Efficacy of mGlu2 -positive allosteric modulators alone and in combination with levetiracetam in the mouse 6 Hz model of psychomotor seizures.

OBJECTIVE: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds. METHODS: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model. RESULTS: In the 6 Hz (32 mA stimulus intensity) model, median effective dose (ED50 ) values were determined for JNJ-42153605 (3.8 mg/kg), JNJ-40411813 (12.2 mg/kg), and LY404039 (10.9 mg/kg). At the 44 mA stimulus intensity, ED50 values were determined for JNJ-42153605 (5.9 mg/kg), JNJ-40411813 (21.0 mg/kg), LY404039 (14.1 mg/kg), and LEV (345 mg/kg). In addition, subprotective doses of each mGlu2 -acting compound, administered in combination with various doses of LEV, were able to shift the 6 Hz 44 mA ED50 for LEV by >25-fold. When JNJ-42153605 was administered at varying doses in combination with a single dose of LEV (10 mg/kg), the potency of JNJ-42153605 was increased 3.7-fold. Similarly, when a moderately effective dose of LEV (350 mg/kg) was administered in combination with varying doses of JNJ-40411813, the potency of JNJ-40411813 was increased approximately 14-fold. Plasma levels of JNJ-40411813 and LEV were not different when administered alone or in combination, suggesting that increases in potency are not due to pharmacokinetic effects. SIGNIFICANCE: These studies suggest a potential positive pharmacodynamic effect of mGlu2 -acting compounds in combination with LEV. If this effect is translated in a clinical setting, it can support a rational polypharmacy concept in treatment of epilepsy patients.

A case of complex partial seizure with reversible MRI abnormalities in the elderly.

A 79-year-old woman was admitted to our hospital because of prolonged impaired consciousness and right hemiparesis. She was treated for acute cerebral infarction because her brain magnetic resonance imaging showed extensive cortical lesions similar to acute infarction in diffusion weighted image, fluid attenuated inversion recovery, and T2 weighted images. On the fifth day, she had a focal seizure on the right side. A new lesion during imaging and electroencephalogram abnormality were observed at that time. After the antiepileptic drug treatment was started, her right hemiparesis considered as ictal paresis, confusion, and the magnetic resonance imaging findings gradually improved. There was also an old, irreversible lesion in the left hippocampus, which was considered as the focus of her complex partial seizure. In the elderly, the post-ictal period of confusion, which occurs with complex partial seizure, may be prolonged. In our case, improvement of hemiparesis and confusion occurred after about 2 weeks.

Repeated 6-Hz Corneal Stimulation Progressively Increases FosB/ΔFosB Levels in the Lateral Amygdala and Induces Seizure Generalization to the Hippocampus.

Exposure to repetitive seizures is known to promote convulsions which depend on specific patterns of network activity. We aimed at evaluating the changes in seizure phenotype and neuronal network activation caused by a modified 6-Hz corneal stimulation model of psychomotor seizures. Mice received up to 4 sessions of 6-Hz corneal stimulation with fixed current amplitude of 32 mA and inter-stimulation interval of 72 h. Video-electroencephalography showed that evoked seizures were characterized by a motor component and a non-motor component. Seizures always appeared in frontal cortex, but only at the fourth stimulation they involved the hippocampus, suggesting the establishment of an epileptogenic process. Duration of seizure non-motor component progressively decreased after the second session, whereas convulsive seizures remained unchanged. In addition, a more severe seizure phenotype, consisting of tonic-clonic generalized convulsions, was predominant after the second session. Immunohistochemistry and double immunofluorescence experiments revealed a significant increase in neuronal activity occurring in the lateral amygdala after the fourth session, most likely due to activity of principal cells. These findings indicate a predominant role of amygdala in promoting progressively more severe convulsions as well as the late recruitment of the hippocampus in the seizure spread. We propose that the repeated 6-Hz corneal stimulation model may be used to investigate some mechanisms of epileptogenesis and to test putative antiepileptogenic drugs.

Amygdalohippocampectomy for epilepsy in a patient with prior ipsilateral deep brain stimulator lead placement.

