Ictal Generalized EEG Attenuation (IGEA) and hypopnea in a child with occipital type 1 cortical dysplasia - Is it a biomarker for SUDEP?

An interesting association of ictal hypopnea and ictal generalized EEG attenuation (IGEA) as possible marker of sudden unexpected death in epilepsy (SUDEP) is reported. We describe a 5-years-old girl with left focal seizures with secondary generalization due to right occipital cortical dysplasia presenting with ictal hypopnea and IGEA. She had repeated episodes of the ictal apnoea in the past requiring ventilator support and intensive care unit (ICU) admission during episodes of status epilepticus. The IGEA lasted for 0.26-4.68 seconds coinciding with the ictal hypopnea during which both clinical seizure and electrical epileptic activity stopped. Review of literature showed correlation between post-ictal apnoea and post ictal generalized EEG suppression and increased risk for SUDEP. The report adds to the growing body of literature on peri-ictal apnea, about its association with IGEA might be considered as a marker for SUDEP. She is seizure free for 4 months following surgery.

Introduction

Occurrence of sudden unexpected death in epilepsy (SUDEP) is rare in children with a prevalence of 0.11-0.43/1000 person-years compared to adults (1.1-5.9/1000 person-years) with chronic refractory epilepsy.[12] The proposed mechanisms for SUDEP might be related to a combined cardiac, respiratory, and autonomic dysfunction during the peri-ictal period. Abnormalities of cardiac rhythms or respiration like bradypnea, hypopnea and apnea during the ictus have been observed. Post-ictal generalized EEG suppression (PGES) and burst suppression, noted in electroencephalography (EEG) of patients with drug resistant epilepsy, have been identified as high risk for SUDEP.[3] Terminal cessation and diffuse suppression of EEG activity before any cardiac or respiratory changes akin to central nervous system (CNS) shutdown has also been reported.[4]

We discuss clinical-EEG profile of a child with localization related occipital epilepsy due to cortical dysplasia manifesting with multiple episodes of ictal generalized EEG attenuation (IGEA) and hypopnea during a prolonged focal motor seizure while undergoing video-EEG recording.

Case Report

This 5-year girl developed fever and seizures at 6 months of age, four hours after Diptheria Pertussis and Tetanus (DPT) vaccination. Subsequent seizures were non-febrile and occurred once/2-3 months for the initial 2 years. The seizure frequency increased to four seizures/week and so did the seizure duration lasting often upto 30-45 minutes. During last 3 years, on four occasions, the prolonged seizures were associated with ictal apnea requiring lifesaving ventilator support. Seizures were characterized by confusion, subdued response, with or without vomiting, left focal motor seizures, deviation of eyes to the left and left hemi-generalized tonic-clonic movements. Occasionally, she would also have a clockwise gyratory movement for 3-4 circles with secondary generalized seizures. There was no history of post-ictal weakness, visual phenomenon, myoclonus, or regression of milestones. She was born by caesarean section at full term gestation. The developmental milestones were appropriate. Despite protracted seizure and several emergency admissions, she had relatively well preserved cognition. However, frequent seizures prevented her to go to school. There was no neurological deficit. Brain magnetic resonance imaging (MRI) (1.5T) was normal.

She received phenobarbitone (60 mg/day), carbamazepine (700 mg/day), valproate (600 mg/day), levetiracetam (600 mg/day), and clobazam (15 mg/day) without much success. She developed skin rash to lamotrigine. By the time of evaluation at our centre, she was already receiving lacosamide 100 mg/day, clobazam 15 mg/day, zonisamide 100 mg/day, and phenytoin 150 mg/day.

