Complex Partial Epilepsy Research Articles

Management of refractory complex partial seizures: current state of the art

Diagnosis of complex partial epilepsy is based on the clinical history, and laboratory tests, including EEG and neuroimaging studies, corroborate the diagnosis. The goal of epilepsy management is to make the patient completely seizure-free without drug-induced side effects, even in the patient with refractory complex partial seizures. Frequently this can be accomplished by choice of the optimal antiepileptic drug (AED) or a combination of drugs, the use of strategies to maximize the effectiveness of drug treatment, or by surgical removal of the seizure focus. Currently there are five "classical" first-line AEDs and 11 new AEDs available in the US and in many other countries for the treatment of localization-related epilepsy. The current state of the evidence is that no AED is clearly superior to other AEDs in the management of refractory complex partial seizures. Therefore the choice of which drug to use in an individual patient has to be based on other considerations, including the potential adverse reactions that may occur in that patient. There are a number of strategies for optimal use of AEDs in the management of refractory complex partial seizures. These include verification of the diagnosis of epilepsy and classification of specific seizure types, use of monotherapy if possible but polytherapy if necessary, starting with a low dose and raising it slowly but, until complete seizure control is achieved, pushing to the maximum tolerated dose, changing timing of dosing to reduce toxicity, using pharmacokinetic principles to fine-tune AED doses, adjusting dose for drug-drug interactions, and never giving up in the pursuit of better seizure control. Resection of the seizure focus can be curative in the majority of patients with seizures localized to one mesial temporal lobe. Success rates for resection of extratemporal seizure foci are lower. Vagus nerve stimulation (VNS) devices result in a significant reduction of seizure frequency in many patients, but patients rarely become completely seizure-free as a result of VNS device implantation. Management of refractory complex partial seizures continues to improve with the identification of new drugs and the development of new approaches to their control and cure.

Acquired hemophagocytic lymphohistiocytosis associated with multiple myeloma

Acquired or secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammation syndrome caused mostly by various infectious agents, autoimmune disorders or malignancy. So far, only anecdotal cases of sHLH associated with multiple myeloma have been published. We provide a review of all these reports and include a previously not published case of myeloma-associated sHLH in a 59-year-old male with complex partial epilepsy. Due to aggressive course of sHLH, increased awareness is indicated in all patients with malignancies which develop unremitting fever, cytopenia and splenomegaly. Early diagnosis and immediate introduction of adequate therapy is crucial for the outcome of HLH.

Alteration in chromogranin A, obestatin and total ghrelin levels of saliva and serum in epilepsy cases

This study was designed to measure the levels of chromogranin A (CgA), ghrelin and obestatin in serum and saliva (including CgA expression in healthy tissue) in epileptic patients to determine any significant differences between these patients and healthy controls. Samples were obtained from a total of 91 subjects: 10 newly-diagnosed primary generalized epilepsy (PGE) patients who had started treatment with valproic acid and phenytoin for seizure control; 18 PGE patients who were previously and currently receiving treatment with valproic acid and phenytoin for seizure control; 37 patients with partial epilepsy (PE) (simple, n = 17 or complex, n = 20) who had been and were still being treated with carbazebime for seizures; and 26 healthy controls. CgA immunoreactivity in healthy salivary gland was analyzed by immunohistochemistry and ELISA. The levels of CgA, total ghrelin and obestatin in serum and saliva were measured by ELISA. The results revealed that normal salivary gland produces its own CgA. Before treatment, CgA levels in saliva and serum were significantly greater in patients newly-diagnosed with PGE than controls. Ghrelin and CgA concentrations were also greater in PGE patients previously or currently treated with drugs, and in patients with simple or complex partial epilepsy (PE) previously or currently treated with drugs, than in healthy normal controls. In conclusion, salivary concentrations of CgA, ghrelin and obestatin were similar to their serum levels, so saliva might be a desirable alternative to serum for measuring these hormones because it is easy and painless to collect.

Clinical profile of vigabatrin as monotherapy for treatment of infantile spasms

Vigabatrin, the first therapeutic agent to be approved by the Food and Drug Administration for the treatment of infantile spasms, as well as for adjunctive use in the treatment of refractory complex partial epilepsy, represents an important advance for patients with difficult-to-manage epilepsy. This review summarizes the complex history, chemistry, and pharmacology, as well as the clinical data leading to the approval of vigabatrin for infantile spasms in the US. The long path to its approval reflects the visual system and white matter toxicity concerns with this agent. This review provides a brief description of these concerns, and the regulatory safety monitoring and mitigation systems that have been put in place to enhance benefit over risk.