In light of failed medical therapy for movement disorders, the use of deep brain stimulation (DBS) has increased the last two decades. Many complications may transpire; however, to our knowledge, the literature does not mention the phenomena of brain shift from a second unrelated neurosurgical procedure and its theoretical effect on lead displacement and lead function. We present a patient with a left sided DBS for essential tremor and subsequent left amygdalohippocampectomy for temporal lobe epilepsy with minimal radiographic distortion of the DBS lead and without clinical or functional complications. A 47-year-old woman presented with bitemporal epilepsy secondary to a brain injury acquired in childhood in addition to a comorbid bilateral essential tremor, both refractory to medical intervention. A successful left-sided DBS placement was performed with satisfactory resolution of her essential tremor. The patient subsequently developed deterioration of seizure control, becoming refractory to anti-epileptic medications, requiring surgical intervention. A left-sided selective amygdalohippocampectomy and techniques to minimize brain shift were performed without complications. Postoperative imaging suggested minimal distortion of the DBS lead. This did not correspond with reemergence of her essential tremor, implying that the lead maintained functional utility. Brain shift secondary to a craniotomy may cause DBS lead displacement. This phenomenon should be considered when planning operative approaches and can be limited by selective resections. With the growing propensity for placement of DBS leads and the risk of lead displacement, it is important to consider operative approaches to minimize brain shift.

Effects of WIN 55,212-2 (a non-selective cannabinoid CB1 and CB 2 receptor agonist) on the protective action of various classical antiepileptic drugs in the mouse 6 Hz psychomotor seizure model.

The aim of this study was to characterize the influence of WIN 55,212-2 (WIN--a non-selective cannabinoid CB1 and CB2 receptor agonist) on the anticonvulsant effects of various classical antiepileptic drugs (clobazam, clonazepam, phenobarbital and valproate) in the mouse 6 Hz-induced psychomotor seizure model. Limbic (psychomotor) seizure activity was evoked in albino Swiss mice by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via ocular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), step-through passive avoidance task (assessing learning) and grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5 mg/kg, administered intraperitoneally) significantly enhanced the anticonvulsant action of clonazepam (P < 0.001), phenobarbital (P < 0.05) and valproate (P < 0.05), but not that of clobazam in the mouse 6 Hz model. Moreover, WIN (2.5 mg/kg) significantly potentiated the anticonvulsant action of clonazepam (P < 0.01), but not that of clobazam, phenobarbital or valproate in the 6 Hz test in mice. None of the investigated combinations of WIN with antiepileptic drugs was associated with any concurrent adverse effects with regard to motor performance, learning or muscular strength. Pharmacokinetic experiments revealed that WIN had no impact on total brain concentrations of antiepileptic drugs in mice. These preclinical data would suggest that WIN in combination with clonazepam, phenobarbital and valproate is associated with beneficial anticonvulsant pharmacodynamic interactions in the mouse 6 Hz-induced psychomotor seizure test.

Jazz, guitar, and neurosurgery: the Pat Martino case report.

OBJECTIVE: We present the case of a professional jazz guitarist with temporal lobe epilepsy secondary to an arteriovenous cerebral malformation. CASE DESCRIPTION: The patient underwent a left temporal lobectomy in 1980. After surgery, he presented with severe retrograde amnesia and complete loss of musical interest and capabilities. The patient's musical abilities recovered over time, and he regained his previous virtuoso status. In 2007, his medical history, neuropsychologic functions, and structural magnetic resonance imaging study were examined and revealed a remarkable degree of recovery of memory and musical abilities in the context of extensive temporal lobe resection. The neuropsychologic findings and neuroanatomic features of the magnetic resonance imaging study were analyzed to try to understand the high degree of recovery of both long-term memory and musical processing abilities in this musician. CONCLUSIONS: This case reveals the possibility of an unusual degree of cerebral plasticity and reorganization. Additionally, it emphasizes the question of musical virtuosity. This report shows that the musical capabilities of professional musicians, in specific cases, can completely recover even when much of the left temporal lobe has been removed.

An unusual recurrence of dysembroplastic neuroepithelial tumours after a seizure-free period of 8 years.

Dysembryoplastic neuroepithelial tumours (DNETs) are grade 1 central nervous tumours, which can be diagnosed judiciously based on clinical features and radiological investigations, having a good prognosis after surgical resection. However, the recurrence of tumours due to variable epileptic zones leading to persistence of seizures can make the management of such cases challenging. We present a case of DNET where the patient had recurrence of the tumour with worsening of seizure activity 8 years after initial surgical resection.

Adverse effects of antiepileptic drugs in North Indian pediatric outpatients.

