This led us to test one of the novel AEDs, levetiracetam (LEV), in a rat model of temporal lobe epilepsy (TLE) with spontaneous recurrent seizures.

Methods: Wistar rats were subjected to pilocarpine‐induced status epilepticus and recorded for spontaneous recurrent seizures in the months after pilocarpine treatment. A group of rats with frequent spontaneous seizures was used for the drug trial with LEV. The experimental protocol for drug testing in these rats was as follows. For 2 weeks, rats received subcutaneous implantation of osmotic minipumps filled with saline (predrug control period), followed by a 2‐week period with implantation of LEV‐filled minipumps (drug period), after which pumps were replaced by drug‐free pumps for 2 weeks (postdrug control period). The LEV concentration in the pumps during the drug period was adjusted to give daily doses resulting in the maximal plasma concentration range determined previously in patients with TLE during prolonged treatment with LEV. During the 6 weeks of the experiment in epileptic rats, seizures were recorded by video monitoring.

Results: Average seizure frequency during the pre‐ and postdrug control period in a group of eight epileptic rats was 21 and 25 seizures. This was reduced to an average seizure frequency of 8 seizures during the 2 weeks of treatment with LEV. However, the individual response of rats to LEV varied markedly from complete seizure control to no effect at all, although plasma drug levels were within the therapeutic range in all rats. When seizure frequency was separately calculated for the first and second week of treatment, the significant anticonvulsant effect determined in the first week was partially diminished in the second week, suggesting that tolerance may have developed in some of the rats.

Conclusions: The data demonstrate that interesting results can be obtained by drug testing in epileptic rats, giving a more realistic prediction of clinical efficacy than results from drug testing in animal models with elicited seizures. Thus, although drug trials in rats with spontaneous recurrent seizures are laborious and time‐consuming, such trials should be added to the preclinical characterization of novel AEDs.
Psychiatric Comorbidity and Hostility in Patients with Psychogenic Nonepileptic Seizures Compared with Somatoform Disorders and Healthy Controls
Authors: Mökleby Kjell , Blomhoff Svein , Malt Ulrik Fr. , Dahlström Astri , Tauböll Erik , Gjerstad Leif
Published: March 2003

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

Methods:Twenty‐three patients with psychogenic nonepileptic seizures (PNESs) and 23 age‐ and sex‐matched patients with somatoform disorders (SDs) underwent a clinical and a semistructured psychiatric interview (MINI) and filled in the Hospital Anxiety and Depression scale (HAD) and the Aggression Questionnaire (AQ). Twenty‐three sex‐ and age‐matched controls without psychopathology also underwent a clinical interview and completed the HAD and AQ.

Results:PNES reported more minor head injuries in the past than did the two comparison groups, and more unspecific EEG dysrhythmias were observed on EEG. Twenty‐one PNES patients and 18 with SDs had comorbid psychiatric diagnoses. However, the mean number of comorbid psychiatric diagnoses was higher in the PNES group (1.9 ± 0.3 compared with 1.5 ± 0.5 in the SD group; p = 0.003). Ten PNES patients additionally had a somatoform pain disorder, and seven had an undifferentiated somatoform disorder. Both patient groups reported significantly higher levels of anxiety, depression, and anger than did the healthy controls, but the PNES patients had significantly higher level of hostility than both comparison groups.

Conclusions:Increased psychiatric comorbidity is known to be associated with poorer response to regular interventions, and hostility is associated with more hostile coping patterns, often interfering with treatment compliance. Thus the increased prevalence of soft neurologic signs and comorbid psychiatric disorders and increased hostility as well in the PNES group, emphasizes that assessment and treatment of patients with PNES referred to a tertiary center requires an integrated approach involving both neurologic and psychiatric resources.
Autonomic Auras: Left Hemispheric Predominance of Epileptic Generators of Cold Shivers and Goose Bumps?
Authors: Stefan H. , Pauli E. , Kerling F. , Schwarz A. , Koebnick C.
Published: March 2003

Summary: Purpose:Autonomic seizures in temporal lobe epilepsies associated with “cold shivers and goose bumps” as a principal ictal sign or aura have only rarely been studied.

