Rainer Surges

Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy, and most frequently occurs in people with chronic epilepsy. The main risk factors for SUDEP are associated with poorly controlled seizures, suggesting that most cases of SUDEP are seizure-related events. Dysregulation in cardiac and respiratory physiology, dysfunction in systemic and cerebral circulation physiology, and seizure-induced hormonal and metabolic changes might all contribute to SUDEP. Cardiac factors include bradyarrhythmias and asystole, as well as tachyarrhythmias and alterations to cardiac repolarization. Altered electrolytes and blood pH, as well as the release of catecholamines, modulate cardiac excitability and might facilitate arrhythmias. Respiratory symptoms are not uncommon during seizures and comprise central apnea or bradypnea, and, less frequently, obstruction of the airways and neurogenic pulmonary edema. Alterations to autonomic function, such as a reduction in heart rate variability or disturbed baroreflex sensitivity, can impair the bodys capacity to cope with challenging situations of elevated stress, such as seizures. Here, we summarize data on the incidence of and risk factors for SUDEP, and consider the pathophysiological aspects of chronic epilepsy that might lead to sudden death. We suggest that SUDEP is caused by the fatal coexistence of several predisposing and triggering factors.

Sudden unexpected death in epilepsy: mechanisms, prevalence, and prevention.

PURPOSE OF REVIEWnSudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy with incidence rates of up to nine per 1000 patient-years in candidates for epilepsy surgery. Ongoing collaborative research is aiming to improve assessment of individual SUDEP risk and to develop preventive measures based on pathophysiological considerations. This review focuses on novel findings in humans and animal models related to pathophysiology, risk factors and prevention of SUDEP.nnnRECENT FINDINGSnPotential mechanisms include cardiac arrhythmia, postictal cardiomyopathy, depressed autonomic function and seizure-related respiratory failure. Electrocardiography predictors of sudden cardiac death have been described in people with chronic epilepsy, but their significance for SUDEP remains to be confirmed. Epidemiological risk factors comprise male sex, young age at epilepsy onset, symptomatic cause, longer duration of epilepsy, frequent convulsive seizures and polytherapy. Efficacious adjunctive antiepileptic medication may reduce the risk of SUDEP.nnnSUMMARYnNovel clinical features may help to define better the individual risk of SUDEP. Potentially therapeutic strategies including pharmacological modulation of respiratory arrest and implantation of cardiac devices could reduce the risk of SUDEP in some individuals. Antiepileptic drugs lower the risk, stressing the importance of successful seizure control for prevention.

Enhanced QT shortening and persistent tachycardia after generalized seizures

Objective: Generalized tonic-clonic seizures (GTCS) are a major risk factor for sudden unexpected death in epilepsy (SUDEP). We investigated whether ictal/postictal cardiac features were dependent on seizure type within individual patients. Methods: ECG data from patients with medically refractory temporal lobe epilepsy (TLE) undergoing presurgical investigation who had both complex partial seizures and secondarily GTCS during video-EEG telemetry were retrospectively reviewed. Peri-ictal heart rate (HR), corrected QT interval (QTc), HR variability, and cardiac rhythm were assessed. Results: Twenty-five patients were included in this study. Secondarily GTCS led to higher ictal HR, persistent postictal tachycardia, and decreased postictal HR variability. Moreover, abnormal shortening of QTc occurred in 17 patients mainly during the early postictal phase and significantly more often in secondarily GTCS. Abnormal QTc prolongation occurred in 3 patients with no significant association with GTCS. Benign cardiac arrhythmias occurred in 14 patients and were independent of seizure type. Conclusions: Our data suggest a substantial disturbance of autonomic function following secondarily generalized tonic-clonic seizures (GTCS) in patients with medically refractory temporal lobe epilepsy. The observed alterations could potentially facilitate sudden cardiac death and might contribute to the association of sudden unexpected death in epilepsy with GTCS.

Too long or too short? New insights into abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death.

Sudden unexpected death in epilepsy (SUDEP) is probably caused by periictal cardiorespiratory alterations such as central apnea, bradyarrhythmia, and neurogenic pulmonary edema. These alterations may occur in people with epilepsy and vary in duration and severity. Seizure‐related ventricular tachyarrhythmias have also been hypothesized to be involved in SUDEP, but compelling evidence of these, or of predisposition to these, is lacking.

Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: A case-control study

Purpose:u2002 To determine whether abnormal cardiac repolarization and other electrocardiography (ECG) predictors for cardiac mortality occur in epilepsy patients and whether they are associated with an increased risk for sudden unexpected death in epilepsy (SUDEP).

