Epilepsy in twins: insights from unique historical data of William Lennox.

OBJECTIVE: To classify the Lennox twin pairs according to modern epilepsy classifications, use the classic twin model to identify which epilepsy syndromes have an inherited component, search for evidence of syndrome-specific genes, and compare concordances from Lennox's series with a contemporary Australian series. METHODS: Following review of Lennox's original files describing twins with seizures from 1934 through 1958, the International League Against Epilepsy classifications of seizures and epileptic syndromes were applied to 169 pairs. Monozygous (MZ) and dizygous (DZ) pairs were subdivided into epilepsy syndromes and casewise concordances estimated. RESULTS: The authors excluded 26 pairs, with 71 MZ and 72 DZ pairs remaining. Seizure analysis demonstrated strong parallels between contemporary seizure classification and Lennox's terminology. Epilepsy syndrome diagnoses were made in 75%. The MZ and DZ casewise concordance estimates gave strong evidence for a major genetic influence in idiopathic generalized epilepsies (0.80 versus 0.00; n = 23). High MZ casewise concordances also supported a genetic etiology in symptomatic generalized epilepsies and febrile seizures. The pairs who were concordant for seizures usually had the same syndromic diagnoses in both twins (86% in MZ, 60% in DZ), suggesting syndrome-specific genes. Apart from partial epilepsies, the MZ casewise concordances were similar to those derived from Australian twin data. CONCLUSIONS: The authors were able to apply contemporary classifications to Lennox's twins. The data confirm genetic bases for common generalized epilepsies as well as febrile seizures and provide further support for syndrome-specific genes. Finally, comparable results to our Australian series were obtained, verifying the value of twin studies.

Operative results without invasive monitoring in patients with frontal lobe epileptogenic lesions.

PURPOSE: To further explore the still controversial issues regarding whether all or most candidates for epilepsy surgery should be investigated preoperatively with invasive long-term video-EEG monitoring techniques (ILTVE). METHODS: We studied five patients with intractable seizures since early childhood using the same protocol: clinical evaluation, magnetic resonance imaging (MRI) with fluid-attenuated inversion recovery (FLAIR) sequences, long-term video-EEG (LTVE) monitoring with scalp electroencephalogram (EEG), interictal single photon emission computed tomography (SPECT), positron emission tomography (PET), and neuropsychological testing. The patients' seizures had clinical features suggesting a frontal lobe (FL) origin. MRI scans revealed focal cortical dysplasia (CD) in four patients and a probable gliotic lesion in the fifth. The findings in both PET and SPECT images were congruent with those of the MRI. Scalp LTVE failed to localize the ictal onset, although the data exhibited features suggestive of both CDs and FL seizures. On the basis of these results, surgery was performed with intraoperative corticography, and the cortical area exhibiting the greatest degree of spiking was ablated. RESULTS: Histopathologic study of four of the resected specimens confirmed the presence of CD, whereas in the fifth, there were features consistent with a remote encephaloclastic lesion. There were no postoperative deficits. Seizures in three of the patients were completely controlled at 2-3.5 years of follow-up; a fourth patient is still having a few seizures, which have required reinstitution of pharmacotherapy, and the fifth has obtained > or =70% control. All patients have had significant improvement in psychosocial measures. For comparison, five patients with generally similar clinical and neuroradiologic features to the previous group underwent preoperative ILTVE monitoring. The surgical outcomes between the two groups have not differed significantly. CONCLUSIONS: We conclude that patients with FL epilepsies may be able to undergo successful surgery without preoperative ILTVE monitoring, provided there is high concordance between neuroimaging tests (MRI, SPECT, PET) and the seizure phenotypes, even when routine EEGs and scalp LVTE fail to localize ictal onset unambiguously. The surgical outcomes of these patients generally paralleled those of the other subjects who also had FL epilepsy but who were operated on only after standard ILTVE monitoring.

Pavor nocturnus of proven epileptic origin.

PURPOSE: To evaluate the suspected epileptic origin in children with episodes masquerading as sleep terrors. METHOD: One such child was investigated with scalp-derived long-term monitoring (LTM), inter and ictal single photon emission computed tomography (SPECT) scans, and an invasive LTM, followed by surgical subpial slicing of the focally discharging motor cortex. RESULTS: The scalp-derived LTM and the SPECT scans did not localize the suspected epileptogenic focus. The invasive LTM revealed the focal onset of the ictal discharge. After the surgery, the seizures have been 90% controlled. No deficits resulted from the surgery. CONCLUSIONS: Although most nocturnal terrors (NTs) are parasomnias, in a few children their frequent episodes that masquerade as NTs have an epileptic origin. There are several features to distinguish these from common NTs or from other frontal lobe epilepsies.

