Ictal and Postictal Central Apnea in DEPDC5-Related Epilepsy

Abstract

Objectives: DEPDC5-related epilepsy carries an increased risk of sudden unexpected death in epilepsy. We evaluated the occurrence and features of ictal central apnea (ICA) in patients with pathogenic sequence variant in DEPDC5.

Methods: We reviewed data of 108 patients collected in 2 independent cohorts of patients with focal epilepsy who prospectively underwent long-term video-EEG monitoring (LTVM) with cardiorespiratory polygraphy. All patients underwent (1) at least an overnight polysomnography, (2) a high-field (3T) brain MRI study, and (3) CSF analysis when clinically indicated. Genetic testing (next-generation sequencing [NGS]) was offered for diagnostic purposes to patients with focal epilepsy of unknown etiology.

Results: In this cohort, NGS was finally performed in 29 patients, resulting in DEPDC5 pathogenic mutations in 5 patients. According to the presence of ictal apnea events, 5 of 14 patients with ICA showed pathogenic DEPDC5 variants (35%) while none of the 15 patients without ICA showed pathogenic mutation. Notably, DEPDC5 patients showed ICA in all recorded seizures (n = 15) with apnea duration ranging from 20 seconds to more than 1 minute. All seizures were characterized by motor arrest without overt automatic behaviors during ictal apnea. Scalp EEG showed the involvement of temporal lobe leads in all events. Severe oxygen desaturation was observed in 2 cases.

Discussion: In our cohort, ictal central apnea was a common finding in DEPDC5. These results support (1) the need for respiratory polygraphy during LTVM in DEPDC5-related epilepsy and (2) the potential relevance of genetic testing in patients with focal epilepsy of unknown etiology and ictal apnea.

Figure 1. DEPDC5 Families and Genetic Findings

(A) Flowchart of the investigated patients according to etiology, ictal respiratory findings (ICA), and genetic testing (NGS). (B) Pedigrees of families with the proband indicated by an arrow. Patients with a mutation are indicated by m/+, and patients negative for the mutation are indicated by +/+. (C) Schematic structure of the DEPDC5 gene (NM_001242896) with the position of sequence variants found in our patients. Variants indicated in black are nonsense or frameshift mutations while the variant in orange is predicted to alter mRNA splicing. FCD = focal cortical dysplasia; ICA = ictal central apnea; LEAT = low-grade epilepsy-related tumors; MCD = other malformations of cortical development; NGS = next-generation sequencing.

Figure 2. Polygraphic Features of Ictal Apnea in Patient 1

In both A and B, 2 minutes of long-term EEG monitoring are shown for 2 seizures. (A) Regular breathing (RTA channel) is interrupted with the appearance of a prolonged apnea (>30 s). Red asterisks mark the start and termination of the ictal discharge on scalp EEG. The apnea was followed by a marked tachypnea with gasping that started during the seizure then prolonging into the postictal period for several seconds. ECG shows tachycardia during the apnea persisting in the postictal period. The EEG channels show EMG artifacts during the first part of the seizure; then, a generalized EEG suppression with anterior slow waves is evident in the second part of the seizure and in the postictal period. Oxygen saturation is 100% at seizure onset; then, a decrease is observed until 74%. (B) A second seizure with a similar sequence is reported. However, in this ictal event, the apnea period is preceded by a prolonged period of hypoventilation that precedes the EEG seizure onset (red asterisk). This event was more prolonged and associated with an oxygen desaturation until 71%. The end of the seizure and the postictal period are not shown. EEG channels show bipolar recordings according to the 10–20 international system. Filters: high-pass 0.1 Hz; low-pass 35 Hz. Amplitude 10 uV/mm. Polygraphic channels are as follows: channel 1: ocular movement (green color); channel 20 (milo): EMG activity from mylohyoid muscle (brown color); channels 23–24 (tib dx, tib sx): EMG activity from right and left tibialis anterior muscles (purple color); channel 25 (ECG): cardiac activity (red color); channel 26 (RTA): thoracoabdominal respiration (blue). The last 2 channels: pulse and oxygen saturation (light blue).