Semiologic aspects of epileptic seizures in 31 patients with hypothalamic hamartoma

Purpose: Characterization of seizure semiology in patients with hypothalamic hamartoma (HH) based on video–electroencephalography (EEG) monitoring (VEM). Methods: We retrospectively analyzed seizure semiology of 31 patients (20 male, mean age 23.5 years) who underwent VEM at the University Hospitals Freiburg or Heidelberg, Germany. Inclusion criteria were magnetic resonance evidence of an HH, no prior surgical or radiosurgical treatment, and at least two video‐documented seizures. A total of 263 seizures were included (mean number of seizures/patient 8.5, range 2–10). To analyze age‐dependent changes in seizure semiology, patients were grouped into “children” (3–11 years, n = 5), “adolescents” (12–17 years, n = 4), and “adults” (≥18 years, n = 22). Results: According to patient history, gelastic seizures had occurred in all patients, in 74% as the initial seizure type at epilepsy onset. In VEM, epileptic laughter varied from facial grinning to intense contractions of the diaphragm and body shaking. Unilateral motor signs were seen ipsi‐ and contralaterally to the HH. Tonic seizures were frequent and did not depend on the state of vigilance. Children, in contrast to adults and adolescents, did not show secondarily generalized tonic–clonic seizures, the gelastic component was the dominating and initial semiologic element, and seizures were significantly shorter. Conclusion: Seizure semiology is highly variable and age dependent. This may reflect network modulations with different propagation of ictal activity and/or secondary epileptogenesis. Detailed knowledge about such changes may contribute to both earlier recognition of seizures during childhood and better assignment of seizure types to a hypothalamic origin.     

Cingulate epileptogenesis in hypothalamic hamartoma

Hypothalamic hamartoma (HH) is a relatively rare cause of epilepsy, mainly affecting children. Nearly all patients develop gelastic seizures, often followed by other focal seizure types. Our case illustrates the mechanisms of epileptogenesis in HH. The patient developed gelastic attacks as a baby, and secondarily generalized seizures and drop attacks at 9 years of age. Magnetic resonance imaging (MRI) confirmed the presence of a HH. Presurgical assessment with intracranial electroencephalography (EEG) monitoring recorded gelastic seizures with generalized epileptiform activity. Functional stimulation of the hamartoma provoked gelastic attacks. Single pulse electrical stimulation (SPES) was used to identify epileptogenic cortex. SPES of the left cingular cortex provoked generalized responses similar to the spontaneous generalized discharges. Our results suggest that long-standing history of epilepsy in patients with HH may be related to additional sources of epileptogenic activity. Electrical stimulation performed in this patient provided additional data to favor the hypothesis of secondarily epileptogenesis in the cingulate gyrus independently from the primary origin in the HH.     

The clinical spectrum of epilepsy in children and adults with hypothalamic hamartoma

PURPOSE: Hamartomas of the hypothalamus (HH) cause an uncommon and unusual epilepsy syndrome. The condition is recognized to affect children, but the presentation in adults is not well understood. We present 19 children and adult patients with HH, including three patients whose epilepsy began in adult life. The patterns of clinical presentation, evolution of the epilepsy from childhood to adult life, and electroclinical diagnostic features are presented. METHODS: Nineteen patients, both children and adults with HH and epilepsy, were evaluated clinically, with EEG, video-EEG, and magnetic resonance imaging (MRI) scanning. Seven patients underwent surgical resection of the hamartoma. Stereotactic thermocoagulation of the hamartoma was performed in two patients. RESULTS: Gelastic seizures occurred at onset of epilepsy in 15 of 16 early-onset cases. Subsequently, multiple seizures types occurred, which then evolved to mainly partial epilepsy with tonic or complex partial seizures (five of eight adults), or became entrenched symptomatic generalized epilepsy with atypical absences, drop attacks, and secondarily generalized seizures, and cognitive impairment (three of eight adults). In the adult-onset patients, gelastic seizures were not prominent, the epilepsy was milder, and they functioned normally. Stereotactic thermocoagulation of the hamartoma resulted in improvement in seizure control in two patients. CONCLUSIONS: Gelastic seizures are not a prominent feature of epilepsy in adult patients with HH. The epilepsy associated with HH, although severe at onset, can evolve into a milder syndrome in later life. For less severely affected patients, minimally invasive alternatives to the traditionally difficult open surgical treatment should be considered.     