Nocturnal paroxysmal dystonia due to a subfrontal cortical dysplasia.

The nature and nosology of nocturnal paroxysmal dystonia (NPD) have been controversial. Some authors consider it as a type of parasomnia, akin to night terrors and the official Classification of Sleep Disorder includes NPD within the parasomnias [1]. Others have opened for its epileptic nature, although mainly on circumstantial evidence. The location of the epileptogenic area has been so far unknown. A child with NPD was studied extensively, and in spite of normal scalp EEGs, all of his attacks were shown to originate from his right orbitofrontal cortex. Surgical ablation of an unsuspected cortical dysplastic lesion led to full control.

Can early postnatal closed head injury induce cortical dysplasia.

PURPOSE: Increased availability of surgically resected epileptogenic tissues reveals often unsuspected cortical dysplasia (CD). There is some controversy about the ontogenic stages in which these occur. Although most take place during neuroblast proliferation and migration, there is some evidence for some CD occurring during postmigrational intrinsic cortical organization. It has been shown that various kinds of focal cortical manipulations in rats, if performed within 3-4 postnatal days, lead to the genesis of various cortical malformations including a four-layered microgyrus or an unlayered CD. It is not known whether such events also might occur in the human brain. METHODS: Two children sustained minor head trauma within 4 postnatal days and later developed intractable epilepsy, which was relieved by surgery. Neuropathologic analysis of the resected tissues revealed an unsuspected microdysplastic cortex immediately adjacent to a focal, modest meningeal fibrosis, presumably secondary to the old closed head trauma. RESULTS: The main histologic features were a disorganized, unlayered cortex; abnormal clusters of neurons, often with complex, randomly oriented proximal dendritic patterns with absent apical orientation; the presence of a number of heterotopic small and large neurons in the white matter; absence of inflammatory infiltrates, of hemosiderine, of reactive gliosis, or of an excessive number of blood vessels. The morphologic features in these surgical specimens suggest that these focal malformations occur because of a regional disorder of postmigrational intrinsic cortical remodeling. CONCLUSIONS: The clinical histories and the pathologic findings lend some support to the hypothesis that minor morbid events occuring in the immediate postnatal period may lead to microdysplasia in the human similar to those induced in rat pups. The animal model could be helpful to clarify the genesis of some cases of CD and of the epileptogenicity often manifesting later in life.

Lamotrigine-induced tourettism.

BACKGROUND: Lamotrigine (LTG) has a broad spectrum of antiepileptic efficacy and generally benign side effects except for idiosyncratic rashes. OBJECTIVE: Three children are described in whom LTG caused dose-related Tourette syndrome (TS) symptoms. Although undoubtedly rare, this interesting phenomenon supports the mounting evidence in favor of the multifactorial genesis of TS symptoms. RESULTS: The main known antiseizure mechanism of LTG is to block excessive presynaptic release of excitatory amino acids (EAAs), which occurs when there are sustained neuronal burst firings, as happens within epileptogenic brain tissue. LTG does not prevent the spontaneous release of EAAs and thus does not affect their normal functions. CONCLUSIONS: Among the many proposed explanations for the pathogenesis of TS is the dopamine hypothesis: a dysfunction in dopamine uptake in the striatum. EAAs can also interfere with striatal dopamine uptake. Conceivably, LTG may cause TS symptoms by failing, at high doses, to regulate the presynaptic release of EAAs in the striatum properly.

Paroxysmal non-kinesigenic dyskinesia: pathophysiological investigations.

The paroxysmal dyskinesias constitute a heterogeneous group of disorders whose pathophysiologies and nosologies are still generally unknown. In a boy with severe, paroxysmal non-kinesigenic dyskinesia (PNKD), an invasive video-electrographic study demonstrated that his PNKD did not originate from the cortex, while a discharge was registered from the caudate nuclei. An 18FDG PET scan failed to show metabolic anomalies. A 18FDOPA and a 11C raclopride PET scans revealed a marked reduction in the density of presynaptic dopa decarboxylase activity in the striatum, together with an increased density of postsynaptic dopamine D2 receptors. These findings may suggest a chronic upregulation of postsynaptic dopa receptors, either because of an increase in their numbers or changes in their affinity. It remains unknown if these are secondary to reduced dopamine synthesis or altered release, or if the changes in striatal dopamine receptor binding are a primary or a compensatory mechanism.

