F. Andermann

Congenital malformations due to antiepileptic drugs

To identify the major risk factors for the increased incidence of congenital malformations in offspring of mothers being treated for epilepsy with antiepileptic drugs (AEDs) during pregnancy and, to determine the relative teratogenic risk of AEDs, we prospectively analyzed 983 offspring born in Japan, Italy, and Canada. The incidence of congenital malformations in offspring without drug exposure was 3.1%, versus an incidence with drug exposure of 9.0%. The highest incidence in offspring exposed to a single AED occurred with primidone (PRM; 14.3%), which was followed by valproate (VPA; 11.1%), phenytoin (PHT; 9.1%), carbamazepine (CBZ; 5.7%), and phenobarbital (PB; 5.1%). The VPA dose and level positively correlated with the incidence of malformations. This study first determined a cut-off value of VPA dose and level at 1000 mg/day and 70 microg/ml, respectively, to avoid the occurrence of malformations. The incidence of malformations increases as the number of drugs increases, and as the total daily dose increases. Specific combinations of AEDs such as VPA + CBZ and PHT + PRM + PB produced a higher incidence of congenital malformations. The incidence of malformations was not associated with any background factors studied except for the presence of malformations in siblings. These results indicate that the increased incidence of congenital malformations was caused primarily by AEDs, suggesting that malformations can be prevented by improvements in drug regimen, and by avoiding polypharmacy and high levels of VPA (more than 70 microg/ml) in the treatment of epileptic women of childbearimg age.

Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder

We describe a distinctive epilepsy syndrome in six families, which is the first partial epilepsy syndrome to follow single gene inheritance. The predominant seizure pattern had frontal lobe seizure semiology with clusters of brief motor attacks occurring in sleep. Onset was usually in childhood, often persisting through adult life. Misdiagnosis as night terrors, nightmares, hysteria, or paroxysmal nocturnal dystonia was common, and the inheritance pattern was often not appreciated. This autosomal dominant epilepsy syndrome is ideal for identification of partial epilepsy genes.

Congenital bilateral perisylvian syndrome: study of 31 patients

Advances in neuroimaging techniques have enabled the recognition of developmental malformations of the brain during life. Careful correlation of clinical and imaging features has identified several new syndromes. We have studied 31 patients with a congenital neurological syndrome characterised by pseudobulbar palsy, cognitive deficits, and bilateral perisylvian abnormalities on imaging studies. All patients had diplegia of the facial pharyngeal, and masticatory muscles, of variable severity. Some patients had slight dysarthria, whereas others were unable to speak. 85% of patients had mental retardation, ranging from mild to severe. Epilepsy was present in 27 (87%) and commonly consisted of atypical absence, atonic/tonic, tonic-clonic seizures, and, less frequently, partial attacks. Seizures were poorly controlled in 55%. Magnetic resonance imaging showed bilateral perisylvian cortical malformations consistent with polymicrogyria, confirmed at necropsy. Division of the corpus callosum in several patients resulted in seizure improvement. This congenital bilateral perisylvian syndrome can be clinically diagnosed and confirmed by imaging studies. Further studies are necessary to elucidate its cause.

Autosomal Dominant Nocturnal Frontal-Lobe Epilepsy: Genetic Heterogeneity and Evidence for a Second Locus at 15q24

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.

Severe Myoclonic Epilepsy of Infancy: Extended Spectrum of GEFS+?

Summary: u2002Purpose: Severe myoclonic epilepsy of infancy (SMEI) is an intractable epilepsy of early childhood of unknown etiology. It is often associated with a family history of seizure disorders, but epilepsy phenotypes have not been well described. We sought to characterize the seizure phenotypes of relatives to better understand to the genetic basis of SMEI.

