Giancarlo Di Gennaro

Ictal heart rate increase precedes EEG discharge in drug-resistant mesial temporal lobe seizures

OBJECTIVE Heart rate (HR) changes, mainly tachycardia, are often observed during seizures originating from the temporal lobe. The aim of this study was to analyze the role of ictal HR changes in localizing both mesial and lateral temporal lobe epilepsy (TLE) in a group of 68 patients. The influence of the gender and the side of epilepsy on HR modulation was also evaluated. METHODS Ictal HR was recorded during prolonged Video-EEG monitoring performed in 68 patients affected by drug-resistant TLE during a non-invasive pre-surgical protocol. According to the electro-clinical correlation, obtained by video-EEG monitoring, one hundred-thirteen seizures (n=113) and one hundred-forty-four auras (n=144) were identified and included in the study. Furthermore, the electro-clinical correlation allowed the classification of all the epileptic events (seizures and auras) as having mesial or lateral origin, based on the temporal lobe seizure onset zone. Ictal HR was calculated with respect to the R-R waves, and assessed from 15 sec (s) before (T(- 15)) to 15 s after (T(+15)) the time of EEG seizure onset (T(0)). RESULTS We observed a high incidence (92%) of ictal HR increase in TLE seizures. When the ictal EEG indicated a seizure onset from the mesial temporal structures, the onset of ictal HR increase preceded by about 5 s the EEG ictal onset (SD+/-18.4), whereas the onset of HR increase coincided with the onset of EEG discharges (SD+/-14.8) when the ictal EEG indicated the onset of seizures from the lateral temporal structures. No significant differences were found between male and female patients; and between right and left TLE. CONCLUSIONS Our findings show that ictal HR increase, preceding the onset of the EEG discharge, is associated with ictal EEG seizure pattern defining temporal lobe seizures originating from the mesial temporal lobe structures; this association suggests that the HR changes may be coupled to the functional impairment of neural circuits involved in sympathetic cardiovascular regulation, in the mesial temporal lobe structures. Further studies investigating the relationship between intracranial EEG monitoring and ECG recording are worthwhile, to confirm our results and to give further indications on the pathogenesis of ictal HR abnormalities.

Hippocampal, amygdala, and neocortical synchronization of theta rhythms is related to an immediate recall during Rey auditory verbal learning test

It is well known that theta rhythms (3–8 Hz) are the fingerprint of hippocampus, and that neural activity accompanying encoding of words differs according to whether the items are later remembered or forgotten [“subsequent memory effect” (SME)]. Here, we tested the hypothesis that temporal synchronization of theta rhythms among hippocampus, amygdala, and neocortex is related to immediate memorization of repeated words. To address this issue, intracerebral electroencephalographic (EEG) activity was recorded in five subjects with drug‐resistant temporal lobe epilepsy (TLE), under presurgical monitoring routine. During the recording of the intracerebral EEG activity, the subjects performed a computerized version of Rey auditory verbal learning test (RAVLT), a popular test for the clinical evaluation of the immediate and delayed memory. They heard the same list of 15 common words for five times. Each time, immediately after listening the list, the subjects were required to repeat as many words as they could recall. Spectral coherence of the intracerebral EEG activity was computed in order to assess the temporal synchronization of the theta (about 3–8 Hz) rhythms among hippocampus, amygdala, and temporal‐occipital neocortex. We found that theta coherence values between amygdala and hippocampus, and between hippocampus and occipital‐temporal cortex, were higher in amplitude during successful than unsuccessful immediate recall. A control analysis showed that this was true also for a gamma band (40–45 Hz). Furthermore, these theta and gamma effects were not observed in an additional (control) subject with drug‐resistant TLE and a wide lesion to hippocampus. In conclusion, a successful immediate recall to the RAVLT was associated to the enhancement of temporal synchronization of the theta (gamma) rhythms within a cerebral network including hippocampus, amygdala, and temporal–occipital neocortex. Hum Brain Mapp, 2009.