Consistent EEG focalities detected in subjects with primary generalized epilepsies monitored for two decades.

PURPOSE: To describe the evolution of interictal findings in serial EEGs from patients with primary generalized epilepsy. METHODS: A cohort of 89 subjects with various primary generalized epilepsies were reviewed. Thirty-one did not meet a priori criteria. Of the 58 patients analyzed, 12 had only absence seizures, 28 had absence seizures followed by one or more generalized tonic-clonic seizures, 9 had generalized tonic-clonic seizures followed by absence and/or myoclonic seizures. and 9 had juvenile myoclonic epilepsy. Patients were followed for a mean of 16 years. An average of 39 EEGs were obtained on each patient. RESULTS: Thirty-two patients (56%) had focal features present in up to 65% of the EEGs in each of the patients. Accepted focalities were only those that were consistent in lateralization, location and, often, morphology across the span of the study. Focal findings were most often temporal or frontal. CONCLUSIONS: Patients with typical primary generalized epilepsies show a high incidence of focal EEG features that cannot be explained on the basis of structural lesions, coincidental factors, or to artifacts of the selection criteria. Although the data do not allow a definitive explanation, possible mechanisms include associated focal cortical pathology such as microdysgenesis, and development over time of localized, self-sustaining hyperexcitability in low-threshold cortical structures subjected to repeated generalized spike-wave activity. Either hypothesis implies the participation and interaction of genetic, ontogenic, and environmental factors.

Prognostic value of visual evoked potentials (VEP) in infants with visual inattentiveness.

Visual evoked potentials elicited by strobe flash (fVEPs) were recorded in 56 infants (3 months to 15 months of age) with visual inattentiveness but without prechiasmal problems. Their visual status was reexamined one or more years later when 41 children were found to be visually competent (Group NB) and 15 were blind (Group B). We also evaluated a group of 32 age-matched children who had no visual symptoms (Group C). It was found that well organized VEP waveforms over one or both hemispheres (Types U and S), or those with a characteristic negative shift (Type N) suggest favorable prognosis. Integrated voltage of the VEP correlated well with long-term prognosis for visual recovery. The vertex VEP also (had) provided some predictions for visual prognosis. Overall results indicate good prognosis if related to sufficient voltage and complexity of the VEP components.

Neonatal seizures: a clinician's overview.

Seizures are the most frequent neurological event in newborns (NBs), provoked often by noxae not apt to cause them in later life. This is because receptor families of excitatory amino acids (EAA) are overexpressed at this stage of brain ontogenesis, which is also why most neonatal seizures rapidly abate, even when neurological deficits persist. The brain's immaturities dictate distinct seizure phenotypes. A classification proposed in the late 1960s has been criticized, and a new one has been advocated, based on correlations between EEGs and behaviors, leading to a classification of seizures into 'epileptic' and 'non-epileptic'. The taxonomic pitfalls of these classifications are discussed, and the notion advanced that many seizures fail to fulfil the criteria to label them as epileptic. While etiological factors have changed in time, the striking dichotomy in outcome has persisted. Many etiologies, often multifactorial, are unique in NBs, and they are discussed with reference to diagnosis and therapies. Four syndromes of NB seizures, accepted into the International Classification of the Epilepsies, are critically analyzed, some appearing to rest on fragile grounds. Controversies persist whether seizures per se are injurious to the immature brain. Clinical studies suggest that neither duration in days or length of seizure phenotypes correlates with outcomes, the most valid prognostic indices being offered by etiologies and by patterns of EEG polygraphy. However, because most seizures are symptomatic, it may be difficult to distinguish morbidity due to underlying pathology from that possibly added by seizures. Animal experiments suggested that they are injurious. The theory of energy failure, postulated to cause a cascade of events leading to inhibitions of DNA, proteins, lipids and disrupted neuronal proliferation, synaptogenesis, myelination, has largely been disproved. Brains of immature animals have been shown to have the oxidative machinery needed to fulfill energy demands, even during status convulsivus. They are also capable of using anaerobic metabolism and require less ATP when aerobic energy production ceases. Recent explanations for the injurious consequences of hypoxic ischemia and of prolonged convulsions postulate that neuronal damage occurs from excessive release of EAA which, by binding to their ligand-gated ionic receptors, cause a large influx of Ca2+, resulting in cell death. Because of the overabundance of EAA receptors in early ontogenesis, the excitotoxic hypothesis would appear attractive, but some observations militate against it. Among these is the dissociation found between the focal neurotoxicities induced by EAA injected into the brain and their absence following the concomitant convulsions. The latter are not blocked by pretreatment with EAA antagonists, while these prevent injuries caused by the injected EAA. There is no convincing evidence that excessive release of EAA occurs during NBs' seizures. Even if it does occur, it has been shown that immature neurons have a better capacity to self-protect from increased Ca2+ influx, and also that direct application of glutamate to immature neurons leads to significantly lower Ca2+ influx. These data raise doubts about the postulated excitotoxicity caused by NBs' seizures, being consistent with the fact that no one, so far, has observed neuronal damage from drug-induced convulsive states in NBs. Lack of overt neuronal injuries does not preclude that long-term subtle changes might be induced by noxae apt to provoke transient ictal events. Thus models developed in our laboratories demonstrate that long-term epileptogenicity results following postnatal O2 deprivation without evidence of neuronal injuries or of long-term behavioral or electrophysiological alteration. However, both age at which hypoxia occurs and specific proconvulsant methods used strictly determine whether increased epileptogenicity will occur.

