A case of hyperventilation-induced high-amplitude rhythmic slowing with altered awareness requiring differentiation from typical absence seizure

The involvement of limbic structures in typical and atypical absence epilepsy

Two hundred and seventy eight absence seizures were recorded from 60 patients by an intensive monitoring device. They were divided into two subtypes, typical and atypical absences based on their ictal discharges whether the spike-wave rhythm was at 3 cps or not. These two absence seizures did not differ so much with regard to loss of consciousness except that: 1) the durations of discharge in atypical absences were longer than those of typical ones, 2) the recovery from clouded consciousness to a state of full-awareness was apparently delayed in atypical absences after the termination of epileptic discharges, 3) the oral automatisms were more associated with typical absences and the decreased postural tones with atypical absences. By a numerical analysis of two parameters of spike-wave, that is, its frequency ad rhythmicity, it was shown that absences with spike-waves slower than 30 cps and with poor rhythmicity which roughly corresponded with atypical absences were more therapy-resistant in comparison with those having 3 cps spike waves and good rhythm which were usually typical absences. Sodium valproate was more effective on typical absences, however, there was no difference between typical and atypical absences in the therapeutic maintenance concentrations of serum valproate acid. We would like to emphasize that the comparison of the symptomatology between typical and atypical absences is of significance not only for understanding the etiology of the epilepsies but for the guideline of practical pharmacotherapy.

The clinical and electroencephalographic (EEG) features of absence seizures in children were evaluated using EEG frequency modulation radiotelemetry and videotape monitoring. The only seizures evaluated were those with a spike-and-wave or multiple spike-and-wave duration lasting at least 3 seconds. A total of 926 absence seizures (426 typical, 500 atypical) were reviewed in 54 patients. Abnormal interictal EEGs, multiple seizure types, mental retardation, or developmental delay were more likely in patients with atypical absence seizures than in patients with typical absence seizures. Both types of absence seizures usually had a clear onset and cessation. Atypical absence seizures lasted significantly longer than did typical absence seizures. Automatisms occurred more frequently in typical absence seizures than in atypical ones, while decreases in postural tone or tonic activity occurred more frequently in atypical absence seizures. Receptive and expressive speech were retained in some patients during both types of seizures. This study demonstrates that typical and atypical absence seizures are not discrete entities but rather form a continuum. No single clinical feature can adequately distinguish the two seizure types.

Typical absence seizures differ from atypical absence seizures in terms of semiology, EEG morphology, network circuitry, and cognitive outcome, yet have the same pharmacological profile. We have compared typical to atypical absence seizures, in terms of the recruitment of different brain areas. Our initial question was whether brain areas that do not display apparent paroxysmal discharges during typical absence seizures, are affected during the ictal event in terms of synchronized activity, by other, distant areas where seizure activity is evident. Because the spike-and-wave paroxysms in atypical absence seizures invade limbic areas, we then asked whether an alteration in inhibitory processes in hippocampi may be related to the spread seizure activity beyond thalamocortical networks, in atypical seizures. We used two models of absence seizures in rats: one of typical and the other of atypical absence seizures. We estimated phase synchronization, and evaluated inhibitory transmission using a paired-pulse paradigm. In typical absence seizures, we observed an increase in synchronization between hippocampal recordings when spike-and-wave discharges occurred in the cortex and thalamus. This indicates that seizure activity in the thalamocortical circuitry enhances the propensity of limbic areas to synchronize, but is not sufficient to drive hippocampal circuitry into a full paroxysmal discharge. Lower paired-pulse depression was then found in hippocampus of rats that displayed atypical absence seizures. These observations suggest that circuitries in brain areas that do not display apparent seizure activity become synchronized as seizures occur within thalamocortical circuitry, and that a weakened hippocampal inhibition may predispose to develop synchronization into full paroxysms during atypical absence seizures.

