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De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk of SUDEP

De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk... Background Various cardiac and autonomic manifestations are frequently reported during seizures. Among the sei- zure-related arrhythmia, ictal tachycardia is the most common, followed by ictal bradycardia, with ictal asystole being the rarest. The occurrence of ictal asystole may obscure the clinical presentation and delay the diagnosis, represent- ing a life-threatening presentation of epilepsy, with an elevated risk of sudden unexpected death in epilepsy patients (SUDEP). These cardiac abnormalities are being increasingly recognized as the key to elucidating the mechanisms of SUDEP. Case presentation We present a 35-year-old man with a history of focal-onset seizures with impaired conscious- ness since his mid-20 s. He developed different types of seizures for 2 years, described as tonic seizure and atonic seizure (drop attack). During such clinical events, he suffered from falls and cardiac arrest. However, thorough cardiac electrophysiology and imaging workup failed to reveal a cardiac etiology. Subsequent video electroencephalograph (EEG) monitoring was performed, and ictal bradycardia and ictal asystole were discovered. A cardiac pacemaker was implanted, and at 3-year follow-up, the patient did not suffer more atonic seizures, or falls. Genetic tests discovered a de novo variant of Adhesion G Protein-Coupled Receptor V1 (ADGRV1), which may provide a clue for the patient’s ictal asystole and the increased risk of SUDEP. Conclusions Considering the important impact of ictal bradycardia and asystole on the morbidity and potential mortality of epileptic patients, it is important to simultaneously utilize EEG and electrocardiogram to confirm the diag- nosis. This case report highlights the link between the de novo variant of ADGRV1 and the ictal bradycardia/asystole phenotype and implicates the importance of genetic testing in adult epilepsy patients. Keywords Ictal asystole, Drug resistant epilepsy, ADGRV1, SUDEP *Correspondence: Ning Zhong ning.zhong@kp.org SQZ Biotechnologies, Watertown, MA 02472, USA Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467, USA College of Medicine, California Northstate University, Elk Grove, CA 95757, USA Pediatric and Adolescent Medicine Residency of Mayo Clinic, MN, Rochester, USA Department of Neurology, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA North Valley Comprehensive Epilepsy Program, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Ji et al. Acta Epileptologica (2023) 5:13 Page 2 of 9 Background Case presentation Epileptic seizure-induced cardiac arrhythmias have We report a 35-year-old Caucasian man with DRE who long been recognized as epileptic ictal manifesta- suffered from ictal asystole. Clinical presentation, brain tions, possibly caused by seizure-induced autonomic imaging, EEG data, genetic testing results, and treatment imbalances [1]. The most common arrhythmia asso- outcome were reported. ciated with epilepsy is ictal tachycardia, which occurs in ~ 80% of all seizures. Ictal bradycardia occurs Clinical characteristics in < 6% of seizures. Ictal asystole, the absence of ven- The 35-year-old, right-handed male had a history of focal tricular complexes for more than 4  s, accompanied by seizures with impaired consciousness initially diagnosed electrographic seizure onset, is found in 0.27–0.4% at age 24 in 2010. Semiology by then was described as of patients undergoing video-electroencephalograph difficulty in speaking, incomprehensible speech, star - (vEEG) monitoring [2]. Ictal bradycardia/asystole is ing spells, behavioral freeze, and impaired awareness. often unrecognized until documented during vEEG– Such episodes lasted from 30  s to minutes. Postictally, electrocardiogram (ECG) monitoring in drug-resistant the patient was amnestic of the event and only spoke in epilepsy (DRE). As lethal arrhythmias during seizures, his native language. The post-ictal state lasted approxi - ictal ventricular tachycardia, ictal bradycardia, and mately 10  min. Based on the described semiology, the ictal asystole, are hypothesized as among the patho- patient was diagnosed as focal onset seizures with physiological causes of Sudden Unexpected Death in impaired awareness (also known as complex partial sei- Epilepsy Patients (SUDEP) [3]. zures). He was prescribed Levetiracetam, and the dose SUDEP is a sudden, unexpected, witnessed, or was increased according to the reported recurrent sei- unwitnessed death in an individual with epilepsy that zures. An EEG during this period showed mild general- is not caused by a traumatic injury, drowning, or other ized slowing in the theta range, though no epileptiform causes. SUDEP occurs in benign circumstances with features were identified. Brain magnetic resonance imag - or without evidence for a seizure and excludes docu- ing (MRI) in 2013 did not reveal any abnormality. mented status epilepticus. Postmortem examination In 2015, he was presented to the Emergency Depart- does not reveal other causes of death [4]. However, at ment (ED) after a witnessed generalized tonic–clonic present, there is no consensus on the causes of ictal seizure (GTCS) secondary to not-taking medication. bradycardia/asystole and their effect on the patho- Nonetheless, Levetiracetam alone failed to control the physiology of SUDEP. The mechanisms of ictal brady- patient’s seizures as the seizure frequency continued to cardia/asystole might be explained by the associations increase to once daily or multiple times per day. Then between the central autonomic network control and lamotrigine was added to his regimen and the dosage was the limbic system structures such as the cingulate eventually maximized. Consequently, seizure control was gyrus, amygdala, and insular and orbitofrontal cor- maintained for 2  years until a recurrent GTCS in 2017. tex [5]. However, such hypothesis does not entirely Follow-up EEG showed frequent left-sided slowing and account for the various clinical manifestations and slow sharp waves at C3T3, and occasional right-sided brain structural lesions documented. Recent studies temporal sharp-waves. are pointing to the genetic susceptibility to SUDEP. A few months later, new seizure semiology developed. A few variants of genes involved in epilepsy as well as The patient was observed to have (1) tonic seizures, with cardiac and respiratory functions have been discov- witnessed body stiffening, lasting 1–2 min; (2) atonic sei - ered, suggesting a highly