Routine EEG showed frequent spike and wave discharges the right posterior quadrant. During the video-EEG recording, she had left focal with secondary generalized seizures that progressed to status epilepticus (SE) lasting for >2 hours, requiring termination of recording, and urgent intervention. She woke up from sleep in a confused state not responding to questions, had bouts of cough and ictal vomiting. There was a relative immobility of the left side of the body. Then there was left facial twitching and tonic-clonic movements of the left side of the body and limbs. Subsequently, she had short periods (total of 45 episodes, duration ranging from 260-4684 ms) where the convulsions would stop and she would have a shallow breathing possibly “hypopnea”. Seizure continued despite administering intravenous lorazepam (2 mg). She was shifted to ICU and administered intravenous valproate (250 mg) followed by levetiracetam (250 mg) for seizure control. The total seizure duration was nearly 90 minutes.

VEEG revealed a normal background activity. Inter-ictally, there were frequent spike and sharp wave discharges from right posterior quadrant (T6-O2) [Figure 1a]. Prior to clinical seizure, there was build-up of spikes and sharp waves in the right temporo-occipital leads (T6, O2) [Figure 1b] which lasted for a very long period, later spreading to the right hemisphere before becoming generalized. During the apparent periods of hypopnea there was cessation of the clinical seizure, and EEG showed absence of epileptiform activity and generalized attenuation of the cerebral electrical activity (right > left) [Figure 1c] lasting for 260-4682 msec with mean amplitude of 20 ± 10 μV, compared to the average background amplitude of 175.55 ± 19.11μV. Interestingly on some occasions, IGEA would be followed by either generalized seizure activity or seizure onset building up again in the right occipital region [Figure 1g]. Ictal tachycardia was noted (125-135 bpm). Simultaneous chest lead electrocardiography (ECG) showed tachycardia with ST segment inversion during the IGEA periods which was not noted during the baseline ECG recording. However, during the seizure the ECG was marred by movement artifacts. Four hours later, she was conscious and interacting with her parents.

Figure 1

(a) Inter-ictal EEG shows right occipital discharges with normal symmetrical background activity and posterior dominant alpha waves; (b) Ictal onset was in the right occipital region; (c) IGEA noted during the seizure the mean amplitude was 62.40 ± 15.1 μV. During this period the ECG was normal but with decreased chest excursions

Evaluation with plasma ammonia, lactate, tandem mass spectroscopy (TMS) profile, abnormal urine metabolites was unremarkable. Cardio-pulmonary evaluation was unremarkable. A 3-Tesla brain MRI revealed focal loss of grey-white matter differentiation on T2W imaging with subtle cortical hyperintensity on 3D-Flair involving the right lateral superior temporo-occipital gyrus, suggesting cortical dysplasia [Figure 2a]. Inter-ictal positron emission tomography (PET) scan revealed right temporo-occipital hypometabolism [Figure 2b]. Magnetoencephalography (MEG) revealed dipole clusters from the right occipital region [Figure 2c,d]. The case was in the pre-surgical meet as possible surgical candidate for better seizure control, to avoid SE and ictal apnea. In view of concordant EEG, MRI, Video-EEG, PET and MEG findings, she underwent right occipital lobectomy under electrocorticographic (ECoG) guidance. Intra-operative ECoG revealed almost continuous spikes over the temporo-occipital region and extending to neocortical posterior temporal lobe. Based on ECoG findings, resection of posterior temporal cortex, and then hippocampus and amygdala through the temporal horn were performed. Histo-pathological examination revealed focal widening of the cortical ribbon [Figure 2e]. NeuNimmuno labeling revealed radial dyslamination in these zones with micro-columnar organization of neurons [Figure 2f,g] corresponding to focal cortical dysplasia type 1a in the occipital neocortex. Similar findings were also noted in the posterior temporal neocortex. Four months after surgery, the patient is seizure free.