Methods:Sixteen patients with autonomic auras [cold shivers or cold sweats (n = 11), goose bumps (n = 4), one patient showed both ictal signs] were analyzed.

Results:Lesions were detected in 12 patients. The etiology was heterogeneous [cryptogenic, arteriovenous (AV)‐malformation cyst, trauma, hippocampal sclerosis]. Eight patients underwent epilepsy surgery. The localization and lateralization of the focal epileptic activity in the temporal lobes was determined either by magnetic resonance imaging lesions, EEG, ictal signs, or single‐photon emission computed tomography imaging.

Conclusions:The patients with temporal lobe epilepsies associated with ”cold shivers and/or goose bumps” showed a left hemispheric predominance of the focal abnormality in the temporal lobe.
Selective Blockade of N‐Type Calcium Channels by Levetiracetam
Authors: Lukyanetz E. A. , Shkryl V. M. , Kostyuk P. G.
Published: March 2003

Summary:  Purpose: We investigated the effect of the new antiepileptic drug (AED) levetiracetam (LEV) on different types of high‐voltage–activated (HVA) Ca2+ channels in freshly isolated CA1 hippocampal neurons of rats.

Methods: Patch‐clamp recordings of HVA Ca2+ channel activity were obtained from isolated hippocampal CA1 neurons. LEV was applied by gravity flow from a pipette placed near the cell, and solution changes were made by electromicrovalves. Ca2+ channel blockers were used for separation of the channel subtypes.

Results: The currents were measured in controls and after application of 1–200 μM LEV. LEV irreversibly inhibited the HVA calcium current by ∼18% on the average. With a prepulse stimulation protocol, which can eliminate direct inhibition of Ca2+ channels by G proteins, we found that G proteins were not involved in the pathways underlying the LEV inhibitory effect. This suggested that the inhibitory effect arises from a direct action of LEV on the channel molecule. The blocking mechanism of LEV was not related to changes in steady‐state activation or inactivation of Ca2+ channels. LEV also did not influence the rundown of the HVA Ca2+ current during experimental protocols lasting ∼10 min. Finally, LEV at the highest concentration used (200 μM) did not influence the activity of L‐, P‐ or Q‐type Ca2+ channels in CA1 neurons, while selectively influencing the activity of N‐type calcium channels. The maximal effect on these channels separated from other channel types was ∼37%.

Conclusions: Our results provide evidence that LEV selectively inhibits N‐type Ca2+ channels of CA1 pyramidal hippocampal neurons. These data suggest the existence of a subtype of N‐type channels sensitive to LEV, which might be involved in the molecular basis of its antiepileptic action.
Add‐on Phenytoin Fails to Prevent Early Seizures after Surgery for Supratentorial Brain Tumors: A Randomized Controlled Study
Authors: De Santis Antonio , Villani Roberto , Sinisi Marco , Stocchetti Nino , Perucca Emilio
Published: March 2003

Summary:  Purpose: To determine the potential effectiveness of phenytoin (PHT) in preventing early postoperative seizures in patients undergoing craniotomy for supratentorial brain tumors.

Methods: Two hundred patients requiring elective craniotomy for supratentorial brain tumors were randomized to two groups of equal size, with a prospective, open‐label, controlled design. One group received PHT (18 mg/kg as an intravenous intraoperative load, followed by additional daily doses aimed at maintaining serum PHT concentrations within the 10‐ to 20‐æg/ml range) for 7 consecutive days. In the other group, PHT was not administered. More than 90% of patients in both groups continued to take preexisting anticonvulsant medication (AEDs) with carbamazepine or phenobarbital throughout the study. The primary efficacy end point was the number of patients remaining free from seizures during the 7‐day period after the operation.

Results: Of 100 patients allocated to PHT, 13 experienced seizures during the 7‐day observation period, compared with 11 of 100 patients in the placebo group (p > 0.05). Most seizures occurred in the first day after surgery in both groups. There were no differences between groups in the proportion of patients experiencing more than one seizure, but there was a trend for generalized seizures to be more common in PHT‐treated patients than in controls (11 vs. five patients, respectively). Status epilepticus occurred in one patient in the PHT group and in two patients in the control group. Of the 13 PHT‐treated seizure patients, 11 had serum PHT concentrations within the target range, and only two had concentrations below range on the days their seizures occurred.