heterogenic and polygenic zures/drop attack, with witnessed falls and loss of con- contribution to SUDEP [6]. Adhesion G protein-cou- sciousness; and (3) nocturnal brief myoclonic events. pled receptor V1 (ADGRV1) has been implicated in The patient had been admitted to the ED on multiple the regulation of breathing and cardiovascular func- occasions after atonic events. During one incident, he tion, and recent studies have suggested that it also fell backwards onto a concrete floor resulting in a small plays a role in SUDEP. left-sided subarachnoid hemorrhage and temporo-occip- This is in line with the increasing efforts to practice ital skull fracture. There was no witnessed tonic–clonic precision medicine in epilepsy. Based on genetic infor- activity proceeding the fall. As the patient’s seizures mation, therapies such as anti-seizure medication can resulted in more debilitating consequences, Lacosamide be tailored to achieve the best therapeutic efficiency was introduced. However, no clinical improvement was while minimizing side effects and intolerance, ulti- observed. In April 2019, he was witnessed to have full- mately leading to the development of effective, person- body stiffening and shaking before losing consciousness. alized gene therapies [7]. In the field, when paramedics arrived, he was found in Ji  et al. Acta Epileptologica (2023) 5:13 Page 3 of 9 pulseless cardiac arrest. He showed spontaneous resto- temporal regions (Fig. 2 a, b). Subsequently, the ictal pat- ration of normal sinus rhythm before any interventions tern evolved into diffuse semi-rhythmic delta-theta slow - were administered. Cardiac workup including ECG, ing. The ECG RR interval was analyzed at a baseline with trans-esophageal echocardiogram, stress ECG test, and heart rate of 62–63  bpm. During his seizure events, the electrophysiology yielded no findings indicative of a pri - RR interval increased by 100–200  ms, which triggered mary cardiac etiology for his cardiac arrest. the pacemaker (Fig.  2c). The prolongation of RR inter - val often occurred 10–20 s after the onset of clinical sei- Video EGG monitoring zures. This observation demonstrated that cardiac pacing The patient continued to suffer recurrent seizures prevented the development of ictal bradycardia/asystole despite taking three antiseizure medications at suffi - during the patient’s focal seizures. cient dose, so he was diagnosed with DRE. VEEG was Follow-up 3  T MRI showed left mesial temporal scle- performed in May 2019. Ictal bradycardia and ictal asys- rosis with hippocampal volume loss and mild increase of tole were observed. During one of his typical seizures, FLAIR signal (Fig.  3a). Brain PET scan did not show lat- he was observed with frozen behavior and staring; then, eralized hypometabolism (Fig. 3b). he exhibited hand fidgeting with fingers locked in tonic The patient was followed up for three years, and no posture. His body proceeded to fall back to bed, with recurrent tonic or atonic seizures were reported. He con- his head turning to the left accompanied by mild non- tinued with rather sporadic dyscognitive seizures while rhythmic limb shaking. Subsequently, the patient lost taking both Levetiracetam and Lamotrigine, Lacosamide consciousness, followed by myoclonic body jerking. was discontinued because no obvious effects were noted. EEG showed diffuse, irregular delta slowing at the onset of the event. Such diffuse slowing persisted throughout Genetic testing and variant analysis the 13.5  s of asystole. The asystole was also confirmed Genetic analysis was conducted by using the next-gen- with concurrent cardiac-telemetry monitoring. During eration sequencing for DNA sequence variants and copy the asystole, EEG showed diffuse low voltage recording, number variants. Variants in dihydropyrimidine dehy- indicating global cerebral hypoperfusion (Fig.  1a). The drogenase (DPYD, c1905 + 1C > A), adhesion G protein- patient experienced four similar seizures when bradycar- coupled receptor V1 (ADGRV1, c.5785 G > T) and two dia and shorter asystole (heart rate pauses for a few sec- other variants were discovered (Table  1). These variants onds) were captured in EEG-ECG monitoring (Fig.  1b). were not revealed in his parents. We performed in silico The onset of bradycardia and heart-beat pauses were analysis with polyphen-2, SIFT, Grantham score, and noted 20  s after the seizure onset (Fig.  1a). Cardiology Mutation Taster softwares to estimate if the variants were was consulted and the patient underwent emergency car- pathogenic or had a damaging functional effect (Table  1). diac pacemaker implantation to prevent further cardiac We also applied Alphafold, an artificial intelligence sys - complications in DRE. The pacing parameter was set at tem, to investigate whether the discovered variants would 60–130 bpm. affect the protein structures. Results showed that the ADGRV1 variant at the 5q14.3 chromosomal locus, was Follow‑up and treatment outcome likely to have an impact on the protein structure. The Repeated vEEG two months after the pacemaker implan- discovered de novo variant in ADGRV1 was localized tation showed interictal sharp waves in the bilateral in the calx-beta domain within the very close vicinity to temporal regions independently. Temporal intermittent reported genetic loci associated with generalized epilepsy rhythmic delta activity (1–2  Hz) was seen in the right (Fig. 4). temporal regions. During re-monitoring, seizures of bilaterally independent temporal onset were recorded Discussion (Fig.  2). Clinically, while being awake, the patient dem- The case presented in this report reflects the compli - onstrated staring or glassy eyes, with subsequent repeti- cated nature of ictal asystole in the context of evolv- tive swallowing with or without lip smacking, and ictal ing seizure semiology. Before the extensive epilepsy coughing. During the events, the patient did not lose examinations, the patient did not show predisposing consciousness, but he was unable to maintain conversa- factors, and had no family history of cardiac arrhyth- tion and his wife reported that the patient did not make mia or sudden unexpected death. Our report highlights meaningful conversation; such observed semiology was the importance of vEEG-ECG monitoring in confirm - similar to his habitual seizures before developing tonic ing the diagnosis of ictal bradycardia/asystole [8]. and atonic seizures. The patient himself was amnestic Brain MRI indicated left mesial temporal sclerosis in to the events. At the onset of the seizures, EEG showed this patient. EEG re-monitoring after