Absence seizures cause transient impairment of consciousness. Typical absence seizures occur in children, and are accompanied by 3-4-Hz spike-wave discharges (SWDs) on electroencephalography (EEG). Prior EEG-functional magnetic resonance imaging (fMRI) studies of SWDs have shown a network of cortical and subcortical changes during these electrical events. However, fMRI during typical childhood absence seizures with confirmed impaired consciousness has not been previously investigated. We performed EEG-fMRI with simultaneous behavioral testing in 37 children with typical childhood absence epilepsy (CAE). Attentional vigilance was evaluated by a continuous performance task (CPT), and simpler motor performance was evaluated by a repetitive tapping task (RTT). SWD episodes were obtained during fMRI scanning from 9 patients among the 37 studied. fMRI signal increases during SWDs were observed in the thalamus, frontal cortex, primary visual, auditory, somatosensory, and motor cortex, and fMRI decreases were seen in the lateral and medial parietal cortex, cingulate gyrus, and basal ganglia. Omission error rate (missed targets) with SWDs during fMRI was 81% on CPT and 39% on RTT. For those seizure epochs during which CPT performance was impaired, fMRI changes were seen in cortical and subcortical structures typically involved in SWDs, whereas minimal changes were observed for the few epochs during which performance was spared. These findings suggest that typical absence seizures involve a network of cortical-subcortical areas necessary for normal attention and primary information processing. Identification of this network may improve understanding of cognitive impairments in CAE, and may help guide development of new therapies for this disorder.

ABSENCE SEIZURES | Increased GABA A Receptor-Mediated Transmission in Typical Absence Seizures

In this report, we review the pharmacological and non-pharmacological treatments of the different absence seizure types as recently recognized by the International League Against Epilepsy: typical absences, atypical absences, myoclonic absences, and eyelid myoclonia with absences. Overall, valproate and ethosuximide remain the principal anti-absence drugs. Typical absence seizures exhibit a specific electroclinical semiology, pathophysiology, and pharmacological response profile. A large-scale comparative study has recently confirmed the key role of ethosuximide in the treatment of childhood absence epilepsy, more than 50 years after its introduction. No new antiepileptic drug has proven major efficacy against typical absences. Of the medications under development, brivaracetam might be an efficacious anti-absence drug. Some experimental drugs also show efficacy in animal models of typical absence seizures. The treatment of other absence seizure types is not supported with a high level of evidence. Rufinamide appears to be the most promising new antiepileptic drug for atypical absences and possibly for myoclonic absences. The efficacy of vagal nerve stimulation should be further evaluated for atypical absences. Levetiracetam appears to display a particular efficacy in eyelid myoclonia with absences. Finally, it is important to remember that the majority of antiepileptic drugs, whether they be old or new, may aggravate typical and atypical absence seizures.

Mutation screen of GABRA1, GABRB2 and GABRG2 genes in Japanese patients with absence seizures

Epilepsy is a disorder of neural networks that is characterized by spontaneous recurrent seizures. The role of GABAB receptor-mediated mechanisms in the pathogenesis of seizures depends upon neural networks involved, which determine the seizure type. Generalized seizures involve diffuse, bi-hemispheric neuronal networks, while focal seizures involve regional brain networks. GABAB receptor agonists have been shown to diminish seizure activity in mouse models of both generalized convulsive and focal seizures. However, generalized non-convulsive seizures such as typical and atypical absence seizures (AASs) characteristically are exacerbated by GABAB receptor agonists and blocked by GABAB receptor antagonists. The reason for this dichotomy is the involvement of thalamic circuitry in both typical and atypical absence seizures. Thalamocortical circuitry underpins typical absence seizures (TASs) and hippocampal-thalamocortical circuitry is involved in AASs. In addition, high doses of GABAB receptor agonists active at the GABAB receptor/G-protein coupled inwardly rectifying potassium 2 (GIRK2) channel recently have been shown to induce the phenotype of a specific catastrophic epilepsy syndrome of childhood, infantile spasms, in mice. Therefore, GABAB receptor-mediated mechanisms can be pro- or anti-convulsant depending on the nature of the pathological neuronal networks involved. Although there are pre-clinical data in support of the efficacy of GABAB receptor agonists and antagonists in specific experimental models of seizures, these data have not been translated into the clinical arena because of the potential for downstream adverse effects. The therapeutic goal for the use of these compounds in epilepsy awaits a strategy that targets only those GABAB receptor for specific networks that are involved in a given pathological state.