Figure 2(a-g)

(A): 3TMRI Brain FLAIR–axial sequence showing subtle cortical hyperintensity of the right lateral superior (temporo) occipital gyrus with poor grey white matter differentiation; (b) Interictal FDG - PET with CT axial, showed hypometabolism in the right posterior quadrant, predominantly the occipital and posterior temporal regions; (c,d) MEG showing spikes and dipole clusters predominantly from the right occipital regions propagating anteriorly; E-G: Histopathological examination of the occipital lobe revealed focal widening of the cortical ribbon (Figure 1e, arrows) highlighted on Luxol Fast Blue stain (Figure 1e, bracket) and NeuNimmuno labeling compared to adjacent cortex of normal thickness (Figure 1e, asterix). Radial dyslamination and microcolumnar organization of neurons is seen on NeuNimmunolabeling in these zones [Figure 1f, g) corresponding to focal cortical dysplasia type 1a. [e: LFB×8, f,g: neuNimmunostaining; magnification=scale bar]

Discussion

We highlight the possible association of IGEA as cause of hypopnea in a young girl with drug resistant occipital epilepsy due to cortical dysplasia, which might be a marker for SUDEP. Earlier, she did have ictal apnea requiring mechanical ventilatory support.

SUDEP is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration > 30 min or seizures without recovery in between), in which postmortem examination does not reveal a cause of death.[1] Although, epilepsy-related mortality and SUDEP have been recognized, its patho-physiology remains to be ascertained.[3] The underlying mechanisms vary from being unknown to ictal/post-ictal arrhythmia, dysautonomia, pulmonary edema, post ictal generalized EEG suppression and central apnea.[23456] (Table 1[3141516171819202122232425262728]).

Table 1

It shows review of various underlying mechanisms of SUDEP

Profound cortical neuronal inhibition of abrupt onset, possibly with associated inhibition of brainstem respiratory centres and resultant postictal central apnea had been proposed as a mechanism for PGES resultant SUDEP.[47] Burst suppression and PGES have been reported in epilepsy and said to be one of the mechanisms of SUDEP. Steriade and colleagues have demonstrated that EEG burst phases were associated with excitatory activities in cortical neurons, while suppression phases were paralleled by absence of cortical network interactions.[8] Here, there was IGEA, which was characterized by a cessation of the ictal rhythm and a definitive attenuation of generalized EEG activity (right > left). Considering the occipito–temporal nature of the seizures, there is a possibility of seizure activity spreading from the temporal region to the midbrain. According to the network inhibition hypothesis, seizure activity often spreads from the temporal lobe to midline subcortical structures leading to depressed bilateral cortical activity leading to loss of consciousness, which has been implicated in both secondary generalization and suppression of respiratory centers.[910] The prolonged nature of seizures might have resulted in global neuronal exhaustion causing respiratory depression with simultaneous suppression of cerebral electrical activity resulting in IGEA and hypopnea. Conde et al. (2012) had reported ictal bradypnea/hyponea associated with a complete suppression of the EEG activity in two infants with occipital lobe seizures.[11] The association of these ictal changes with occipital lobe seizures is yet to be understood. Systematic evaluation of various mechanisms involved in the causation of occipital lobe seizures, focal cortical dysplasia (FCD), seizure termination/electro-cerebral shut down, etc. and their possible overlap with respiratory mechanisms might unravel the clinico-electrical observation noted in this child.

Autonomic dysfunction as assessed by heart rate variability (HRV) during ongoing seizures have shown poor cardiac-autonomic reserve. Tachycardia as a manifestation of either of these mechanisms is known to occur in SE.[12] In a patient with near SUDEP, ventricular arrhythmia was noted at the end of secondary generalization which was reverted with defibrillation.[13]

It has been suggested that longer the duration of PGES, the higher the risk of SUDEP.[4] The child had ictal apnea during prolonged seizure on four occasions requiring ventilatory assistance. We hypothesize that the IGEA might be linked to seizure-associated respiratory dysfunction like apnea/hypopnea and might result in SUDEP. Though uncommonly observed, timely planned surgical intervention provided seizure freedom, avoided frequent SE and possible apnea.

The drawback of this study was not being able to record the abdomino-thoracic excursion and end-tidal CO2. This study highlighted a possible association of IGEA as cause of ‘hypopnea’ which might be a marker for SUDEP. Physicians need to educate the caregivers prompt medical attention to avoid any untowardly event(s).