the cardiac pace- focal (irregular or semi-rhythmic) delta slowing in both maker implantation also showed focal seizures likely Ji et al. Acta Epileptologica (2023) 5:13 Page 4 of 9 Fig. 1 a Atonic seizure recorded during video EEG (vEEG) monitoring. vEEG showed ictal generalized delta slowing, followed by tonic (stiffening) and clonic ( jerking) phases; and subsequent diffuse voltage attenuation and diffuse distribution of delta slowing (purple arrows). The one lead ECG recording (red lines in the figure) showed HR change (red arrows) when bradycardia and asystole; b Ictal asystole was further confirmed by the ECG traces recorded during cardiac telemetry monitoring Ji  et al. Acta Epileptologica (2023) 5:13 Page 5 of 9 Fig. 2 a A focal-onset seizure arising from the left temporal region. Purple arrow shows EEG focal slowing in the left temporal region at ictal onset and when ictal phase evolution. b A focal-onset seizure arising from the right temporal region. Purple arrow shows EEG focal slowing in the right temporal region at ictal onset and when ictal phase evolution, and red arrow indicates onset of clinical symptoms. c Ictal prolongation of RR interval during the focal-onset seizures, as recorded by the concurrent ECG monitoring. Blue arrow indicates the cardiac pacemaker pacing artifacts Ji et al. Acta Epileptologica (2023) 5:13 Page 6 of 9 Fig. 3 a Brain MRI showed left temporal and hippocampal sclerosis in the last follow up. Yellow arrow shows the increased T2/FLAIR signal and volume loss in the left hippocampus. b Brain PET showed no lateralized hypometabolism arising from the left or the right temporal region. These Understanding the precise etiology of epilepsy is the findings are consistent with literature that reported basis for precision medicine and tailored treatment for ictal asystole occurring in temporal lobe or insular patients with epilepsy. Further exploring the genetic basis epilepsy, especially in patients with DRE [9]. However, of epilepsy may lead to an improved understanding of there are no obvious associations between lateralized the epileptogenesis, personalized medical management, epileptogenesis and autonomic nervous system changes and ultimately improved seizure control/prevention manifested as ictal bradycardia/asystole. The underly - outcomes and quality of life [11]. In our case, genetic ing mechanisms of the correlation between temporal analysis revealed a pathogenic variant in DPYD, a likely lobe seizures and the ictal asystole may be related to pathogenic variant in ADGRV1, and a variant of uncer- the stimulation of the insula, the cingulate cortex, the tain significance in DYNC1H1. Identifying genetic mark - amygdala, and the hypothalamus during such seizures, ers associated with phenotypes has remained challenging which may provoke asystole via autonomic control [9]. due to the complexity of the human genome, the extreme Being secondary to the epileptic seizure, the ictal brad- polygenicity, and lack of reports for rare gene variants ycardia/asystole results from the disruption of normal [12]. In our case, the patient did not present with phe- cardiac rhythm caused by heart rate changes. Clinically, notypes that have been reported in literature, such as the affected patients likely manifest unexpected col - severe epilepsy syndrome, microcephaly, intellectual dis- lapse or fall in later phases of seizures, as presented in ability, cortical malformation, or neuromuscular symp- our case. The changes of seizure semiology with tonic, toms (Table  1). Instead, he had unique presentations of atonic, or nocturnal brief myoclonic features displayed ictal asystole and temporal lobe seizure, and promis- by the patient may be clinical manifestations of cerebral ing treatment outcomes, which prompted us to further hypoperfusion due to ictal bradycardia/asystole. investigate the underlying pathophysiology. With care- Patients with intractable drug-resistant focal epilepsy ful inspection of the genotype–phenotype association are at a higher risk of ictal asystole, which may lead to and comprehensive prediction of functional impact of SUDEP. Besides GTCS, ictal asystole associated with variants, we found that the de novo variant in ADGRV1 DRE has also been considered as a potential mechanism is very likely to be the cause of the patient’s ictal asys- for SUDEP and has received increasing attention [10]. tole. ADGRV1 is a large calcium-binding protein widely Although ictal asystole is rare, its associated red flag expressed in the central nervous system. The ADGRV1 symptoms such as atonia and unexplained falls often lead gene is an epilepsy-associated gene (Table  1) located at to detrimental, life-threatening complications as seen in the 5q14.3 chromosomal locus, a site that has been previ- our case, resulting in intracranial hemorrhage and car- ously reported to be associated with myoclonic epilepsy diac arrest. Thus, cardiac pacemaker implantation is due to haploinsufficiency. ADGRV1 is recently discovered advised for patients with documented ictal asystole and to be strongly associated with SUDEP [13]. We hypoth- would often be a life-saving practice [10]. esized that the discovered missense variant might lead Ji  et al. Acta Epileptologica (2023) 5:13 Page 7 of 9 Table 1 Results of genetic variant analysis Gene name Base change Codon change Variant type Inheritance Polyphen2 SIFT Mutation Grantham Protein Clinical Reported Taster domain relevance clinical Prediction symptoms associated with previously reported gene variants DPYD c.1905 + 1G > A n/a Heterozygous Autosomal n/a n/a Disease-causing n/a n/a Pathogenic Seizures, micro- splice site recessive cephaly, muscular hypotonia, devel- opmental delay, and sensitivity to 5-FU toxicity ADGRV1 c.5785G > T p.Ala1929Ser Heterozygous Autosomal Damaging Tolerated Disease-causing 99 Calx:beta 13 Likely patho- Febrile and missense genic vs VUS afebrile seizures, focal epilepsy and SUDEP, Lennox-Gastaut syndrome, myo- clonic epilepsy, Usher syndrome DYNC1H1 c.11894C > T p.Ser3965Phe Heterozygous Autosomal Benign Not Tolerated Disease-causing 155 n/a Variant of Intellectual dis- missense recessive unknown ability, malforma- significance tions in cortical development, West syndrome, epileptic encephalopathy with continu- ous spikes and waves during slow sleep, spinal muscular atrophy, and Charcot- Marie-Tooth syndrome ASPM c.6711C > A p.Asn2237Lys Heterozygous Autosomal Benign Tolerated Polymorphism 94 IQ repeat Likely benign Intellectual dis- missense dominant region ability, primary microcephaly Abbreviations: polyphen-2 Polymorphism Phenotyping