Localizing significance of temporal intermittent rhythmic delta activity (TIRDA) in drug-resistant focal epilepsy

OBJECTIVE Temporal intermittent rhythmic delta activity (TIRDA) is an EEG pattern characterized by sinusoidal trains of activity, ranging from 1 to 3.5 Hz, and well localized over the temporal regions. It is considered to be an indicator of temporal lobe epilepsy (TLE), but full agreement between different authors has still not been reached. The aim of this study was therefore to assess the role of TIRDA in localizing the epileptogenic zone, which was estimated using anatomo-electro-clinical correlations obtained from non-invasive pre-surgical investigations, in a large group of patients affected by drug-resistant partial epilepsy. METHODS The occurrence of TIRDA was investigated using a prolonged Video-EEG recording of 129 patients affected by drug-resistant partial epilepsy that underwent a non-invasive pre-surgical protocol. Patients were divided into 3 groups: TLE only, extratemporal epilepsy, and multilobar epilepsy including temporal lobe. According to the epileptogenic zone identified using anatomo-clinical-radiological correlations, 3 different subgroups of TLE were identified: mesial, lateral, and mesio-lateral. Statistical analysis was performed in order to evaluate the relationship between TIRDA and the epileptogenic zone, and neuroradiological, neuropathological, EEG interictal and ictal findings. RESULTS The pattern of TIRDA was observed in 52 out of the 129 (40.3%) patients studied. Significant correlations were found between TIRDA and: (i) mesial and mesio-lateral TLE; (ii) mesial temporal sclerosis; (iii) interictal epileptiform discharge localized over the anterior temporal regions; and (iv) 5-9 Hz temporal ictal discharge. CONCLUSIONS Our research shows that TIRDA plays a role in localizing the epileptogenic zone, suggesting that this pattern might be considered as an EEG marker of an epileptogenesis that involves the mesial structures of the temporal lobe. However, further studies investigating the relationship between intracranial EEG monitoring and simultaneous scalp EEG recording are needed in order to confirm our findings and improve our understanding of the significance of TIRDA.

Epilepsy and polymicrogyria in Kabuki make-up (Niikawa-Kuroki) syndrome.

Kabuki make-up syndrome is a rare dysmorphogenic disorder characterized by peculiar facial appearance (resembling the make-up of actors in Kabuki, the traditional Japanese theatre), skeletal anomalies, dermatoglyphic abnormalities, postnatal growth deficiency, and mental retardation. Central nervous system dysfunctions, other than mental retardation, are rarely reported; they include microcephaly, brachycephaly, early hypotonia, feeding disorders, subatrophy of the optic nerves, subarachnoid cyst, cerebellar and brainstem atrophy, and epilepsy. These manifestations appear to be more common in non-Japanese patients. Reported is an Italian child with phenotypical appearance of Kabuki make-up syndrome and partial epilepsy who demonstrated polymicrogyria on neuroimaging. This article is the first report of a gyration disorder in Kabuki make-up syndrome. The relationship between epilepsy and polymicrogyria in this patient is discussed.

The Antiepileptic Drug Levetiracetam Stabilizes the Human Epileptic GABAA Receptors upon Repetitive Activation

Summary:  Purpose: GABAA receptors from the brain of patients afflicted with mesial temporal lobe epilepsy (MTLE) become less efficient (run‐down) when repetitively activated by GABA. Experiments were designed to investigate whether the antiepileptic drug, levetiracetam (LEV), which is used as an adjunctive treatment for medically intractable MTLE, counteracts the GABAA receptor run‐down.