Postictal generalized electroencephalographic suppression is associated with generalized seizures.

Postictal generalized electroencephalographic suppression (PGES) may be involved in sudden unexpected death in epilepsy (SUDEP). We examined whether the occurrence of PGES depends on seizure type and whether PGES occurs more frequently in people with epilepsy who died suddenly. EEG recordings of people with pharmacoresistant focal epilepsies who died from SUDEP after presurgical video/EEG telemetry were compared with recordings of living controls. To test if PGES depends on seizure type, EEG recordings of people with temporal lobe epilepsy who had complex partial seizures (CPS) and secondarily generalized tonic-clonic seizures (GTCS) were reviewed. A total of 122 seizures in 57 individuals have been included. PGES was observed in 15% of all seizures in 26% of all individuals. Secondarily GTCS were significantly associated with PGES. Neither presence nor duration of PGES differed between the SUDEP and control groups. In conclusion, PGES is facilitated by secondarily GTCS, but does not seem to be an independent risk factor for SUDEP.

Outcome of limbic encephalitis with VGKC-complex antibodies: relation to antigenic specificity

In limbic encephalitis (LE) with antibodies (Abs) to the voltage-gated potassium channel complex (VGKC), the Abs are mainly directed to the VGKC-complex proteins, leucine-rich, glioma inactivated 1 protein (LGI1) or contactin-associated protein-like 2 (CASPR-2) or neither. Here, we relate the outcomes of VGKC-LE patients to the presence of Abs to LGI1, CASPR-2 or neither antigen (LGI1/CASPR-2-Ab−). Clinical, neuropsychology and MRI data were obtained from patient records for all LE patients from the Bonn Epilepsy Centre positive for VGKC-Abs by radioimmunoprecipitation assay between 2002 and 2011. Eighteen VGKC-LE patients were identified: nine patients (50xa0%) had LGI1-Abs, three (16xa0%) had CASPR-2-Abs; and six (33xa0%) were negative for both LGI1- and CASPR-2-Abs. At first assessment, the groups did not differ clinically or radiologically, but faciobrachial dystonic seizures were only observed in two LGI1-Ab+ patients. All patients received monthly intravenous methylprednisolone (MP) pulses. At the most recent follow up (median 26xa0months), thirteen (72xa0%) were seizure-free, and seizure-freedom rates did not differ between the Ab groups. Hippocampal atrophy had developed in 7/9 LGI1-Ab+ patients, but in none of the CASPR-2-Ab+ or LGI/CASPR-2-Ab− patients (pxa0=xa00.003). While all subgroups improved, memory scores only normalized in six patients (33xa0%) and LGI1-Ab+ patients were left with significantly poorer memory than the other two subgroups. Most VGKC-LE patients become seizure-free with pulsed monthly MP, but memory outcome is less favourable. Hippocampal atrophy and poor memory recovery is common in patients with LGI1-Abs and suggests permanent functional damage. More intense immunotherapies could improve outcomes in LGI1-Ab+-LE.

Is Levetiracetam Different from Other Antiepileptic Drugs? Levetiracetam and its Cellular Mechanism of Action in Epilepsy Revisited

Levetiracetam (LEV) is a new antiepileptic drug that is clinically effective in generalized and partial epilepsy syndromes as sole or add-on medication. Nevertheless, its underlying mechanism of action is poorly understood. It has a unique preclinical profile; unlike other antiepileptic drugs (AEDs), it modulates seizure-activity in animal models of chronic epilepsy with no effect in most animal models of acute seizures. Yet it is effective in acute in-vitro `seizure models. A possible explanation for these dichotomous findings is that LEV has different mechanisms of actions, whether given acutely or chronically and in `epileptic and control tissue. Here we review the general mechanism of action of AEDs, give an updated and critical overview about the experimental findings of LEVs cellular targets (in particular the synaptic vesicular protein SV2A) and ask whether LEV represents a new class of AED.

Do alterations in inter-ictal heart rate variability predict sudden unexpected death in epilepsy?

Reduced heart rate variability (HRV) may predispose to sudden unexpected death in epilepsy (SUDEP). We ascertained whether HRV predicts SUDEP in chronic epilepsy using a case-control design and investigated parameters of inter-ictal HRV in 14 patients (7 had died from SUDEP). No HRV parameter was associated with SUDEP. Thus, although altered HRV might be involved in SUDEP, HRV parameters are not clear-cut predictors for SUDEP.