EEG and video-EEG seizure monitoring has limited utility in patients with hypothalamic hamartoma and epilepsy

Purpose: Hypothalamic hamartomas (HHs) are a malformation of the ventral hypothalamus and tuber cinereum, associated with gelastic seizures and epilepsy. We sought to determine the spectrum of electroencephalography (EEG) abnormalities in a large cohort of HH patients. Methods: Data was collected for HH patients undergoing evaluation between 2003 and 2007. Data included seizure history, prior treatment, and results of diagnostic studies. After informed consent, data were entered into a database. Key Findings: We reviewed 133 HH patients. Mean age at time of data analysis was 15.7 years (59.4% male). Most patients had gelastic (77%) and/or complex partial seizures (58%). Records for 102 EEG studies on 73 patients were reviewed. Interictal epileptiform abnormalities were seen in 77%, localizing predominately to the temporal and frontal regions. Records for 104 video‐EEG (VEEG) studies on 65 patients were reviewed. Of 584 gelastic seizures (GS) captured, no ictal EEG change was noted in 438 (75%). Of GS with localizing features, 89% suggested onset from the temporal and/or frontal regions. There were 160 complex partial seizures (CPS). For those with localizing features, 100% localized to the temporal and/or frontal head regions. EEG and VEEG findings correlated with the side of HH attachment. VEEG did not influence outcome. Significance: EEG features in HH patients are diverse. The majority of gelastic seizures fail to demonstrate change in the EEG. The lack of EEG changes with many clinical seizures, and the false localization seen in those events with an ictal change suggest the utility of EEG is limited in the evaluation of these patients.     

Interictal high-frequency oscillations (80-500 Hz) are an indicator of seizure onset areas independent of spikes in the human epileptic brain

Purpose: High‐frequency oscillations (HFOs) known as ripples (80–250 Hz) and fast ripples (250–500 Hz) can be recorded from macroelectrodes inserted in patients with intractable focal epilepsy. They are most likely linked to epileptogenesis and have been found in the seizure onset zone (SOZ) of human ictal and interictal recordings. HFOs occur frequently at the time of interictal spikes, but were also found independently. This study analyses the relationship between spikes and HFOs and the occurrence of HFOs in nonspiking channels. Methods: Intracerebral EEGs of 10 patients with intractable focal epilepsy were studied using macroelectrodes. Rates of HFOs within and outside spikes, the overlap between events, event durations, and the percentage of spikes carrying HFOs were calculated and compared according to anatomical localization, spiking activity, and relationship to the SOZ. Results: HFOs were found in all patients, significantly more within mesial temporal lobe structures than in neocortex. HFOs could be seen in spiking as well as nonspiking channels in all structures. Rates and durations of HFOs were significantly higher in the SOZ than outside. It was possible to establish a rate of HFOs to identify the SOZ with better sensitivity and specificity than with the rate of spikes. Discussion: HFOs occurred to a large extent independently of spikes. They are most frequent in mesial temporal structures. They are prominent in the SOZ and provide additional information on epileptogenicity independently of spikes. It was possible to identify the SOZ with a high specificity by looking at only 10 min of HFO activity.     

Thalamo-cortical network dysfunction in temporal lobe epilepsy

ObjectivesImaging and neurophysiological data shows that the cortical disfunction caused by focal epilepsy is not limited to the epileptic focus, thus raising the modern vision of focal epilepsy as a network disorder. The involvement of deep thalamo-cortical projections in temporal lobe epilepsy is a clear example. We aimed at demonstrating the interictal functional impairment of thalamo-cortical network in drug-naïve TLE patients through the study of high frequency oscillations of somatosensory evoked potentials (HF-SEP).MethodsTwelve healthy controls (HC; 8 females, 52.2 ± 17.3 years-old) and 12 drug-naïve TLE patients (8 females, 55.5 ± 21.5 years-old) underwent bilateral median HF-SEP, recorded by scalp electrodes. Cp3′-Fz and Cp4′-Fz traces were filtered (400–800 Hz) to evidence HF-SEP.ResultsHF-SEP duration in the affected hemisphere was significantly longer when compared to that of both the unaffected hemisphere and HC hemispheres. No significant inter-hemispheric differences were found in areas, powers and latencies of HF-SEP wavelets.ConclusionOur results demonstrate that TLE induces early interictal functional impairments of the thalamo-cortical network.SignificanceOur data strongly corroborates the vision of focal epilepsy as a network disorder and offers a new neurophysiological tool to test pharmacological, surgical and neuromodulatory therapies.     

