Absence epilepsy with onset before age three years: a heterogeneous and often severe condition

PURPOSE: The classification of epilepsies and epileptic syndromes recognizes three syndromes with typical absences [TA, i.e., childhood and juvenile absence epilepsies (CAE and JAE), and epilepsy with myoclonic absences (EMA), none of which is characterized by onset in early childhood]. Although several other forms of absence epilepsies have been described recently, none concerns infants and very young children, and little is known about the nosology and prognosis of early-onset absences. METHODS: We retrospectively selected all cases with onset of absences as the only or major seizure type before age 3 years and >/=2 years of follow-up among cases newly referred between 1986 and 2002. Neuropsychological assessments (generally IQ measure), behavior patterns, and schooling situations were reviewed for each child. RESULTS: We found 10 patients (7 F, 3 M). No child had sensory or motor deficits: neuroimaging was performed in nine and was normal in eight, with aspecific findings in one. Only two could be characterized as CAE and EMA, respectively, both with seizure control and a good cognitive outcome. Among the remaining eight cases, four had a fairly homogeneous presentation with predominantly brief absences and clearly asymmetric interictal EEGs. All eight had neuropsychological and/or behavioral difficulties. Three had full seizure control, and five, persisting absences, with a follow-up ranging between 2 years 8 months to 9 years 4 months; only one child was older than 12 years. CONCLUSIONS: Great heterogeneity exists among absence epilepsies of early onset, which are rare conditions. Only a few patients can be categorized into well-known syndromes. The overall prognosis is poor. Early onset of absences is uncommon, and multicenter studies should help clarify the nosology and prognosis.     

[18F]FDG-PET and Whole-Scalp MEG Localization of Epileptogenic Cortex

PURPOSE: To evaluate combined [18F]fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 122-channel whole-scalp magnetoencephalography (MEG) in lateralizing the epileptogenic cortex in patients whose routine presurgical evaluations gave discordant results about the location of the epileptic focus. METHODS: Nine patients (five women, four men) aged 13-40 years were studied. Subdural EEG (SEEG) was recorded from eight patients. Six patients were operated on. RESULTS: In seven of nine patients, PET and MEG agreed in localizing the epileptogenic cortex. When PET and MEG were in congruence, SEEG agreed with the findings. In five of six operated-on patients, PET and MEG results were congruent, and the outcome of the operation was successful. Two patients had discordant PET and MEG results. In one patient, PET showed bitemporal hypometabolism, whereas MEG showed epileptiform activity in the right parietal lobe. The surgical outcome of the palliative temporal lobectomy was poor. Another patient had unilateral temporal hypometabolism in PET and bitemporal activity in MEG. She was not operated on. CONCLUSIONS: In most patients, PET and MEG were congruent in locating the epileptogenic cortex. Thus the combination of these techniques may provide useful support for the localization of the seizure onset and reduce the need for invasive procedures.     

全脑照射治疗大鼠癫痫的实验研究

目的 观察20Gy外照射对大鼠癫痫模型癫痫发作的影响，并着重检测该剂量照射后大鼠脑皮层内兴奋性氨基酸类递质—谷氨酸含量的变化。方法 建立戊四氮慢性癫痫模型，继以用20Gy剂量对模型大鼠皮层进行垂直照射。照射后48h，观察大鼠对致癫刺激的反应，并在接受致癫刺激后30min，取大鼠皮层，利用高压液相检测其中谷氨酸含量。结果 癫痫模型大鼠接受20Gy照射后48h，其癫痫发作明显受抑制。谷氨酸的检测结果显示，未接受照射的模型大鼠，受到致癫刺激后，脑内谷氨酸含量明显升高；而照射后的模型大鼠，接受相同刺激，脑内谷氨酸含量却没有明显升高。结论20Gy外照射后48h即可抑制模型大鼠癫痫发作，其抑制作用可能与照射降低了脑内兴奋性氨基酸类递质—谷氨酸的作用有关。     