V2, Grantham Grantham scores for conservative, SIFT Sorting Intolerant From Tolerant, DPYD dihydropyridine dehydrogenase, ADGRV1 adhesion G protein-coupled receptor V1, DYNC1H1 dynein cytoplasmic 1 heavy chain 1, ASPM assembly factor for spindle microtubules, VUS Variant of unknown significance Ji et al. Acta Epileptologica (2023) 5:13 Page 8 of 9 Fig. 4 ADGRV1 variants associated with epilepsy and SUDEP. Red,gene variants associated with genetic generalized epilepsy (GGE); black, variants associated with other type of epilepsy; blue, reported variants associated with SUDEP; purple, the de novo variant reported in our case. LGS: Lennox-Gastaut Syndrome; EOAE: early-onset absence epilepsy; ID: intellectual disability; EAR: epilepsy-associated repeat; GPS: G-protein-coupled receptors (GPCR) proteolytic site to dysfunction of ADGRV1 protein, contributing to the risk of SUDEP is deemed to be high based on observed or unique phenotypes, temporal lobe epilepsy and ictal potential cardiac rhythm disturbances. Continuing phar- asystole observed in our patient. Recent animal studies macological treatment is important, and further moni- showed that ADGRV1 is required for the development of toring after pacemaker implantation can provide critical γ-aminobutyric acid (GABA)ergic interneurons. It is pos- information such as the lateralization of the seizure onset sible that the disruption of ADGRV1 function may result in our case. in dysfunction of cortical GABAergic neurons, which Ictal asystole and SUDEP are rare, and the underly- serves as a potential epileptogenic mechanism in humans ing pathophysiological mechanisms remain elusive. The [14]. Intriguingly, the discovered pathogenic variant genetic basis of epilepsy is increasingly explored, which in DPYD in our patient did not appear to be associated will encourage the possibility of precision treatments for with the severe clinical phenotypes reported in literature. specific genetic etiologies [11]. Our genetic testing and DPYD plays an important role in the metabolism of the analysis suggested that the ADGRV1 gene is a contributor antineoplastic agent 5-fluorouracil (5-FU) and patients to SUDEP. Such findings not only draw attention to the with DPYD deficiencies can have severe cardiac toxicity mutation spectrum of the ADGRV1 gene, but also inspire [15]. A previous paper reported that 5-FU administration genetic testing and early identification of patients with in a patient with DPYD mutation led to Takotsubo car- epilepsy who are at a high risk of SUDEP. diomyopathy due to autonomic imbalance. This raises the possibility that DPYD variants may be a predisposing fac- Abbreviations tor for autonomic dysfunction [15]. ADGRV1 Adhesion G protein-coupled receptor V1 Although the precise causes for the variants remain DPYD Dihydropyridine dehydrogenase DRE Drug-resistant epilepsy to be further investigated, our report calls for increased EEG Electroencephalogram recognition of and access to genetic testing for adult epi- GTCS Generalized tonic–clonic seizure lepsy patients. Phenotypic and clinical information are SUDEP Sudden unexpected death in epilepsy patients often critical to interpreting the significance of the dis - Acknowledgements covered genetic variants, which improves the quality and Not applicable. accuracy in reclassifying the VUS [16]. Authors’ contributions LD, AD, and NZ collected the clinical information. NZ performed protein structure analysis. TJ, AD and NZ drafted the manuscript. TJ and NZ reviewed Conclusions related articles and extracted the data. All authors have read and approved The diagnosis of ictal asystole requires long-term vEEG- the final manuscript. ECG monitoring. Treatment after the confirmed diagno - Funding sis should be aimed at preventing recurrent seizures. The The study was not supported by any funding. implantation of a pacemaker is recommended when the Ji  et al. Acta Epileptologica (2023) 5:13 Page 9 of 9 Availability of data and materials profiling and proposal for a novel classification. J Hum Genet. The datasets analyzed during the current study are available from the cor- 2020;65(11):1003–17. responding author on reasonable request. 16. Berg JS. Exploring the importance of case-level clinical information for variant interpretation. Genet Med. 2017;19(1):3–5. Declarations Ethics approval and consent to participate This study was approved by the Institutional Ethics Committee of Kaiser Per- manente Foundation Hospital (KPSAC 131–21) and written informed consent has been obtained from the patient. Consent for publication Written informed consent for publication was obtained from the patient. Competing interests The authors declare that they have no competing interests. Received: 28 February 2023 Accepted: 15 May 2023 References 1. Tenyi D, Gyimesi C, Kupo P, Horvath R, Bone B, Barsi P, et al. Ictal asystole: A systemic review. Epilepsia. 2017;58:356–62. 2. Khalil M, Shukralla AA, Kilbride R, Mullins G, Widdess-Walsh P, Delanty N, et al. Ictal asystole during long-term video-EEG; semiology, localization, and intervention. Epilepsy Behav Rep. 2020;15: 100416. 3. Schuele SU, Widdess-Walsh P, Bermeo A, Lüders HO. Sudden unexplained death in epilepsy: the role of the heart. Cleve Clin J Med. 2007;74(Suppl 1):S121–7. 4. Giussani G, Faicicchio G, La Neve A, Costagliola G, Striano P, Scarabello A, et al. Sudden unexpected death in epilepsy. A critical view of the litera- ture. Epilepsia Open. 2023. 5. Leung H, Kwan P, Elger CE. Finding the missing link between ictal brad- yarrhythmia, ictal asystole, and sudden unexpected death in epilepsy. Epilepsy Behav. 2006;9(1):19–30. 6. Coll M, Oliva A, Grassi S, Brugada R, Campuzano O. Update on the Genetic Basis of Sudden Unexpected Death in Epilepsy. Int J Mol Sci. 2019;20(8):1979. 7. Johannesen KM. From precision diagnosis to precision treatment in epilepsy. Nat Rev Neurol. 2023;19(2):69–70. 8. van der Lende M, Surges R, Sander JW, Thijs RD. Cardiac arrhythmias during or after epileptic seizures. J Neurol Neurosurg Psychiatry. 2016;87(1):69–74. 9. Giovannini G, Meletti S. Ictal asystole as the first presentation of epilepsy: A case report and systematic literature review. Epilepsy Behav Case Rep. 2014;2:136–41. 10. Wittekind SG, Lie O, Hubbard S, Viswanathan MN. Ictal asystole: an indica- tion for pacemaker implantation and emerging cause of sudden death. Pacing Clin Electrophysiol. 2012;35(7):e193–6. 11. Knowles JK, Helbig I, Metcalf CS, Lubbers LS, Isom LL, Demarest S, et al. Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress. Epilepsia. 2022;63(10):2461–75. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 12. Johnson B, Ouyang K, Frank L, Truty R, Rojahn S, Morales A, et al. Sys- tematic use of phenotype evidence in clinical genetic testing reduces fast, convenient online submission the frequency of variants of uncertain significance. Am J Med Genet. 2022;188(9):2642–51. thorough peer review by experienced researchers in your field 13. Coll M, Striano P, Ferrer-Costa C, Campuzano O, Matés J, Del Olmo B, et al. rapid publication on acceptance Targeted next-generation sequencing provides novel clues for associated support for research data, including large and complex data types epilepsy and cardiac conduction disorder/SUDEP. PLoS ONE. 2017;12(12): e0189618. • gold Open Access which fosters wider collaboration and increased citations 14. Kusuluri DK, Güler BE, Knapp B, Horn N, Boldt K, Ueffing M, et al. Adhesion maximum visibility for your research: over 100M website views per year G protein-coupled receptor VLGR1/ADGRV1 regulates cell spread- ing and migration by mechanosensing at focal adhesions. iScience. At BMC, research is always in progress. 2021;24(4):102283. 15. Becker LL, Dafsari HS, Schallner J, Abdin D, Seifert M, Petit F, et al. The Learn more biomedcentral.com/submissions clinical-phenotype continuum in DYNC1H1-related disorders-genomic http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Acta Epileptologica Springer Journals

De novo ADGRV1 variant in a patient with ictal asystole provides novel clues for increased risk of SUDEP

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Abstract

Background Various cardiac and autonomic manifestations are frequently reported during seizures. Among the sei- zure-related arrhythmia, ictal tachycardia is the most common, followed by ictal bradycardia, with ictal asystole being the rarest. The occurrence of ictal asystole may obscure the clinical presentation and delay the diagnosis, represent- ing a life-threatening presentation of epilepsy, with an elevated risk of sudden unexpected death in epilepsy patients (SUDEP). These cardiac abnormalities are being increasingly recognized as the key to elucidating the mechanisms of SUDEP. Case presentation We present a 35-year-old man with a history of focal-onset seizures with impaired conscious- ness since his mid-20 s. He developed different types of seizures for 2 years, described as tonic seizure and atonic seizure (drop attack). During such clinical events, he suffered from falls and cardiac arrest. However, thorough cardiac electrophysiology and imaging workup failed to reveal a cardiac etiology. Subsequent video electroencephalograph (EEG) monitoring was performed, and ictal bradycardia and ictal asystole were discovered. A cardiac pacemaker was implanted, and at 3-year follow-up, the patient did not suffer more atonic seizures, or falls. Genetic tests discovered a de novo variant of Adhesion G Protein-Coupled Receptor V1 (ADGRV1), which may provide a clue for the patient’s ictal asystole and the increased risk of SUDEP. Conclusions Considering the important impact of ictal bradycardia and asystole on the morbidity and potential mortality of epileptic patients, it is important to simultaneously utilize EEG and electrocardiogram to confirm the diag- nosis. This case report highlights the link between the de novo variant of ADGRV1 and the ictal bradycardia/asystole phenotype and implicates the importance of genetic testing in adult epilepsy patients. Keywords Ictal asystole, Drug resistant epilepsy, ADGRV1, SUDEP *Correspondence: Ning Zhong ning.zhong@kp.org SQZ Biotechnologies, Watertown, MA 02472, USA Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA 02467, USA College of Medicine, California Northstate University, Elk Grove, CA 95757, USA Pediatric and Adolescent Medicine Residency of Mayo Clinic, MN, Rochester, USA Department of Neurology, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA North Valley Comprehensive Epilepsy Program, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Ji et al. Acta Epileptologica (2023) 5:13 Page 2 of 9 Background Case presentation Epileptic seizure-induced cardiac arrhythmias have We report a 35-year-old Caucasian man with DRE who long been recognized as epileptic ictal manifesta- suffered from ictal asystole. Clinical presentation, brain tions, possibly caused by seizure-induced autonomic imaging, EEG data, genetic testing results, and treatment imbalances [1]. The most common arrhythmia asso- outcome were reported. ciated with epilepsy is ictal tachycardia, which occurs in ~ 80% of all seizures. Ictal bradycardia occurs Clinical characteristics in < 6% of seizures. Ictal asystole, the absence of ven- The 35-year-old, right-handed male had a history of focal tricular complexes for more than 4  s, accompanied by seizures with impaired consciousness initially diagnosed electrographic seizure onset, is found in 0.27–0.4% at age 24 in 2010. Semiology by then was described as of patients undergoing video-electroencephalograph difficulty in speaking, incomprehensible speech, star - (vEEG) monitoring [2]. Ictal bradycardia/asystole is ing spells, behavioral freeze, and impaired awareness. often unrecognized until documented during vEEG– Such episodes lasted from 30  s to minutes. Postictally, electrocardiogram (ECG) monitoring in drug-resistant the patient was amnestic of the event and only spoke in epilepsy (DRE). As lethal arrhythmias during seizures, his native language. The post-ictal state lasted approxi - ictal ventricular tachycardia, ictal bradycardia, and mately 10  min. Based on the described semiology, the ictal asystole, are hypothesized as among the patho- patient was diagnosed as focal onset seizures with physiological causes of Sudden Unexpected Death in impaired awareness (also known as complex partial sei- Epilepsy Patients (SUDEP) [3]. zures). He was prescribed Levetiracetam, and the dose SUDEP is a sudden, unexpected, witnessed, or was increased according to the reported recurrent sei- unwitnessed death in an individual with epilepsy that zures. An EEG during this period showed mild general- is not caused by a traumatic injury, drowning, or other ized slowing in the theta range, though no epileptiform causes. SUDEP occurs in benign circumstances with features were identified. Brain magnetic resonance imag - or without evidence for a seizure and excludes docu- ing (MRI) in 2013 did not reveal any abnormality. mented status epilepticus. Postmortem examination In 2015, he was presented to the Emergency Depart- does not reveal other causes of death [4]. However, at ment (ED) after a witnessed generalized tonic–clonic present, there