Seizure clusters and adverse events during pre-surgical video-EEG monitoring with a slow anti-epileptic drug (AED) taper

OBJECTIVE To evaluate the efficiency and safety of pre-surgical video-EEG monitoring with a slow anti-epileptic drug (AED) taper and a rescue benzodiazepine protocol. METHODS Fifty-four consecutive patients with refractory focal epilepsy who underwent pre-surgical video-electroencephalography (EEG) monitoring during the year 2010 were included in the study. Time to first seizure, duration of monitoring, incidence of 4-h and 24-h seizure clustering, secondarily generalised tonic-clonic seizures (sGTCS), status epilepticus, falls and cardiac asystole were evaluated. RESULTS A total of 190 seizures were recorded. Six (11%) patients had 4-h clusters and 21 (39%) patients had 24-h clusters. While 15 sGTCS were recorded in 14 patients (26%), status epilepticus did not occur and no seizure was complicated with cardiac asystole. Epileptic falls with no significant injuries occurred in three patients. The mean time to first seizure was 3.3days and the time to conclude video-EEG monitoring averaged 6days. CONCLUSION Seizure clustering was common during pre-surgical video-EEG monitoring, although serious adverse events were rare with a slow AED tapering and a rescue benzodiazepine protocol. SIGNIFICANCE Slow AED taper pre-surgical video-EEG monitoring is fairly safe when performed in a highly specialised and supervised hospital setting.

Adenosine receptor antagonists alter the stability of human epileptic GABAA receptors

We examined how the endogenous anticonvulsant adenosine might influence γ-aminobutyric acid type A (GABAA) receptor stability and which adenosine receptors (ARs) were involved. Upon repetitive activation (GABA 500 μM), GABAA receptors, microtransplanted into Xenopus oocytes from neurosurgically resected epileptic human nervous tissues, exhibited an obvious GABAA-current (IGABA) run-down, which was consistently and significantly reduced by treatment with the nonselective adenosine receptor antagonist CGS15943 (100 nM) or with adenosine deaminase (ADA) (1 units/ml), that inactivates adenosine. It was also found that selective antagonists of A2B (MRS1706, 10 nM) or A3 (MRS1334, 30 nM) receptors reduced IGABA run-down, whereas treatment with the specific A1 receptor antagonist DPCPX (10 nM) was ineffective. The selective A2A receptor antagonist SCH58261 (10 nM) reduced or potentiated IGABA run-down in ≈40% and ≈20% of tested oocytes, respectively. The ADA-resistant, AR agonist 2-chloroadenosine (2-CA) (10 μM) potentiated IGABA run-down but only in ≈20% of tested oocytes. CGS15943 administration again decreased IGABA run-down in patch-clamped neurons from either human or rat neocortex slices. IGABA run-down in pyramidal neurons was equivalent in A1 receptor-deficient and wt neurons but much larger in neurons from A2A receptor-deficient mice, indicating that, in mouse cortex, GABAA-receptor stability is tonically influenced by A2A but not by A1 receptors. IGABA run-down from wt mice was not affected by 2-CA, suggesting maximal ARs activity by endogenous adenosine. Our findings strongly suggest that cortical A2–A3 receptors alter the stability of GABAA receptors, which could offer therapeutic opportunities.

Expression of human epileptic temporal lobe neurotransmitter receptors in Xenopus oocytes: An innovative approach to study epilepsy

Poly(A+) RNA was extracted from the temporal lobe (TL) of medically intractable epileptic patients which underwent surgical TL resection. Injection of this mRNA into Xenopus oocytes led to the expression of ionotropic receptors for γ-aminobutyric acid (GABA), kainate (KAI) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Membrane currents elicited by GABA inverted polarity at −15 mV, close to the oocytes chloride equilibrium potential, were inhibited by bicuculline, and were potentiated by pentobarbital and flunitrazepam. These basic characteristics were also displayed by GABA currents elicited in oocytes injected with mRNAs isolated from human TL glioma (TLG) or from mouse TL. However, the GABA receptors expressed by the epileptic TL mRNA exhibited some unusual properties, consisting in a rapid current run-down after repetitive GABA applications and a large EC50 (125 μM). AMPA alone evoked very small or nil currents, whereas KAI induced larger currents. Nevertheless, upon cyclothiazide treatment, AMPA elicited substantial currents that, like the KAI currents, were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). Furthermore, the glutamate receptor 5 (GluR5) agonist, ATPA, failed to evoke an obvious current although both RT-PCR and Western blot analyses showed GluR5 expression in the epileptic TL. Oocytes injected with mouse TL or human TLG mRNAs generated KAI and AMPA currents similar to those evoked in oocytes injected with epileptic TL mRNA but, in contrast to these, the mouse TL and human TLG oocytes were also responsive to ATPA. Our findings are in accord with the concept that both a depression of GABA inhibition and a dysfunction of the KAI-receptor system maintain a high neuronal excitability that results in epileptic seizures.