Entorhinal cortex in temporal lobe epilepsy: A quantitative MRI study

Background: The entorhinal cortex (EC) is a distinct anatomic and functional region of the anterior parahippocampal gyrus, which plays a role in seizure generation and propagation in temporal lobe epilepsy (TLE). In tissue resected from TLE patients, cell loss in the EC has been described. Objectives: To develop a standardized protocol for identifying the anatomic boundaries of the EC using high-resolution MRI and to examine morphologic changes of the EC in TLE. Methods: We performed T1-weighted MRIs in 20 patients (7 males) with TLE (mean age 34 years) and 18 normal controls (mean age 26 years). Eleven patients had a left and 9 a right epileptic focus as defined by history, video-EEG, and surgical outcome. The volumes of the EC, the hippocampus, and the amygdala were measured using a standardized MRI protocol. Analysis of variance (ANOVA) was used to examine the effect of seizure focus lateralization and hemisphere on these volumes. An asymmetry ratio [A (%) = 100 × (R−L)/(R+L)/2] was also compared between groups using ANOVA. Results: In normal controls the volume of the right EC was 1,247 ± 127 mm3 (mean ± standard deviation), and that of the left EC was 1,215 ± 135 mm3 (p > 0.05). We found a bilateral reduction in the volume of the EC in TLE patients compared with controls (p < 0.05). Examination of the asymmetry ratios showed that the reduction in volume of the EC was greater ipsilateral to the epileptic focus (p < 0.05). The volumes of the hippocampus and the amygdala were smaller on the side of the focus in TLE patients compared with controls (p < 0.05). Conclusions: With a standardized protocol for the quantitative assessment of the EC, patients with unilateral TLE show bilateral reduction in the volume of the EC. However, this reduction is more severe ipsilateral to the epileptic focus.

Absence Status A Reappraisal following Review of Thirty-eight Patients

We have recently reviewed our series of 38 patients with absence status. This is a clearly recognizable seizure pattern but by no means a uniform one. Its occurrence is often overlooked, but may be revealed by specific inquiry except in small children, patients with severe mental retardation, or patients with a great deal of on‐going epileptic discharge.

Resection of the lesion in patients with hypothalamic hamartomas and catastrophic epilepsy

BackgroundPatients with hypothalamic hamartomas (HH) often have severe refractory epilepsy, incapacitating behavioral abnormalities, and cognitive decline. Attempts to control the seizure disorder by resection of apparently epileptogenic mesial temporal or other cortical structures have failed consistently. Objective To report a series of 13 patients in whom the hamartoma itself was resected. Methods All patients underwent preoperative evaluation between ages 2 and 33 years and had subtotal or complete resection of the hamartoma. Follow-up ranged from 1 to 5.5 years (mean: 2.8 y). Results Preoperatively, all patients had variable combinations of gelastic, complex partial, and generalized seizures. Eight had drop attacks. In addition, all had marked behavior abnormalities and cognitive impairment. Postoperatively, two patients are completely seizure-free and 11 are either seizure-free or have achieved a greater than 90% reduction of drop attacks and generalized tonic-clonic seizures. However, minor gelastic, complex partial, and atypical absence seizures have persisted in 11 patients, although at significantly reduced rates. In addition, there has been a dramatic improvement in behavior and cognition. Three patients had an anterior thalamic and one a capsular infarct, which left only minimal long-term deficits. Exact location of the lesion in relation to the interpeduncular fossa and the walls of the third ventricle correlated with extent of excision, seizure control, and complication rate. Conclusion Resection can alleviate both the seizures and the behavioral and cognitive abnormalities of hypothalamic hamartomas, but complications are frequent.

Morphometric Analysis of the Temporal Lobe in Temporal Lobe Epilepsy

Summary: Purpose: Using high‐resolution magnetic resonance imaging (MRI), we examined the temporal neocortex and the underlying white matter in patients with unilateral temporal lobe epilepsy (TLE) and in control subjects.

Occipitotemporal Epilepsies: Evaluation of Selected Patients Requiring Depth Electrodes Studies and Rationale for Surgical Approaches

Summary: In 8 patients in whom it was uncertain whether they had occipital or temporal lobe (TL) epilepsy, clinical, scalp EEG, and radiologic features were correlated with the sites of seizure onset as determined by depth EEG. The 8 patients were selected from >40 with occipital epilepsy because they had (a) an aura considered to be of occipital lobe (OL) origin, (b) an occipital interictal epileptic focus, (c) an OL lesion, or (d) a combination of all of these. Scalp EEG and clinical patterns suggested temporal involvement in all, however. Extracranial EEG recordings were often misleading, showing multilobar interictal epileptic abnormalities, and seizure onset was of poor localizing value and did not clarify the problem sufficiently. Intracranial EEG recordings showed that seizure onset could be ordered along an Occipitotemporal gradient. Consistent OL seizure onset was observed in patients who had only elementary visual auras. Those who had inconsistent aura or no aura, suggesting OL origin, had onset of most attacks in the TL. All patients had a seizure spread pattern suggesting early TL involvement. To prevent visual field defect, surgical approaches included temporal resection when temporal seizure origin or spread was demonstrated; although occasionally this produced excellent results, it was of limited benefit in most patients, even when some seizures were proven to originate in TL structures. In patients with malignant epilepsy and in those with an occipital lesion, occipital resection should be considered.