is no consensus on the causes of ictal seizure (GTCS) secondary to not-taking medication. bradycardia/asystole and their effect on the patho- Nonetheless, Levetiracetam alone failed to control the physiology of SUDEP. The mechanisms of ictal brady- patient’s seizures as the seizure frequency continued to cardia/asystole might be explained by the associations increase to once daily or multiple times per day. Then between the central autonomic network control and lamotrigine was added to his regimen and the dosage was the limbic system structures such as the cingulate eventually maximized. Consequently, seizure control was gyrus, amygdala, and insular and orbitofrontal cor- maintained for 2  years until a recurrent GTCS in 2017. tex [5]. However, such hypothesis does not entirely Follow-up EEG showed frequent left-sided slowing and account for the various clinical manifestations and slow sharp waves at C3T3, and occasional right-sided brain structural lesions documented. Recent studies temporal sharp-waves. are pointing to the genetic susceptibility to SUDEP. A few months later, new seizure semiology developed. A few variants of genes involved in epilepsy as well as The patient was observed to have (1) tonic seizures, with cardiac and respiratory functions have been discov- witnessed body stiffening, lasting 1–2 min; (2) atonic sei - ered, suggesting a highly heterogenic and polygenic zures/drop attack, with witnessed falls and loss of con- contribution to SUDEP [6]. Adhesion G protein-cou- sciousness; and (3) nocturnal brief myoclonic events. pled receptor V1 (ADGRV1) has been implicated in The patient had been admitted to the ED on multiple the regulation of breathing and cardiovascular func- occasions after atonic events. During one incident, he tion, and recent studies have suggested that it also fell backwards onto a concrete floor resulting in a small plays a role in SUDEP. left-sided subarachnoid hemorrhage and temporo-occip- This is in line with the increasing efforts to practice ital skull fracture. There was no witnessed tonic–clonic precision medicine in epilepsy. Based on genetic infor- activity proceeding the fall. As the patient’s seizures mation, therapies such as anti-seizure medication can resulted in more debilitating consequences, Lacosamide be tailored to achieve the best therapeutic efficiency was introduced. However, no clinical improvement was while minimizing side effects and intolerance, ulti- observed. In April 2019, he was witnessed to have full- mately leading to the development of effective, person- body stiffening and shaking before losing consciousness. alized gene therapies [7]. In the field, when paramedics arrived, he was found in Ji  et al. Acta Epileptologica (2023) 5:13 Page 3 of 9 pulseless cardiac arrest. He showed spontaneous resto- temporal regions (Fig. 2 a, b). Subsequently, the ictal pat- ration of normal sinus rhythm before any interventions tern evolved into diffuse semi-rhythmic delta-theta slow - were administered. Cardiac workup including ECG, ing. The ECG RR interval was analyzed at a baseline with trans-esophageal echocardiogram, stress ECG test, and heart rate of 62–63  bpm. During his seizure events, the electrophysiology yielded no findings indicative of a pri - RR interval increased by 100–200  ms, which triggered mary cardiac etiology for his cardiac arrest. the pacemaker (Fig.  2c). The prolongation of RR inter - val often occurred 10–20 s after the onset of clinical sei- Video EGG monitoring zures. This observation demonstrated that cardiac pacing The patient continued to suffer recurrent seizures prevented the development of ictal bradycardia/asystole despite taking three antiseizure medications at suffi - during the patient’s focal seizures. cient dose, so he was diagnosed with DRE. VEEG was Follow-up 3  T MRI showed left mesial temporal scle- performed in May 2019. Ictal bradycardia and ictal asys- rosis with hippocampal volume loss and mild increase of tole were observed. During one of his typical seizures, FLAIR signal (Fig.  3a). Brain PET scan did not show lat- he was observed with frozen behavior and staring; then, eralized hypometabolism (Fig. 3b). he exhibited hand fidgeting with fingers locked in tonic The patient was followed up for three years, and no posture. His body proceeded to fall back to bed, with recurrent tonic or atonic seizures were reported. He con- his head turning to the left accompanied by mild non- tinued with rather sporadic dyscognitive seizures while rhythmic limb shaking. Subsequently, the patient lost taking both Levetiracetam and Lamotrigine, Lacosamide consciousness, followed by myoclonic body jerking. was discontinued because no obvious effects were noted. EEG showed diffuse, irregular delta slowing at the onset of the event. Such diffuse slowing persisted throughout Genetic testing and variant analysis the 13.5  s of asystole. The asystole was also confirmed Genetic analysis was conducted by using the next-gen- with concurrent cardiac-telemetry monitoring. During eration sequencing for DNA sequence variants and copy the asystole, EEG showed diffuse low voltage recording, number variants. Variants in dihydropyrimidine dehy- indicating global cerebral hypoperfusion (Fig.  1a). The drogenase (DPYD, c1905 + 1C > A), adhesion G protein- patient experienced four similar seizures when bradycar- coupled receptor V1 (ADGRV1, c.5785 G > T) and two dia and shorter asystole (heart rate pauses for a few sec- other variants were discovered (Table  1). These variants onds) were captured in EEG-ECG monitoring (Fig.  1b). were not revealed in his parents. We performed in silico The onset of bradycardia and heart-beat pauses were analysis with polyphen-2, SIFT, Grantham score, and noted 20  s after the seizure onset (Fig.  1a). Cardiology Mutation Taster softwares to estimate if the variants were was consulted and the patient underwent emergency car- pathogenic or had a damaging functional effect (Table  1). diac pacemaker implantation to prevent further cardiac We also applied Alphafold, an artificial intelligence sys - complications in DRE. The pacing parameter was set at tem, to investigate whether the discovered variants would 60–130 bpm. affect the protein structures. Results showed that the ADGRV1 variant at the 5q14.3 chromosomal locus, was Follow‑up and treatment outcome likely to have an impact on the protein structure. The Repeated vEEG two months after the pacemaker implan- discovered de novo variant in ADGRV1 was localized tation showed interictal sharp waves in the bilateral in the calx-beta domain within the very close vicinity