Stimulation of the parietal cortex affects reaching in a patient with epilepsy

A 15-year-old girl with complex partial epilepsy had subdural electrodes implanted. She was tested on reaching tasks during electrocortical stimulation prior to neurosurgery. MRI showed left mesial parietal dysplasia. Stimulation of the superior parietal cortex (electrode pair 37–45, figure, A) during line bisection and visually guided reaching resulted in movement arrest followed by the arm drifting upward (figure, B, …

The usefulness of olfactory bulb kindling as a model for evaluation of antiepileptics

The present study was undertaken to clarify the behavioral and electroencephalographic characteristics of olfactory bulb (OB) kindling in rats, in comparison with those of amygdala (AMG) kindling. In addition, the usefulness of OB kindling as a model to evaluate antiepileptics was studied. Bipolar electrical stimulation was applied to the OB or AMG every day until generalized seizure was achieved. Antiepileptics (carbamazepine, sodium valproate, zonisamide, clobazam, and topiramate), which are used for complex partial epilepsy or secondary generalized epilepsy in clinical practice, were orally administrated to kindled rats. The afterdischarge (AD) threshold of OB kindling is not different from that of AMG kindling. OB-kindled rats showed more rapid development of the seizure stage and AD duration than AMG-kindled rats; however, fully kindled AD duration did not differ between groups. In AMG kindled rats, AD on day 1 was localized only at the stimulation site, whereas in OB-kindled rats, AD on day 1 was observed at not only the stimulation site (OB) but also in the frontal cortex, hippocampus, and AMG. All five antiepileptics significantly inhibited both the seizure stage and AD duration in OB-kindled rats. In addition, carbamazepine, zonisamide, and topiramate were more effective in suppressing OB-kindled seizures. Zonisamide was not effective at any dose tested in AMG-kindled rats. OB kindling can be used as a new valuable model to evaluate antiepileptic drugs, with the advantage of its rapid development and the efficacy of antiepileptics.

Successful management of refractory psychomotor seizures with gabapentin and phenobarbital in a Doberman pinscher dog

Gabapentin is a new antiepileptic drug which is used in humans with complex partial epilepsy. Recently, two published studies described the efficacy of gabapentin in dogs with refractory epilepsy. However, clinical application of gabapentin in dogs with refractory psychomotor seizure has not been documented. The present report describes a 2-year-old male Doberman pinscher dog with a history of recurrent bizarre behaviors such as aggression, circling, and flank-biting. Initial oral administration of phenobarbital resulted in resolution of psychomotor seizures, but 3 months after the initial presentation, the dog became refractory to the selected treatment. The treatment was changed to a combination therapy with phenobarbital and gabapentin. Two days after starting the combination therapy, the dog became seizure-free, and there were no detectable signs of previous abnormal behaviors during the 14-month follow-up period.

Features of a Subset of Children With Complex Partial Epilepsy Requiring Combination Therapy for Effective Seizure Control

To identify children with complex partial seizures with increased risk for suboptimal seizure control with 1 medication, a computerized database containing all patients seen in the context of a single pediatric neurology practice was reviewed for patients with complex partial seizures. Participants included in analysis were then divided into groups; a group in whom seizure control was attained with a single medication (group 1) and a group for whom 2 or more medications were required for seizure control (group 2). Status epilepticus, developmental disabilities, and the presence of coexisting other seizures/types were also significantly different, with a higher predominance in group 2 children. Patients with status epilepticus, coexistent seizure types, and developmental disabilities should be identified and more carefully followed, with a lower threshold for starting these children on a combination of antiepileptic drugs adhered to.

Interhemispheric and intrahemispheric language reorganization in complex partial epilepsy

To investigate interhemispheric and intrahemispheric reorganization in patients with localization-related epilepsy. We studied 50 patients with a left hemispheric focus and 20 normal right-handed controls with a 3T echoplanar imaging blood oxygen level dependent functional MRI auditory-based word definition decision task. Data were analyzed using SPM 2. Using region of interest for Broca and Wernicke areas and an asymmetry index (AI), patients were categorized as left language (LL; AI > or = 0.20) or atypical language (AL; AI <0.20) for region. The point maxima activation for normal controls (p <0.05 corrected FDR) was identified in Broca and midtemporal regions and then used as a point of reference for individual point maxima identified at p < 0.001, uncorrected. Patient groups showed increased frequency of having activation in right homologues. Activation in AL groups occurred in homologous right regions; distances for point maxima activation in homologous regions were the same as point maxima distances in normal control activation in left regions. Distances for LL patient in left regions showed a trend for differences for midtemporal gyrus (6 mm posterior, 3 mm superior) but variability around mean difference distance was significant. There was no effect of age at epilepsy onset, duration, or pathology on activation maxima. Right hemisphere language regions in patients with left hemispheric focus are homologues of left hemisphere Broca and broadly defined Wernicke areas. We found little evidence for intrahemispheric reorganization in patients with left hemisphere epilepsy who remain left language dominant by these methods.