Topographic movie of intracranial ictal high-frequency oscillations with seizure semiology: epileptic network in Jacksonian seizures

Purpose: We developed a technique to produce images of dynamic changes in ictal high‐frequency oscillations (HFOs) >40 Hz recorded on subdural electroencephalography (EEG) that are time‐locked to the ictal EEG and ictal semiology video. We applied this technique to Jacksonian seizures to demonstrate ictal HFO propagation along the homunculus in the primary sensory‐motor cortex to visualize the underlying epileptic network. Methods: We analyzed intracranial ictal EEGs from two patients with intractable Jacksonian seizures who underwent epilepsy surgery. We calculated the degrees of increase in amplitude within 40–80, 80–200, and 200–300 Hz frequency bands compared to the interictal period and converted them into topographic movies projected onto the brain surface picture. We combined these data with the ictal EEGs and video of the patient demonstrating ictal semiology. Key Findings: The ictal HFOs began in the sensory cortex and appeared concomitantly with the sensory aura. They then propagated to the motor cortex at the same time that focal motor symptoms evolved. As the seizure progressed, the ictal HFOs spread or reverberated in the rolandic region. However, even when the seizure became secondarily generalized, the ictal HFOs were confined to the rolandic region. In both cases, there was increased amplitude of higher frequency bands during seizure initiation compared to seizure progression. Significance: This combined movie showed the ictal HFO propagation corresponding to the ictal semiology in Jacksonian seizures and revealed the epileptic network involved in seizure initiation and progression. This method may advance understanding of neural network activities relating to clinical seizure generation and propagation.     

Continuous high-frequency activity in mesial temporal lobe structures

Purpose: Many recent studies have reported the importance of high‐frequency oscillations (HFOs) in the intracerebral electroencephalography (EEG) of patients with epilepsy. These HFOs have been defined as events that stand out from the background. We have noticed that this background often consists itself of high‐frequency rhythmic activity. The purpose of this study is to perform a first evaluation of the characteristics of high‐frequency continuous or semicontinuous background activity. Methods: Because the continuous high‐frequency pattern was noted mainly in mesial temporal structures, we reviewed the EEG studies from these structures in 24 unselected patients with electrodes implanted in these regions. Sections of background away from interictal spikes were marked visually during periods of slow‐wave sleep and wakefulness. They were then high‐passed filtered at 80 Hz and categorized as having high‐frequency rhythmic activity in one of three patterns: continuous/semicontinuous, irregular, sporadic. Wavelet entropy, which measures the degree of rhythmicity of a signal, was calculated for the marked background sections. Key Findings: Ninety‐six bipolar channels were analyzed. The continuous/semicontinuous pattern was found frequently (29/96 channels during wake and 34/96 during sleep). The different patterns were consistent between sleep and wakefulness. The continuous/semicontinuous pattern was found significantly more often in the hippocampus than in the parahippocampal gyrus and was rarely found in the amygdala. The types of pattern were not influenced by whether a channel was within the seizure‐onset zone, or whether it was a lesional channel. The continuous/semicontinuous pattern was associated with a higher frequency of spikes and with high rates of ripples and fast ripples. Significance: It appears that high‐frequency activity (above 80 Hz) does not appear only in the form of brief paroxysmal events but also in the form of continuous rhythmic activity or very long bursts. In this study limited to mesial temporal structures, we found a clear anatomic preference for the hippocampus. Although associated with spikes and with distinct HFOs, this pattern was not clearly associated with the seizure‐onset zone. Future studies will need to evaluate systematically the presence of this pattern, as it may have a pathophysiologic significance and it will also have an important influence on the very definition of HFOs.     