to temporal regions independently. Temporal intermittent reported genetic loci associated with generalized epilepsy rhythmic delta activity (1–2  Hz) was seen in the right (Fig. 4). temporal regions. During re-monitoring, seizures of bilaterally independent temporal onset were recorded Discussion (Fig.  2). Clinically, while being awake, the patient dem- The case presented in this report reflects the compli - onstrated staring or glassy eyes, with subsequent repeti- cated nature of ictal asystole in the context of evolv- tive swallowing with or without lip smacking, and ictal ing seizure semiology. Before the extensive epilepsy coughing. During the events, the patient did not lose examinations, the patient did not show predisposing consciousness, but he was unable to maintain conversa- factors, and had no family history of cardiac arrhyth- tion and his wife reported that the patient did not make mia or sudden unexpected death. Our report highlights meaningful conversation; such observed semiology was the importance of vEEG-ECG monitoring in confirm - similar to his habitual seizures before developing tonic ing the diagnosis of ictal bradycardia/asystole [8]. and atonic seizures. The patient himself was amnestic Brain MRI indicated left mesial temporal sclerosis in to the events. At the onset of the seizures, EEG showed this patient. EEG re-monitoring after the cardiac pace- focal (irregular or semi-rhythmic) delta slowing in both maker implantation also showed focal seizures likely Ji et al. Acta Epileptologica (2023) 5:13 Page 4 of 9 Fig. 1 a Atonic seizure recorded during video EEG (vEEG) monitoring. vEEG showed ictal generalized delta slowing, followed by tonic (stiffening) and clonic ( jerking) phases; and subsequent diffuse voltage attenuation and diffuse distribution of delta slowing (purple arrows). The one lead ECG recording (red lines in the figure) showed HR change (red arrows) when bradycardia and asystole; b Ictal asystole was further confirmed by the ECG traces recorded during cardiac telemetry monitoring Ji  et al. Acta Epileptologica (2023) 5:13 Page 5 of 9 Fig. 2 a A focal-onset seizure arising from the left temporal region. Purple arrow shows EEG focal slowing in the left temporal region at ictal onset and when ictal phase evolution. b A focal-onset seizure arising from the right temporal region. Purple arrow shows EEG focal slowing in the right temporal region at ictal onset and when ictal phase evolution, and red arrow indicates onset of clinical symptoms. c Ictal prolongation of RR interval during the focal-onset seizures, as recorded by the concurrent ECG monitoring. Blue arrow indicates the cardiac pacemaker pacing artifacts Ji et al. Acta Epileptologica (2023) 5:13 Page 6 of 9 Fig. 3 a Brain MRI showed left temporal and hippocampal sclerosis in the last follow up. Yellow arrow shows the increased T2/FLAIR signal and volume loss in the left hippocampus. b Brain PET showed no lateralized hypometabolism arising from the left or the right temporal region. These Understanding the precise etiology of epilepsy is the findings are consistent with literature that reported basis for precision medicine and tailored treatment for ictal asystole occurring in temporal lobe or insular patients with epilepsy. Further exploring the genetic basis epilepsy, especially in patients with DRE [9]. However, of epilepsy may lead to an improved understanding of there are no obvious associations between lateralized the epileptogenesis, personalized medical management, epileptogenesis and autonomic nervous system changes and ultimately improved seizure control/prevention manifested as ictal bradycardia/asystole. The underly - outcomes and quality of life [11]. In our case, genetic ing mechanisms of the correlation between temporal analysis revealed a pathogenic variant in DPYD, a likely lobe seizures and the ictal asystole may be related to pathogenic variant in ADGRV1, and a variant of uncer- the stimulation of the insula, the cingulate cortex, the tain significance in DYNC1H1. Identifying genetic mark - amygdala, and the hypothalamus during such seizures, ers associated with phenotypes has remained challenging which may provoke asystole via autonomic control [9]. due to the complexity of the human genome, the extreme Being secondary to the epileptic seizure, the ictal brad- polygenicity, and lack of reports for rare gene variants ycardia/asystole results from the disruption of normal [12]. In our case, the patient did not present with phe- cardiac rhythm caused by heart rate changes. Clinically, notypes that have been reported in literature, such as the affected patients likely manifest unexpected col - severe epilepsy syndrome, microcephaly, intellectual dis- lapse or fall in later phases of seizures, as presented in ability, cortical malformation, or neuromuscular symp- our case. The changes of seizure semiology with tonic, toms (Table  1). Instead, he had unique presentations of atonic, or nocturnal brief myoclonic features displayed ictal asystole and temporal lobe seizure, and promis- by the patient may be clinical manifestations of cerebral ing treatment outcomes, which prompted us to further hypoperfusion due to ictal bradycardia/asystole. investigate the underlying pathophysiology. With care- Patients with intractable drug-resistant focal epilepsy ful inspection of the genotype–phenotype association are at a higher risk of ictal asystole, which may lead to and comprehensive prediction of functional impact of SUDEP. Besides GTCS, ictal asystole associated with variants, we found that the de novo variant in ADGRV1 DRE has also been considered as a potential mechanism is very likely to be the cause of the patient’s ictal asys- for SUDEP and has received increasing attention [10]. tole. ADGRV1 is a large calcium-binding protein widely Although ictal asystole is rare, its associated red flag expressed in the central nervous system. The ADGRV1 symptoms such as atonia and unexplained falls often lead gene is an epilepsy-associated gene (Table  1) located at to detrimental, life-threatening complications as seen in the 5q14.3 chromosomal locus, a site that has been previ- our case, resulting in intracranial hemorrhage and car- ously reported to be associated with myoclonic epilepsy diac arrest. Thus, cardiac pacemaker implantation is due to haploinsufficiency. ADGRV1 is recently discovered advised for patients with documented ictal asystole and to be strongly associated with SUDEP [13]. We hypoth- would often be a life-saving practice [10]. esized that the discovered missense variant might lead Ji  et al. Acta