Sleep disorders and ADHD symptoms in children and adolescents with typical absence seizures: An observational study

To investigate ictal cerebral haemodynamic characteristics during spontaneous typical absence seizures (TAS) and hyperventilation-evoked absence seizures in paediatric patients, relative to brief complex partial seizures (BCPS). All children diagnosed with seizures using real-time transcranial doppler ultrasonography (TCD) and sleep-deprived video-EEG (vEEG) from 2015 to 2017 in our hospital were included. The seizures were diagnosed based on the video and EEG findings. Mean cerebral blood flow velocity (CBFVm) of the unilateral middle cerebral artery was measured using TCD. TCD and vEEG data were integrated for a synchronous assessment of CBFVm changes and epileptic status. Baseline and peak CBFVm for TAS and BCPS were compared by T-test. Six children (two boys and four girls) with TAS and two girls with BCPS were enrolled. A total of 15 spontaneous TAS, 14 hyperventilation-evoked absence seizures, and six BCPS were recorded using real-time TCD-vEEG monitoring. During spontaneous TAS, whether awake or asleep, the CBFVm decreased by 20-40% compared to baseline. During hyperventilation-evoked absence seizures and BCPS, the CBFVm increased by 50-150% and 20-30% over baseline levels, respectively. The haemodynamic characteristics during TAS and BCPS are distinct, and thus our results may provide a new method to diagnose typical absence seizures using dynamic CBFVm curves. Ictal cerebral haemodynamic characteristics during spontaneous typical absence seizures and hyperventilation-evoked absence seizures may reflect different pathophysiological mechanisms and networks compared with BCPS.