Paroxysmal choreoathetosis: an epileptic or non-epileptic disorder?

The pathophysiology of paroxysmal kinesigenic choreoathetosis (PKC) is controversial. Some classify it as a non-epileptic movement disorder, others consider PKC as a form of reflex-epilepsy but postulate that the epileptogenic source is within basal ganglia rather than in the cortex. An extensive invasive longterm monitoring in a girl with PKC demonstrated a consistent ictal discharge arising focally from the supplementary sensory-motor cortex (SMC), with a concomitant discharge recorded from the ipsilateral caudate nucleus, without significant spread to other neocortical areas. An hypothesis is presented to explain how a focal discharge within the supplementary motor cortex, demonstrated for the first time to occur in a patient with PKC, might cause phenomenologies distinct from the habitual SMC seizures and strongly suggesting a basal ganglia semeiology.

EEG prior to hemispherectomy: correlation with outcome and pathology.

Hemispherectomy, for the treatment of seizures, is highly successful but has a significant morbidity rate. The procedure is usually restricted to patients with an intractable seizure disorder and hemiparesis. Because of the inherent risk of surgery, patient selection is a critical issue. This report describes the evaluation of background activity and ictal patterns on surface and invasive EEG in 12 children who underwent both anatomical (7) and functional (5) hemispherectomy in order to determine the role of electroencephalography in the selection of patients for hemispherectomy, and to correlate EEG findings with underlying pathology and outcome. A favorable outcome was predicted by an interictal EEG with two or more of the following: suppression over the abnormal hemisphere, absence of contralateral slowing, absence of generalized discharges and absence of bilateral independent spiking; or by unilateral onset of ictal discharges on invasive intracerebral EEG recording. Outcome did not correlate with the underlying pathology. Hemispherectomy can be successful in patients with a variety of predominantly unilateral pathologic entities.

Technetium-99m HmPAO brain SPECT and outcome of hemispherectomy for intractable seizures.

With recent descriptions of the modified hemispherectomies and hemicorticectomy, there has been renewed interest in hemispherectomy for treatment of intractable seizures with hemiparesis. Because long-term outcome remains uncertain, patient selection remains difficult. 99mTc-HmPAO brain SPECT has been a helpful adjunct in the evaluation of epilepsy surgery candidates. We report SPECT scan findings in 7 patients who underwent hemispherectomy and compare these results with scalp EEG findings. Six patients had unilateral SPECT findings and all had a favorable outcome, regardless of surface EEG findings.

Prognostic value of background patterns in the neonatal EEG.

The prognostic value of background activity in the neonatal EEG has been well established. Whereas in older children the neonatal EEG is useful in the diagnosis of seizures, in neonates the test also provides a particularly valuable assessment of cerebral functioning following a variety of insults. In this review, the prognostic significance of abnormalities of amplitude, continuity, frequency, symmetry, synchrony, sleep state, and maturation are discussed. Certain abnormalities, such as cerebral electrical inactivity or burst suppression, are highly predictive of outcome, whereas other abnormalities of background activity are associated with more variable outcomes. Since the ill neonate may have more than one abnormality, predicting outcome based on a single EEG feature is discouraged. As in older children, drugs may affect EEG background rhythms. Although abnormalities on the neonatal EEG are not specific for diagnosis, certain EEG patterns may be highly suggestive for the diagnosis of pyridoxine dependency and neonatal herpes encephalitis. In both term and preterm infants, the prognostic value of the neonatal EEG is increased by performing serial studies.