Epileptologica (2023) 5:13 Page 7 of 9 Table 1 Results of genetic variant analysis Gene name Base change Codon change Variant type Inheritance Polyphen2 SIFT Mutation Grantham Protein Clinical Reported Taster domain relevance clinical Prediction symptoms associated with previously reported gene variants DPYD c.1905 + 1G > A n/a Heterozygous Autosomal n/a n/a Disease-causing n/a n/a Pathogenic Seizures, micro- splice site recessive cephaly, muscular hypotonia, devel- opmental delay, and sensitivity to 5-FU toxicity ADGRV1 c.5785G > T p.Ala1929Ser Heterozygous Autosomal Damaging Tolerated Disease-causing 99 Calx:beta 13 Likely patho- Febrile and missense genic vs VUS afebrile seizures, focal epilepsy and SUDEP, Lennox-Gastaut syndrome, myo- clonic epilepsy, Usher syndrome DYNC1H1 c.11894C > T p.Ser3965Phe Heterozygous Autosomal Benign Not Tolerated Disease-causing 155 n/a Variant of Intellectual dis- missense recessive unknown ability, malforma- significance tions in cortical development, West syndrome, epileptic encephalopathy with continu- ous spikes and waves during slow sleep, spinal muscular atrophy, and Charcot- Marie-Tooth syndrome ASPM c.6711C > A p.Asn2237Lys Heterozygous Autosomal Benign Tolerated Polymorphism 94 IQ repeat Likely benign Intellectual dis- missense dominant region ability, primary microcephaly Abbreviations: polyphen-2 Polymorphism Phenotyping V2, Grantham Grantham scores for conservative, SIFT Sorting Intolerant From Tolerant, DPYD dihydropyridine dehydrogenase, ADGRV1 adhesion G protein-coupled receptor V1, DYNC1H1 dynein cytoplasmic 1 heavy chain 1, ASPM assembly factor for spindle microtubules, VUS Variant of unknown significance Ji et al. Acta Epileptologica (2023) 5:13 Page 8 of 9 Fig. 4 ADGRV1 variants associated with epilepsy and SUDEP. Red,gene variants associated with genetic generalized epilepsy (GGE); black, variants associated with other type of epilepsy; blue, reported variants associated with SUDEP; purple, the de novo variant reported in our case. LGS: Lennox-Gastaut Syndrome; EOAE: early-onset absence epilepsy; ID: intellectual disability; EAR: epilepsy-associated repeat; GPS: G-protein-coupled receptors (GPCR) proteolytic site to dysfunction of ADGRV1 protein, contributing to the risk of SUDEP is deemed to be high based on observed or unique phenotypes, temporal lobe epilepsy and ictal potential cardiac rhythm disturbances. Continuing phar- asystole observed in our patient. Recent animal studies macological treatment is important, and further moni- showed that ADGRV1 is required for the development of toring after pacemaker implantation can provide critical γ-aminobutyric acid (GABA)ergic interneurons. It is pos- information such as the lateralization of the seizure onset sible that the disruption of ADGRV1 function may result in our case. in dysfunction of cortical GABAergic neurons, which Ictal asystole and SUDEP are rare, and the underly- serves as a potential epileptogenic mechanism in humans ing pathophysiological mechanisms remain elusive. The [14]. Intriguingly, the discovered pathogenic variant genetic basis of epilepsy is increasingly explored, which in DPYD in our patient did not appear to be associated will encourage the possibility of precision treatments for with the severe clinical phenotypes reported in literature. specific genetic etiologies [11]. Our genetic testing and DPYD plays an important role in the metabolism of the analysis suggested that the ADGRV1 gene is a contributor antineoplastic agent 5-fluorouracil (5-FU) and patients to SUDEP. Such findings not only draw attention to the with DPYD deficiencies can have severe cardiac toxicity mutation spectrum of the ADGRV1 gene, but also inspire [15]. A previous paper reported that 5-FU administration genetic testing and early identification of patients with in a patient with DPYD mutation led to Takotsubo car- epilepsy who are at a high risk of SUDEP. diomyopathy due to autonomic imbalance. This raises the possibility that DPYD variants may be a predisposing fac- Abbreviations tor for autonomic dysfunction [15]. ADGRV1 Adhesion G protein-coupled receptor V1 Although the precise causes for the variants remain DPYD Dihydropyridine dehydrogenase DRE Drug-resistant epilepsy to be further investigated, our report calls for increased EEG Electroencephalogram recognition of and access to genetic testing for adult epi- GTCS Generalized tonic–clonic seizure lepsy patients. Phenotypic and clinical information are SUDEP Sudden unexpected death in epilepsy patients often critical to interpreting the significance of the dis - Acknowledgements covered genetic variants, which improves the quality and Not applicable. accuracy in reclassifying the VUS [16]. Authors’ contributions LD, AD, and NZ collected the clinical information. NZ performed protein structure analysis. TJ, AD and NZ drafted the manuscript. TJ and NZ reviewed Conclusions related articles and extracted the data. All authors have read and approved The diagnosis of ictal asystole requires long-term vEEG- the final manuscript. ECG monitoring. Treatment after the confirmed diagno - Funding sis should be aimed at preventing recurrent seizures. The The study was not supported by any funding. implantation of a pacemaker is recommended when the Ji  et al. Acta Epileptologica (2023) 5:13 Page 9 of 9 Availability of data and materials profiling and proposal for a novel classification. J Hum Genet. The datasets analyzed during the current study are available from the cor- 2020;65(11):1003–17. responding author on reasonable request. 16. Berg JS. Exploring the importance of case-level clinical information for variant interpretation. Genet Med. 2017;19(1):3–5. Declarations Ethics approval and consent to participate This study was approved by the Institutional Ethics Committee of Kaiser Per- manente Foundation Hospital (KPSAC 131–21) and written informed consent has been obtained from the patient. Consent for publication Written informed consent for publication was obtained from the patient. Competing interests The authors declare that they have no competing interests. Received: 28 February 2023 Accepted: 15 May 2023 References 1. Tenyi D, Gyimesi C, Kupo P, Horvath R, Bone B, Barsi P, et al. Ictal asystole: A systemic review. Epilepsia. 2017;58:356–62. 2. Khalil M, Shukralla AA, Kilbride R, Mullins G, Widdess-Walsh P, Delanty N, et al. 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Journal

Acta EpileptologicaSpringer Journals

Published: May 24, 2023

Keywords: Ictal asystole; Drug resistant epilepsy; ADGRV1; SUDEP

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