Conclusions: PHT, given at dosages producing serum concentrations within the target range, failed to prevent early postoperative seizures in patients treated with concomitant AEDs. Prophylactic administration of PHT cannot be recommended in these patients.
Optimizing Epilepsy Surgery with Intraoperative MR Imaging
Authors: Kaibara Taro , Myles S. Terence , Lee Mary Anne , Sutherland Garnette R.
Published: March 2003

Summary:  Purpose: The surgical treatment of medically intractable temporal lobe epilepsy includes the resection of temporal lobe structures. Although the reported seizure‐free outcomes are highly variable, there is growing evidence that the extent of resection of the mesiotemporal lobe directly correlates with seizure control.

Methods: A moveable, high‐field intraoperative magnetic resonance (MR) system was used to monitor and optimize the resection of the amygdala and hippocampus in 14 epilepsy patients. Fourteen patients with intractable seizures of temporal lobe origin underwent standard preoperative investigations including MR imaging, EEG telemetry, single‐photon emission computed tomography, and neuropsychologic and sodium amytal testing. Anterior temporal lobectomy was performed on 10 patients, whereas four were treated with selective amygdalohippocampectomy. Intraoperative electrocorticography was applied as required. For all procedures, the objective was to resect the amygdala completely, and hippocampus to the posterior margin of the brainstem.

Results: Interdissection intraoperative MR imaging taken when optimal resection was thought to have been achieved revealed residual unresected amygdala or hippocampus in seven of 14 patients. An unexpected acute hematoma was found in one patient. At 17 months' follow‐up, 13 (93%) of 14 patients are seizure free or have significantly improved seizure control.

Conclusions: The mobile high‐field intraoperative MR system provides high‐resolution images without restriction on surgical instruments or techniques. The ability to identify and resect residual mesial temporal lobe targets before craniotomy closure is of potentially tremendous value in optimizing seizure control.
Frontal Lobe Tumoral Epilepsy: Clinical, Neurophysiologic Features and Predictors of Surgical Outcome
Authors: Zaatreh Megdad M. , Spencer Dennis D. , Thompson James L. , Blumenfeld Hal , Novotny Edward J. , Mattson Richard H. , Spencer Susan S.
Published: March 2003

Summary:  Purpose: To review the clinical, neurophysiologic features and surgical outcomes in patients with frontal lobe tumors and chronic intractable seizures.

Methods: Medical records of patients with intractable epilepsy who underwent resection or stereotactic biopsy of frontal lobe tumor (confirmed by surgical pathology) seen between 1985 and 1999 at Yale University School of Medicine Epilepsy Center were reviewed for age at diagnosis, age at onset of seizures, delay between seizure onset and tumor diagnosis, types and frequencies of seizures, EEG results, use of anticonvulsants, extent of surgery, pathological diagnosis, and tumor recurrence.

Results: Thirty‐seven patients were included. Mean age at seizure onset was 31.6 years, and at tumor diagnosis was 36.2 years. Mean duration between onset of seizures and tumor diagnosis was 6.1 years. Seventeen patients had auras. Seizure frequency averaged 7.6 seizures per week, with 58% of patients having more than one seizure type. All patients used anticonvulsants, with 90% eventually using polytherapy. All patients eventually underwent at least one surgical procedure. Only 13 (35.1%) patients were class I. Twelve (32.4%) patients were class II, seven (18.9%) class III, and five (13.5%) class IV. No statistically significant differences were seen between good and poor long‐term seizure outcome in relation to specific tumor pathology, seizure types, or type of resection.

Conclusions: Long‐term surgical outcomes in tumoral frontal lobe epilepsy are more favorable than those in nontumoral intractable frontal lobe epilepsy (65% class I or II) and less favorable than those in other tumoral epilepsy (overall, 70% class I). Frontal location of intracranial neoplasm may predict a less favorable long‐term epilepsy prognosis than tumoral epilepsy in general, an observation for which several explanations are proposed.