In the rat maximal dentate activation model of partial complex epilepsy, the anticonvulsant activity of levetiracetam is modulated by nitric oxide-active drugs

The effects of nitric oxide-active drugs on the anticonvulsant action of the antiepileptic drug levetiracetam in an experimental model of partial complex seizures named maximal dentate gyrus activation were studied in rats. Levetiracetam was given alone or in combination with 7-nitroindazole, a preferential inhibitor of neuronal nitric oxide synthase, or with L: -arginine, the precursor of nitric oxide synthesis. The maximal dentate activation parameters were the time of latency and the durations of maximal dentate activation and afterdischarge responses. The administration of levetiracetam showed an anticonvulsant effect that was increased when given in combination with 7-nitroindazole. The co-administration of levetiracetam and L: -arginine, which is pro-convulsant, did not significantly modify all the parameters. The present results indicate that the acute administration of levetiracetam, at the lower effective dose, exerts an efficacious inhibitory effect on the severity of maximal dentate activation seizures. Levetiracetam-induced antiepileptic effect is significantly increased by the simultaneous inhibition of neuronal nitric oxide synthase.

Assessment of the attention impairment in absence epilepsy: Comparison of visual and auditory P300

We report an investigation of P300 measures of information processing in patients with generalized epilepsy of the absence type and those with complex partial epilepsy. Studies have demonstrated that absence patients perform more poorly than complex partial patients on behavioral tests of sustained attention (the Continuous Performance Test, or CPT). Duncan [Duncan, C.C., 1988. Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: Myslobodsky, M.S., Mirsky, A.F. (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, pp. 341–364] reported that P300 was significantly reduced in a group of absence patients as compared with healthy controls. The present investigation was undertaken to compare the attention deficit in absence patients to that in complex partial seizure patients. Thus, ERPs were recorded while participants with absence seizure disorder, complex partial seizure disorder, and healthy controls performed auditory and visual versions of the CPT. A significant reduction in the amplitude of P300 on the visual CPT was observed in both groups of seizure patients as compared to controls. In contrast, P300 on the auditory CPT was reduced only in the group with absence seizures. These ERP data support and amplify previous behavioral findings of the impaired capacity of absence patients to mobilize and sustain attentional resources. Auditory sustained attention seems to be more affected by the pathophysiology of absence epilepsy than visual attention. Two possible factors may be involved: (a) There are separate visual and auditory attention systems in the brain, and the latter is more vulnerable than the former [Duncan, C.C., Kosmidis, M.H., Mirsky, A.F., 2005. Closed head injury-related information processing deficits: An event-related potential analysis. Int. J. Psychophysiol. 58, 133–157]; and (b) Auditory processing depends on intact mechanisms in the brainstem, which are dysfunctional in patients with absence seizures.

Cholecystokinin‐8 sulfate modulates the anticonvulsant efficacy of vigabatrin in an experimental model of partial complex epilepsy in the rat

We evaluated the possible additive effect induced by the administration of the anticonvulsant vigabatrin (VGB) and cholecystokinin-8 sulfate (CCK-8S) on an experimental model of partial complex seizures (maximal dentate gyrus activation, MDA). Moreover, the functional involvement of gamma-aminobutyric acid (GABA) neurotransmission was tested by iontophoretically administering bicuculline (GABA receptor antagonist) in the dentate gyrus. Urethane anesthetized rats were pretreated with VGB (50, 100 or 200 mg/kg, i.p.) or CCK-8S (8 nmol/kg, i.p.) alone or coadministered with VGB (50 mg/kg, i.p.). Dentate gyrus epileptic activity was obtained through the repetitive electrical stimulation of the angular bundle. MDA latency, duration, and poststimulus afterdischarge (AD) duration were evaluated. The extracellular activity of some dentate neurons was recorded before and during bicuculline iontophoresis. Only the higher dose of VGB reduced the mean duration of dentate MDA and AD. CCK-8S significantly decreased the number of animals exhibiting MDA responses, characterized by increased latency and shorter duration. The coadministration of CCK-8S and VGB (50 mg/kg) significantly increased the anticonvulsant effects, either reducing the number of responding animals or decreasing both MDA and AD durations. During bicuculline iontophoresis, all the modifications induced on the MDA-related activity of dentate neurons by the pretreatments (VGB and/or CCK-8S) were abolished. The results indicate that CCK-8S significantly enhances the VGB-induced anticonvulsant effect in the MDA model of partial epilepsy, probably through an increase of GABA cerebral levels. Such increased anticonvulsant effect becomes evident by using VGB at a lower dose.