The aim of this commentary is to discuss the published Cochrane Review ‘Ethosuximide, sodium valproate or lamotrigine for absence seizures in children and adolescents’ by Brigo et al.,a under the direct supervision of the Cochrane Epilepsy Group. This Cochrane Corner is produced in agreement with Developmental Medicine & Child Neurology by Cochrane Rehabilitation. Absence seizures account for 10% to 17% of all seizures in children and adolescents.2 Absence seizures present as short sudden episodes of loss of awareness and can be divided into typical absence seizure, atypical absence seizure, and absence seizures with special features.3, 4 Sodium valproate, ethosuximide, and lamotrigine are three antiseizure medications commonly used to treat absence seizures. Ethosuximide is indicated only for the treatment of generalized absence seizure, whilst valproate and lamotrigine are used in other types of seizures. Non-systematic reviews have suggested that ethosuximide and sodium valproate are equally effective, while lamotrigine is considered as a second-line drug, reserved for intractable absence seizure.5 Accidental injury is a common complication of absence seizure; around 20% of adolescents with absence seizure were reported to suffer an injury during an absence seizure.6 This could impact their rehabilitation process and thus prescribing antiseizure medication based on evidence is important. The aim of this Cochrane Review was to determine the best choice of antiseizure medication for children and adolescents with typical absence seizure between ethosuximide, valproate, and lamotrigine compared with placebo and each other. The population addressed in this review were children and adolescents up to 16 years of age with typical absence seizure. The interventions studied were sodium valproate, ethosuximide, or lamotrigine as monotherapy or add-on treatment. The intervention was compared with placebo or with one another. The primary study outcomes were proportion of seizure-free participants at 1 month, 3 months, 6 months, 12 months, and 18 months after randomization; 50% or greater reduction in the frequency of seizures; and incidence of adverse effects. Secondary study outcomes included normalization of electroencephalogram (EEG) and/or negative hyperventilation test. The review authors searched the Cochrane Register of Studies (CRS) and MEDLINE (OVID) up to September 2020. The CRS Web included randomized or quasi-randomized, controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups. The authors also contacted Sanofi Winthrop, Glaxo Wellcome (now GlaxoSmithKline), and Parke Davis (now Pfizer), manufacturers of sodium valproate, lamotrigine, and ethosuximide respectively. They also reviewed references of identified studies and retrieved relevant studies. The review authors did not include any new studies in the present review. The review authors assessed five full-text reports for possible inclusion. However, the studies were excluded for the following reasons: three studies were commentaries; one a review; and another one not relevant to the current review. This current review is based on the eight studies (691 participants) from the 2019 review. The review authors did not perform meta-analysis due to the different methodologies used in the included studies. The authors concluded that ethosuximide represents the optimal initial empirical monotherapy for children and adolescents with absence seizure with regards to both efficacy and tolerability. If absence and generalized tonic–clonic seizures coexist, valproate should be preferred, as ethosuximide is inefficacious on tonic–clonic seizures. The conclusions remain the same as the previous update as there was no new study found since the last version of the review was published. The review would influence the choice of antiseizure medication that should be prescribed for children and adolescents with typical absence seizure. Children with absence seizure are also at risk of having behaviour/psychiatric status, and psychosocial and cognitive function issues including attention, memory, and learning disability.7-9 This group of patients will often require multidisciplinary rehabilitation management. Selecting the best treatment for absence seizure is very important to optimize the outcome and improve the quality of life in patients with absence seizure. Poorly controlled absence seizure will lead to accidental injury and may influence the outcome of coordinated multidisciplinary rehabilitation management. Another issue to consider relates to females of child-bearing age, as a proportion of the adolescents will require antiseizure medication beyond the age group studied.10 There is a need to improve the design of randomized controlled trial research in this area to provide more concrete evidence to guide decision-making as most of the trials included in the systematic review are of poor methodological quality. The authors thank Cochrane Rehabilitation and Cochrane Epilepsy Group for reviewing the contents of the Cochrane Corner. The authors have stated that they had no interests that could be perceived as posing a conflict or bias.

EPILEPSY

On the basis of strong evidence, treatment is highly dependent on the seizure semiology results, electroencephalography (EEG) findings, and origin. • On the basis of moderate evidence and consensus, vigorous use of video EEG recordings and home video cameras should be used to delineate the epileptic syndromes. • On the basis of strong evidence, pediatric epilepsy syndromes have common comorbidities. As a consensus, some pediatric epilepsy centers consider referral to a neuropsychologist to be first-line care in these patients. • On the basis of strong evidence and consensus, antiepileptic drug therapy has its own complications and should be discontinued after an appropriate treatment course. • On the basis of moderate evidence and consensus, uncontrolled seizures put patients at risk for significant morbidity and mortality.

One-channel routine recordings of the scalp electroencephalogram (EEG) from unmedicated children strictly classified as unprovoked typical (3 c/s) absence seizures were selected. The dynamics of spike-and-wave discharges (SWD) were then examined by means of autocorrelation, correlation dimension, averaged pointwise dimension and largest Lyapunov exponent. For one EEG signal with pronounced spike-and-wave (SW) patterns, these measures were used complementary to a surrogate data method, a nonlinear (SETAR) modeling approach, and a SW simulation procedure providing five types of SW test signals. The SETAR model exhibited stationary SW dynamics, visually very similar to the EEG target signal, and with clear nonlinear structure. According to the results, the EEG episodes investigated represent low-dimensional dynamics, possibly recorded during nonstationary periods. Arguments that justify the assumption of deterministic chaos in our EEG signals were not obtained with the current methods. From the results one may conclude that two global oscillatory modes are present for the model, and three modes are active during the EEG recording period.