托吡酯的药物定量脑电图研究

目的 探讨托吡酯对人类脑电图的影响。方法 应用药物定量脑电图的方法，对癫痫患者和健康人单次口服托吡酯前后的脑电图背景活动变化进行动态观察和定量研究。结果 托吡酯对脑电图背景的影响主要表现为慢波(峰值66．76μV^2)和α1频段(峰值57．33μV^2)功率显著升高，双枕总功率(峰值385．12μV^2)和全脑总功率显著升高(峰值2500．75μV^2)。健康人θ频段功率百分比(峰值12．39％)和α1频段功率百分比(峰值17．47％)升高，α3频段功率百分比降低(谷值10．45％)，癫痫病人θ频段功率百分比(右枕)升高(峰值13．94％)。结论 托吡酯对人类的脑电背景活动有影响，且与其他抗癫痫药不同。     

Substantia nigra regulates action of antiepileptic drugs

The cholinergic agonist pilocarpine triggers sustained limbic seizures in rodents. Pilocarpine seizures were blocked by systemic administration of benzodiazepines, barbiturates, valproate and trimethadione, while diphenylhydantoin did not affect, and ethosuximide increased the susceptibility of rats to such seizures. This pattern of action antiepileptic drugs is characteristic for pilocarpine seizures and different from other rodent models of epilepsy. Although the anatomical substrates in the forebrain involved in the expression of anticonvulsant activity are unknown, the basal ganglia are believed to be essential for the motor expression of pilocarpine seizures. Bilateral microinjections into the substantia nigra, a major output station of the basal ganglia, of midazolam (ED₅₀ 38.5 nmol; range 29–52 nmol), phenobarbital (ED₅₀ 16 nmol; range 7–39 nmol) and trimethadione (ED₅₀ 30 nmol; range 16–56 nmol) protected rats against pilocarpine seizures (380 mg/kg i.p.). Diphenylhydantoin (up to 100 nmol) remained inactive, while ethosuximide (ED₅₀ 38 nmol; range 22–65.5 nmol) reduced the threshold for pilocarpine seizures, converting subconvulsant doses of pilocarpine (200 mg/kg i.p.) into convulsant ones. The profiles of action of antiepileptic drugs on pilocarpine seizures were similar following intranigral and systemic administration. These observations suggest that the substantia nigra may mediate some actions of antiepileptic drugs.     

Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis

PURPOSE: To determine the modulation of sodium currents in hippocampal CA1 neurons by carbamazepine (CBZ) and valproate (VPA), before and after kindling epileptogenesis. METHODS: Voltage-dependent sodium current was measured in isolated hippocampal CA1 neurons, by using the whole-cell voltage-clamp technique. CBZ (15-100 microM) or VPA (0.5-5 mM) was applied by bath perfusion. Cells from fully kindled rats were compared with controls, 1 day and 5 weeks after the tenth generalized seizure. RESULTS: CBZ did not affect sodium current activation but selectively shifted the voltage dependence of steady-state inactivation to more hyperpolarized potentials. One day after the last kindled generalized seizure, the shift induced by 15 microM CBZ was 2.1+/-0.5 mV (mean +/- SEM; n = 20) compared with 4.3+/-0.3 mV (n = 16; p<0.001) in matched controls. The EC50 of the concentration-effect relation was 57+/-6 microM compared with 34+/-2 microM (p<0.01) in controls. Five weeks after kindling, these values had recovered to a level not different from control. VPA induces at a relatively high concentration a similar but smaller shift in voltage dependence of inactivation than does CBZ. After kindling, the shift induced by 2 mM VPA (2.8+/-0.6 mV; n = 19) was not different from controls (3.0+/-0.5 mV; n = 22). The EC50 for VPA was 2.6+/-0.3 mM compared with 2.5+/-0.4 mM in controls. CONCLUSIONS: Both CBZ and VPA selectively modulate the voltage dependence of sodium current steady-state inactivation and as a consequence reduce cellular excitability. The effect of CBZ was reduced immediately after kindling epileptogenesis, apparently by a reduced affinity of its receptor. In contrast, the shift induced by VPA was not different at any stage after kindling epileptogenesis. The change in CBZ sensitivity after kindling is related to epileptic activity rather than to the epileptic state, because it almost completely recovers in a period without seizures.     