Protective Efficacy and Potency of Neuroactive Steroids and Benzodiazepines in the Amygdala Kindling Model of Epilepsy

Although neuroactive steroids protects against experimental seizures, the role of GABA‐A receptor‐modulating neuroactive steroids in the development and expression of amygdala kindling remains unclear. In this study, the neuroactive steroid ganaxolone was examined on behavioral and electrographic seizure expression in the amygdala kindling model of epilepsy in mice, and the protective activity was compared with the antiseizure benzodiazepine clonazepam. Mice were kindled by daily stimulation of amygdala until they exhibit consistent behavioral and electrographic seizures. In fully kindled mice showing stage 5 seizures, ganaxolone (1.25‐20 mg/kg, s.c.) significantly reduced both clonic and generalized seizures elicited by amygdala stimulation. The protective effect of ganaxolone was dose‐dependent with an ED50 of 6.6 mg/kg. Ganaxolone treatment was associated with significant reduction in the afterdischarge duration. As expected, there was a substantial suppression of behavioral and electrographic seizures in mice treated with clonazepam. Clonazepam was more potent than ganaxolone, but the overall maximal efficacy of both clonazepam and ganaxolone was similar. These studies provide strong evidence that ganaxolone is highly effective antiseizure agent in the amygdala kindling model, which is a clinically‐relevant model of complex partial epilepsy.

MR Imaging Identification of Oligodendroglial Hyperplasia

We report a case of oligodendroglial hyperplasia detected by using high-resolution high-field MR imaging. This disorder is considered part of the spectrum of cortical migrational abnormalities and is found with increased incidence in patients with epilepsy. Surgery offers the best chance for cure in patients with medically refractory partial complex epilepsy. Accurate localization and detection of the full lesion extent by using a high-resolution imaging technique such as 3T MR imaging is important to surgical success. Detection of subtle dysplastic lesions such as oligodendroglial hyperplasia may be clinically relevant.

Effects of amobarbital and methohexital on epileptic activity in mesial temporal structures in epileptic patients. An EEG study with depth electrodes.

Bilateral intracarotidal Amytal (amobarbital) tests for evaluation of speech and memory function were performed during preoperative evaluation of 30 patients with drug-resistant epilepsy. In 8 of these patients (16 tests), having partial complex epilepsy, EEG was recorded with depth electrodes, implanted bilaterally in anterior mesial temporal structures. The EEGs during 13 tests could be quantified with regard to spike activity. A rapid increase in spike frequency was observed ipsilateral to the injection in all tests but one. No seizure activity or clinical seizures were provoked. This previously unnoticed effect of amobarbital could be due to a direct excitatory effect of the drug on epileptic temporal neurones or, alternatively, to a release of interictal inhibition, exerted upon these neurons by other structures. In 4 patients, the effect was compared with that of methohexital, another barbiturate known to have excitatory effects upon epileptic activity.

Psychomotor epilepsy and psychosis

In a controlled investigation of paranoid hallucinatory chronic or episodic epileptic psychoses, the social data, psychopathological symptoms and the psychological test findings (WAIS, Rorschach, object-sorting, proverb-interpretation and the Stroop test) were analyzed in order to delineate the characteristics of the psychotic syndrome and to evaluate the significance of organic etiological factors. The study comprised 45 patients with complex partial epilepsy followed by psychosis after median 23 years, and 34 control patients with the same type of epilepsy of median 30 years' duration. Among the psychotic symptoms, simple, mostly empathizable persecutory delusions and auditory hallucinations predominated. The affect tended to remain appropiate, and autistic traits were uncommon. In accordance with this finding of a relatively circumscribed psychotic personality disturbance, psychotic test indicators were infrequent in the psychological tests, the Rorschach test 28%, and the object-sorting test 18% of the cases. The poorer test performances in the WAIS and the Stroop tests, and the preponderance of organic Rorschach test signs in the psychotic group indicate that organic cerebral damage is of etiological significance in paranoid epileptic psychosis.