PURPOSE: The present study investigates the pattern and predictors of treatment-emergent adverse drug reactions (ADRs) in children diagnosed with epilepsy. METHODS: We conducted prospective observational study in a tertiary care teaching hospital on 277 epileptic children. Antiepileptic drug (AED)-associated ADRs, demographic and clinical characteristics, AED regimen, and so on were recorded. Causality, severity, and preventability were performed by World Health Organization-Uppsala Monitoring Center scale, Hartwig's severity scale, and Schumock and Thornton questionnaire, respectively. RESULTS: Of the enrolled population, 53% children had symptomatic epilepsy, and 51% were in 5- to 10-year age group. More than two-thirds of children were on monotherapy, with phenytoin (n = 176, 63.5%) being the most common AED. Three hundred fifty-three AED-related ADRs were recorded in 175 children (63.2%). Poor scholastic performance (19%) was the most common ADR, followed by gum hypertrophy (13.3%), headache (10.2%), behavioral problems (5.7%), drowsiness (5.7%), and others. Two hundred sixteen ADRs were probable, and 126 ADRs were possible. Severe ADRs were noted in 6 children. Girls (odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.07-3.45; P = 0.03), children with secondary epilepsy (OR, 3.31; 95% CI, 1.76-6.23; P ≤ 0.001), children older than 5 years (5-10 years; OR, 6.28; 95% CI, 2.79-14.12; P ≤ 0.001), and those older than 10 years (OR, 9.04; 95% CI, 3.69-22.17; P ≤ 0.001) were found to be at higher risk of experiencing ADRs. CONCLUSIONS: Monotherapy was the preferred treatment. Phenytoin was the most common ADR causative agent. Female sex, symptomatic epilepsy, and older age (> 5 years) were found to be associated with higher probability of ADR development.

A patient with type II citrullinemia who developed refractory complex seizure.

A 31-year-old Japanese male was admitted to our hospital for refractory complex seizures. He had no history on medical or psychiatric illness. He began to exhibit aberrant behavior accompanied by cloudiness of consciousness. Thereafter, he exhibited partial seizures followed by a twilight state or abnormal behavior. Previous treatment with valproate and carbamazepine failed to improve his seizures. Because an increase in plasma ammonia was noted, anticonvulsant was discontinued within a week. He was then transferred to our department. Blood examination revealed an increase in ammonia. Amino acid analysis demonstrated a marked increase in citrulline and decrease in arginine. He was diagnosed with type II citrullinemia. After being treated with arginine hydrochloride, the seizures and disturbed consciousness improved. He was then discharged, and remains in remission. Accumulations of citrulline and ammonia and a reduction of arginine are noted in argininosuccinate synthetase deficiency, which results in the sudden emergence of consciousness disturbance and abnormal behavior. It is essential to examine amino acid levels as well as ammonia levels in patients with unexplained neuropsychiatric symptoms, especially those with altered consciousness levels and seizures.

[Insular psammomatous meningioma presenting intractable complex partial seizures].

We describe a 30-year-old female with intractable symptomatic epilepsy caused by an insular calcified mass, which was histologically proved as psammomatous meningioma. Seizures were described as consciousness impairment, motionless stare and automatism. After total removal of the tumor with a neuronavigation system and motor evoked potential (MEP) monitoring, seizures completely disappeared without neurological deficit. We emphasize that insular meningioma presents complex partial seizures which mimic medial temporal lobe epilepsy and seizures are controlled by total resection of the tumor.

Periventricular nodular heterotopia functionally couples with the overlying hippocampus.

Patients with periventricular nodular heterotopia (PVNH) often have severe epilepsy. However, it is unclear how the heterotopia contributes to epileptogenesis. Recently, electrophysiologic studies using intraoperative depth electrodes have indicated that interaction between the heterotopia and overlying cortex is crucial for seizure onset. We performed an in vitro physiologic study using slices of resected brain from a 22-year-old man with PVNH, who manifested medically refractory mesial temporal lobe epilepsy. Preoperative evaluation indicated that the right mesial temporal structure and PVNH were the epileptogenic focus. The resected tissue was immediately immersed in cold artificial cerebrospinal fluid, and then slices of the brain tissue including the heterotopic nodules and overlying hippocampus were prepared. We electrically stimulated the incubated slices, and the elicited neural activities were analyzed as changes in the flavoprotein fluorescence signals. When we stimulated either the heterotopic nodule or the overlying hippocampus, clear functional coupling of neural activities between these structures was observed. The coupling response evoked by stimulation of the subiculum and developing within the heterotopic nodule was enhanced by application of bicuculline. Therefore, activities of the hippocampus and the nodule are closely correlated.