Facilitation of infantile spasms by partial seizures.

We report 16 patients with infantile spasms in whom onset of the clusters of spasms appeared to be triggered by close temporal association with partial seizures. Common features included the presence of focal cerebral lesions in 12 infants (3 were classifiable as cryptogenic); all had partial seizures with EEG localization, clusters of bilateral spasms always preceded by partial seizures, and response to adrenocorticotropic hormone (ACTH) and traditional antiepileptic drugs (AEDs) generally was poor. Three had complete agenesis of the corpus callosum, which argues against interhemispheric callosal spread of focal discharges resulting in the generalized spasms. Surgical cortical resections were performed in 6 of the infants, with good outcomes. This group of patients supports a model in which the spasms, although probably generated at a subcortical level, are facilitated or possibly induced by focal discharges from cortical pathology.

Age-dependent changes in long-term seizure susceptibility and behavior after hypoxia in rats.

We showed that hypoxia is acutely epileptogenic in immature but not in adult rats. In the present study, we evaluated whether hypoxia results in an increase in long-term seizure susceptibility to flurothyl and whether this is associated with impaired performance on behavioral tests. We also determined whether these long-term outcomes are dependent on age at time of O2 deprivation. Long Evans hooded rats were rendered hypoxic on either postnatal day (P)5, P10, or P60. Sixty to 75 days after hypoxia, rats were tested for performance in water maze, open field, and handling tests and for seizure susceptibility to flurothyl. Hypoxia at P10 significantly increased seizure susceptibility to flurothyl, whereas hypoxia at P5 and P60 induced no long-term changes in seizure threshold. At P10, greater seizure severity during hypoxia and more prolonged exposure to hypoxia significantly increased long-term seizure susceptibility. This long-term change in seizure susceptibility appeared to be dissociated from any long-term neurobehavioral consequences, because only animals rendered hypoxic as adults (P60) had impaired behavioral performance. The results suggest that hypoxia-induced seizures can alter long-term seizure susceptibility and that this long-term effect is dependent on age and on severity of seizure activity at the time of previous hypoxia.

Pyridoxine-dependent epilepsy: EEG investigations and long-term follow-up.

The EEG features and clinical correlates were investigated before, directly after, and on long-term follow-up after initiation of pyridoxine therapy in 6 patients with B6-dependent epilepsy. At each phase, the EEG provided important diagnostic and prognostic information. Pre-B6 3 neonates manifested a unique EEG pattern of generalized bursts of 1-4 Hz sharp and slow activity. This pattern has not been previously described in neonates with B6 dependency and in this age group appears to be highly suggestive of the diagnosis. Five patients experienced an apparent initial response to traditional antiepileptics. The parenteral pyridoxine test, performed in all 5, and repeated in 3, proved to be a highly reliable and reproducible diagnostic test. After 50-100 mg of B6 there was cessation of clinical seizures within minutes and of paroxysmal discharges within hours. On long-term follow-up (3-28 years) all 6 patients were seizure free on B6 (10-100 mg/day) monotherapy. Recurrences of seizures and of specific sequential EEG changes (background slowing, photoparoxysmal response, spontaneous discharges, stimulus-induced myoclonus, generalized seizures) occurred upon B6 withdrawal. Long-term prognosis correlated with the EEG. Two patients had persistently abnormal EEG backgrounds and were moderately to severely retarded, while 4 had normal EEGs with normal or near normal development.

Results of surgery for extratemporal partial epilepsy that began in childhood.

Thirty-five consecutive patients who underwent surgery for intractable extratemporal seizures originating in childhood are described. Candidates for surgery were selected on the basis of clinical criteria, neurodiagnostic imaging, and an electroencephalographic investigation that included the use of sphenoidal electrodes and long-term monitoring. Invasive preoperative monitoring was not used. Our results, with respect to the control of seizures and behavioral improvement, are comparable with series in which data from invasive recordings were used in the selection process. Sixty-three percent of the 35 patients (76.5% of those operated on after the introduction of long-term electroencephalographic monitoring) became either seizure free or experienced a reduction in their frequency of seizures by at least 75%. The favorable outcome in this group of patients strengthens the argument for early operation in children with intractable epilepsy, even when the seizure focus is outside the temporal lobe.