Als Panikattacken imponierende Occipitallappenanfälle

Eleven-year-old Stephanie was admitted to a child and adolescent psychiatry day hospital with symptoms of an anxiety and panic disorder, and compulsive and self-harmful behavior. The patient described detailed threatening scenic sequences that caused her to feel panicky. They symptoms could be classified as epilepsy with visually dominated seizures of the occipital lobe. In addition to pharmacological treatment with oxcabazepine, extensive multimodal interventions as part of the child and adolescent psychiatric day hospital treatment program helped all family members to understand and handle the seizures. Eight weeks after initiation of treatment, Stephanie was seizure-free. Complex partial epilepsy can be mistaken for primary child-psychiatric disorder.

In-hospital complications of epilepsy surgery: a six-year nationwide experience

Lobectomy for intractable complex partial epilepsy (iCPE) continues to be underutilized despite numerous reports showing low mortality and complications. Our objective was to evaluate patient demographics and in-hospital complications of intracranial electrode (IE) implantation and lobectomy for evaluation and treatment of iCPE in a nationwide cohort in recent years. We queried the Nationwide Inpatient Sample for patients admitted with iCPE in the years 2000–2005. We excluded patients with brain tumors, vascular malformations, and other diagnoses that might cause alteration of awareness or necessitate brain surgery. Patient demographics and in-hospital complications of patients who underwent surgery (lobectomy, IE implantation, or both) were compared to non-surgical patients. In total, 3,005 patients (mean age 31 ± 16 years, female 51.3%) were included in the analysis. Teaching hospitals admitted the majority (93%), with a median length of stay of 5 days (quartiles 3, 7). Of all iCPE admissions, 484 (16.1%) underwent surgery; 234 patients were evaluated with IE implantation, 182 (6.06%) had lobectomy, and 68 (2.26%) had both procedures in the same hospitalization. We found an increased risk of intracerebral hemorrhage (ICH) in the IE group (OR 14.1, 95% CI 5.22, 38.3), but not in the lobectomy group (OR 1.98, 95% CI 0.24, 16.2). A similar pattern was seen for status epilepticus (SE) between IE implantation (OR 5.12, 95% CI 1.53, 17.3), and lobectomy (OR 1.95, 95% CI 0.24, 15.8). Procedure utilization insignificantly increased over the 6 years studied (p = 0.06). Invasive monitoring is associated with increased risks of ICH and SE. Although the risks of invasive monitoring and lobectomy are low, epilepsy surgery continues to be underutilized in iCPE.

Disruption of Sodium Bicarbonate Transporter SLC4A10 in a Patient With Complex Partial Epilepsy and Mental Retardation

To determine gene(s) disrupted in a patient with partial frontal lobe epilepsy and cognitive impairment with concomitant de novo balanced chromosomal translocation t(2;13)(q24;q31). Fluorescence in situ hybridization and array comparative genomic hybridization were used to map the locations of chromosomal translocation breakpoints. SLC4A10 (OMIM 605556), a sodium bicarbonate transporter gene with high expression in the cerebral cortex and hippocampus, was disrupted by the translocation breakpoint on chromosome 2q24. The breakpoint on chromosome 13q31 was in a 1-megabase (Mb)-gene desert. Genomewide array comparative genomic hybridization confirmed the absence of additional chromosomal abnormalities. SLC4A10 is the third SLC4 base transporter family member to be implicated in human cognition and epilepsy.

Atypical language in lesional and nonlesional complex partial epilepsy

We investigated the relationship between partial epilepsy, MRI findings, and atypical language representation. A total of 102 patients (4 to 55 years) with left hemisphere epileptogenic zones were evaluated using three fMRI language tasks obtained at 1.5 or 3T with EPI BOLD techniques: verbal fluency, reading comprehension, and auditory comprehension. fMRI maps were visually interpreted at a standard threshold and rated as left or atypical language. Atypical language dominance occurred in 30 patients (29%) and varied with MRI type (p < 0.01). Atypical language representation occurred in 36% (13/36) with normal MRI, 21% (6/29) with mesial temporal sclerosis, 14% (4/28) with focal cortical lesions (dysplasia, tumor, vascular malformation), and all (6/6) with a history of stroke. Multivariate logistic regression analysis found handedness, seizure onset, and MRI type accounted for much of the variance in language activation patterns (chi(2) = 24.09, p < 0.01). Atypical language was more prevalent in patients with early seizure onset (43.2%, p < 0.05) and atypical handedness (60%, p < 0.01). None of the three clinical factors were correlated with each other (p > 0.40). Patients with atypical language had lower verbal abilities (F = 6.96, p = 0.01) and a trend toward lower nonverbal abilities (F = 3.58, p = 0.06). There were no differences in rates of atypical language across time, age groups, or MRI scanner. Early seizure onset and atypical handedness, as well as the location and nature of pathologic substrate, are important factors in language reorganization.