In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic Kv1.1α knockout mice

The ketogenic diet (KD) is an effective therapy for pediatric refractory epilepsies; however, whether the KD changes the pathologic network oscillations generated by an epileptic brain remains unknown. We have reported that hippocampal CA3 regions of epileptic Kv1.1α knockout (KO) mice generate pathologic sharp waves (SPWs) and high‐frequency oscillations (HFOs) that have higher incidence, longer duration, and fast ripples compared to wild‐type (WT). Synaptic activity of hyperexcitable KO mossy fibers significantly decreased CA3 principal cell spike‐timing reliability, which contributed to this network pathology. In addition, we have demonstrated that the KD reduces seizures by 75% in KO mice. Here, we determined whether 10‐ to 14‐day in vivo KD treatment exerts disease‐modifying effects that alter the spontaneous SPW‐HFO complexes generated by the hippocampal CA3 region of KO mice in vitro using extracellular multielectrode array recordings. We found that KD treatment significantly attenuated the pathologic features of KO SPWs and ripples and reduced the incidence of fast ripples. The KD also improved spike‐timing reliability of KO CA3 principal cells, decreased mossy fiber excitability, increased mossy fiber‐CA3 paired‐pulse ratios, and reduced coupling of field excitatory postsynaptic potentials and population spikes in the CA3 region. Collectively, these data indicate that KD treatment modulates CA3‐generated pathologic oscillations by dampening hyperactive mossy fiber synapses. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Update on the mechanisms and roles of high‐frequency oscillations in seizures and epileptic disorders

High‐frequency oscillations (HFOs) are a type of brain activity that is recorded from brain regions capable of generating seizures. Because of the close association of HFOs with epileptogenic tissue and ictogenesis, understanding their cellular and network mechanisms could provide valuable information about the organization of epileptogenic networks and how seizures emerge from the abnormal activity of these networks. In this review, we summarize the most recent advances in the field of HFOs and provide a critical evaluation of new observations within the context of already established knowledge. Recent improvements in recording technology and the introduction of optogenetics into epilepsy research have intensified experimental work on HFOs. Using advanced computer models, new cellular substrates of epileptic HFOs were identified and the role of specific neuronal subtypes in HFO genesis was determined. Traditionally, the pathogenesis of HFOs was explored mainly in patients with temporal lobe epilepsy and in animal models mimicking this condition. HFOs have also been reported to occur in other epileptic disorders and models such as neocortical epilepsy, genetically determined epilepsies, and infantile spasms, which further support the significance of HFOs in the pathophysiology of epilepsy. It is increasingly recognized that HFOs are generated by multiple mechanisms at both the cellular and network levels. Future studies on HFOs combining novel high‐resolution in vivo imaging techniques and precise control of neuronal behavior using optogenetics or chemogenetics will provide evidence about the causal role of HFOs in seizures and epileptogenesis. Detailed understanding of the pathophysiology of HFOs will propel better HFO classification and increase their information yield for clinical and diagnostic purposes.     

High frequency EEG activity associated with ictal events in an animal model of infantile spasms

Purpose : To describe high frequency (HF) electrographic activity accompanying ictal discharges in the tetrodotoxin (TTX) model of infantile spasms. Previous studies of HF oscillations in humans and animals suggest that they arise at sites of seizure onset. We compared HF oscillations at several cortical sites to determine regional differences. Methods : TTX was infused for 4 weeks into the neocortex of rats beginning on postnatal days 11 or 12. Electroencephalography (EEG) electrodes were implanted 2 weeks later and video‐EEG recordings were analyzed between postnatal days 31 and 47. EEG recordings were digitally sampled at 2,048 Hz. HF EEG activity (20–900 Hz) was quantified using compressed spectral arrays and band‐pass filtering. Key Findings : Multiple seizures were analyzed in 10 rats. Ictal onset was associated with multiple bands of rhythmic HF activity that could extend to 700 Hz. The earliest and most intense discharging typically occurred contralaterally to where TTX was infused. HF activity continued to occur throughout the seizure (even during the electrodecrement that is recorded with more traditional filter settings), although there was a gradual decrease of the intensity of the highest frequency components as the amplitude of lower frequency oscillations increased. Higher frequencies sometimes reappeared in association with spike/sharp‐waves at seizure termination. Significance : The findings show that HF EEG activity accompanies ictal events in the TTX model. Results also suggest that the seizures in this model do not originate from the TTX infusion site. Instead HF discharges are usually most intense and occur earliest contralaterally, suggesting that these homologous regions may be involved in seizure generation.     

High frequency activity overriding cortico-cortical evoked potentials reflects altered excitability in the human epileptic focus

Objective

We aimed to clarify that high frequency activity (HFA) of cortico-cortical evoked potentials (CCEPs), elicited by single pulse electrical stimulation (SPES), reflects cortical excitability.