Postoperative EEG and seizure outcome in temporal lobe epilepsy surgery.

OBJECTIVE To assess the prognostic value of scalp electroencephalogram (EEG) after epilepsy surgery, we investigated whether postoperative EEG abnormalities (interictal epileptiform discharges, IED; interictal slow activity, ISA) were associated with seizure outcome and other patient characteristics after resective surgery in patients with temporal lobe epilepsy (TLE). METHODS Sixty-two patients with medically refractory TLE who underwent surgery were studied. Patients were categorized according to etiology (mesiotemporal sclerosis vs. tumors/cortical dysplasias); extent of surgical resection (extensive vs. limited); and amount of preoperative IED on wake EEG (oligospikers, <1 IED/h, vs. spikers). Patients were also classified as seizure-free (SF) or having persistent seizures/auras (not-SF) during follow up visits 1 month and 1 year after surgery. Preoperative 60-min interictal EEGs were evaluated for IED and ISA, and compared to postoperative wake EEGs. RESULTS Seizures/auras persisted in 16/62 (25.8%) patients at 1 month and in 8/62 (12.9%) at 1 year follow up. ISA was not significantly related to outcome. Of 42 patients with EEG negative for IED at 1 month, 4 were not-SF; at 1 year, one of 44 such patients was not-SF. IED was significantly associated with seizure/aura persistence in patients categorized as mesiotemporal sclerosis and with extensive surgery. Oligospikers and spikers on preoperative EEG showed no differences in the postoperative seizure outcome, excellent in both cases; moreover, the presence of postoperative IEDs indicated auras/seizures persistence apart from the preoperative EEG spike frequency. CONCLUSIONS Our study showed that the presence of IED of postoperatve EEG strongly indicates seizure/aura persistence. Therefore, serial EEGs should be included in postoperative follow up schedules as a crucial tool in evaluating seizure outcome.

Alpha, beta and gamma electrocorticographic rhythms in somatosensory, motor, premotor and prefrontal cortical areas differ in movement execution and observation in humans

OBJECTIVE In the present study, we tested the hypothesis that both movement execution and observation induce parallel modulations of alpha, beta, and gamma electrocorticographic (ECoG) rhythms in primary somatosensory (Brodmann area 1-2, BA1-2), primary motor (BA4), ventral premotor (BA6), and prefrontal (BA44 and BA45, part of putative human mirror neuron system underlying the understanding of actions of other people) areas. METHODS ECoG activity was recorded in drug-resistant epileptic patients during the execution of actions to reach and grasp common objects according to their affordances, as well as during the observation of the same actions performed by an experimenter. RESULTS Both action execution and observation induced a desynchronization of alpha and beta rhythms in BA1-2, BA4, BA6, BA44 and BA45, which was generally higher in amplitude during the former than the latter condition. Action execution also induced a major synchronization of gamma rhythms in BA4 and BA6, again more during the execution of an action than during its observation. CONCLUSION Human primary sensorimotor, premotor, and prefrontal areas do generate alpha, beta, and gamma rhythms and differently modulate them during action execution and observation. Gamma rhythms of motor areas are especially involved in action execution. SIGNIFICANCE Oscillatory activity of neural populations in sensorimotor, premotor and prefrontal (part of human mirror neuron system) areas represents and distinguishes own actions from those of other people. This methodological approach might be used for a neurophysiological diagnostic imaging of social cognition in epileptic patients.