Discontinuation of Phenytoin, Carbamazepine, and Valproate in Patients with Active Epilepsy

The effects of discontinuing individual antiepileptic drugs (AEDs) in patients with active epilepsy who are receiving combination therapy have not been studied systematically. We report a double-blind, prospective study of discontinuation of phenytoin (PHT), carbamazepine (CBZ), and valproate (VPA) in 70 patients with chronic active epilepsy. Each drug discontinuation was randomized to one of two relatively fast rates of reduction, and a control group of 25 patients continued with stable therapy. Patients who had CBZ removed had a significant increase in seizures that was maintained for 4 weeks after the end of drug reduction, and 10 of these 23 patients had to restart therapy with CBZ. There was no significant change in seizure numbers in the other groups. Two patients discontinued from VPA had to restart the drug; none had to restart PHT. The optimal rates of reduction of CBZ remain uncertain. There was no evidence for a clinically or temporally distinct burst of "discontinuation seizures" in any group. Any marked increase in seizures always resolved on reintroduction of the discontinued drug.     

Sudden Unexplained Death and Injury in Epilepsy

Summary: Seizures may be associated with risk of injury or death. Injuries are common in patients with epilepsy, with up to 30% of patients reporting injuries, most commonly blunt trauma and lacerations. Seizures associated with falls increase the risk of injury, but any seizure that is associated with alteration in consciousness may cause injury. Patients with seizures may injure others, especially by causing motor vehicle accidents. Each state has restrictions on driving, requiring seizure-free intervals that range from 3 to 18 months. Mortality is increased in patients with epilepsy. The standardized mortality ratio is increased two to three times in epilepsy cohorts. Sudden unexplained death in epilepsy (SUDEP) is responsible for 2% to 17% of all deaths in patients with epilepsy, depending on the cohort studied. Population-based studies of SUDEP show a lower overall SUDEP rate compared with clinical trials or epilepsy referral center cohorts. Overall, the risk of sudden death is increased in the epilepsy population by 24 times compared with the general population. Risk factors for SUDEP may include poorly controlled seizures, early onset of epilepsy, and generalized tonic-clonic seizures. The pathophysiology of SUDEP is unknown, but animal data suggest apnea may be the initial factor that results in sudden death.     

Self-Sustaining Status Epilepticus: A Condition Maintained by Potentiation of Glutamate Receptors and by Plastic Changes in Substance P and Other Peptide Neuromodulators

Summary: We describe a model of self-sustaining status epilepticus (SSSE) induced by stimulation of the perforant path in free-running rats. In this model, seizures can be transiently suppressed by intrahippocampal injection of a blocker of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid/kainate synapses but return in the absence of further stimulation when the drug ceases to act. However, seizures are irreversibly abolished by blockers of N -methyl- d -aspartate receptors given locally or systemically. SSSE is enhanced by substance P and its agonists and blocked by its antagonists. SSSE induces novel expression of substance P-like immunoreactivity in hippocampal principal cells. These changes and those in other limbic peptides may contribute to the maintenance of SSSE and to the modulation of hippocampal excitability during epileptic seizures.     

Inhibitory Circuits in Human Dysplastic Tissue

Summary: Purpose : Different types of epilepsies and seizures depend on the nature and location of the primary disturbance and are presumably mediated by different physiopathological mechanisms. We immunocytochemically investigated possible changes in the inhibitory -aminobutyric acid (GABA)ergic system in specimens taken from four patients who underwent surgery for intractable epilepsy and presented two different types of focal cortical dysplasia in the temporal lobe.
Methods : The patients were selected on the basis of electro-clinical, imaging, and routine neuropathological data: two had Taylor focal dysplasia, and two had non-Taylor dysplasia (microdysgenesia). The study was performed using antibodies against parvalbumin (PV), glutamic acid decarboxylase (GAD), and GABA-transporter 1 (GAT1).
Results : In the patients with Taylor dysplasia, laminar disorganization of the cortex was associated with the presence of giant neurons and ballooned cells; there was a reduced number of PV-positive neurons and terminals, the giant neurons were surrounded by clusters of PV- and GAD-positive terminals, and there was an overall reduction in GAT1. Despite the presence of cortical laminar disorganization, no giant or ballooned cells were found in the patients with non-Taylor microdysgenesia; there was a marked decrease in PV and GAD immunoreactive elements, with a patchy distribution of GAD and GAT1 immunoreactivity but no clustering of PV and GAD terminals.
Conclusions : These results suggest that the two forms of cortical dysplasia are characterized by different and selective morphofunctional alterations in the GABAergic system.