Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study

Ryvlin P, Nashef L, Lhatoo SD, Bateman LM, Bird J, Bleasel A, Boon P, Crespel A, Dworetzky BA, Høgenhaven H, Lerche H, Maillard L, Malter MP, Marchal C, Murthy JM, Nitsche M, Pataraia E, Rabben T, Rheims S, Sadzot B, Schulze-Bonhage A, Seyal M, So EL, Spitz M, Szucs A, Tan M, Tao JX, Tomson T. (2013) Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study. Lancet Neurol 12(10): 966-77

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Abstract: BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. METHODS: Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. FINDINGS: 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. INTERPRETATION: SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time.

Context

Comprehensive, retrospective study of possible mechanisms for SUDEP, evaluating cardiorespiratory arrests in epilepsy monitoring units from around the world. Twenty-nine cardiorespiratory arrests were reported, which were there classified as either SUDEP (definite or probable), near SUDEP (fatal or non-fatal), or non-SUDEP. Incidence of death, cardiorespiratory arrest, near SUDEP, and SUDEP was calculated on the basis of an estimation of total patient-years spent in the epilepsy monitoring units. 56% of the cases of SUDEP and near SUDEP had reported Generalized tonic-clonic seizures (GTCSs) within the preceding 3 months, in concurrence with many studies (Timmings, Nashef et al., Opeskin et al., Lhatoo et al., Walczak et al., Langan et al., and Surges et al.). Among the 16 SUDEP cases in which position could be assessed, 14 were prone. SUDEP was successfully continuously monitored in 10 and four consistent features were noticed: rapid breathing during the immediate postictal phase, postictal generalized EEG suppression, early cardiorespiratory dysfunction, and terminal apnea always preceded terminal asystole. Findings of apnea in these SUDEP cases can help support the reports of oxygen desaturation from Blum et al., Hewertson J, Poets CF et al., and Hewertson J, Boyd SG et al..

Ictal respiratory dysfunction and SUDEP There is increasing evidence that ictal respiratory dysfunction is an important contributor to the pathophysiological changes resulting in sudden unexpected death in epilepsy (SUDEP). In cases of SUDEP occurring during epilepsy unit monitoring, respiratory disturbances occurred early in the postictal period and frequently preceded terminal bradycardia and asystole. This article]], Blum et al 2000, Bateman et al 2008, and Lacuey et al., 2018 sought to determine the incidence and severity of ictal hypoxemia in patients with localization-related epilepsy undergoing inpatient video-EEG telemetry. These studies found that ictal hypoxemia occurs often in patients with localization-related epilepsy and may be pronounced and prolonged; even with seizures that do not progress to generalized convulsions. Bateman et al 2008 further found that desaturations below 90% were significantly correlated with seizure localization [P = 0.005; odds ratio (OR) of temporal versus extratemporal = 5.202; 95% CI = (1.665, 16.257)], seizure lateralization [P = 0.001; OR of right versus left = 2.098; 95% CI = (1.078, 4.085)] (see also Yoon et al., 1997), contralateral spread of seizures [P = 0.028; OR of contralateral spread versus no spread = 2.591; 95% CI = (1.112, 6.039)] and gender [P = 0.048; OR of female versus male = 0.422; 95% CI = (0.179, 0.994)].

Hypoventilation and pulmonary edema Bateman et al 2008 also noted that oxygen desaturations are accompanied by increases in ETCO2, supporting the assumption that ictal oxygen desaturation is a consequence of hypoventilation.

Pulmonary edema is a common finding in SUDEP autopsy series and is most likely a rare, but devastating consequence of an epileptic seizure (Cho et al., 2002). This may be (at least in part) due to increased pulmonary vascular permeability that follows intracranial hypertension, as seen in sheep (Bowers et al., 1979). In that study icreasing intracranial pressure to near systemic arterial pressure produced a 3-fold increase in the flow of protein-rich lymph, which indicates increased lung vascular permeability. Johnston et al., 1995) developed a model of status epilepticus in which pulmonary edema and sudden death sometimes occurred. Striking hypoventilation was demonstrated in the sudden death group but not in the surviving animals. Differences in peak left atrial and pulmonary artery pressures and in extravasated fluid in the lungs were also demonstrated but pulmonary edema did not account for the demise of the sudden death animals. Thus, this study of epileptic sudden death supports a role of central hypoventilation in the etiology of sudden unexpected death and confirms the association with pulmonary edema.

Reversing/preventing ictal respiratory dysfunction: The role of the serotonergic system Serotonergic neurons modulate the excitability of the neuronal network generating the respiratory rhythm and arousal (Kennedy and Seyal, 2015). Impairment of the serotonergic neurons therefore may also predispose to SUDEP by impeding the patient's ability to arouse after ictal hypoventilation to reposition the head to facilitate ventilation. In mouse model of epilepsy, selective serotonin reuptake inhibitor (SSRI) fluoxetine has been shown to reverses respiratory arrest. Bateman et al., 2010 reviewed video–electroencephalography (EEG) and pulse oximetry data from 87 seizures in 16 patients taking SSRIs and 409 seizures in 57 patients not taking SSRIs. The proportion of ictal-related oxygen desaturation <85% with partial seizures without secondary convulsions in SSRI-taking patients was REDUCED relative to other patients (p = 0.011). SSRIs are associated with reduced likelihood of ictal oxygen desaturation in patients with partial seizures.