case study of a child with epilepsy

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"Confusion" in a 9-Year-Old Child: An Interactive Case Study on Epilepsy

• Authors: Author: Gregory L. Holmes, MD
• THIS ACTIVITY HAS EXPIRED FOR CREDIT

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This activity is intended for neurologists, primary care providers, internists, and family practitioners.

The goal of this activity is to provide physicians with a challenging interactive clinical case concerning the treatment of epilepsy in children, based on evidence from the literature and expert management suggestions for this patient population.

• Describe the differential diagnosis associated with pediatric epilepsy
• Compare newer vs older antiepilepsy pharmacologic options for children
• Assess the role of imaging and other diagnostic methods used by epileptologists

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Introduction

Seizures are one of the most frequently encountered neurologic problems presenting in childhood. Seizures are commonly seen at the extremes of life, occurring most frequently in children and the elderly. Roughly 2% to 4% of all children in Europe and the United States experience at least 1 convulsion associated with a febrile illness before the age of 5 years. [1] The incidence of epilepsy (recurrent unprovoked seizures) in children and adolescents seems relatively consistent across all populations studied, ranging from 50 to 100/100,000 persons, with the highest incidence in the first year of life. [1] Children with seizures differ from adults in a number of ways, including the type of epileptic syndrome, prognosis, and therapy.

Children with epilepsy carry a heavy burden. Most children with seizure disorders are treated with antiepileptic drugs (AEDs) administered daily. However, despite compliance with AED regimens, between 10% and 30% of children will continue to experience seizures. [2,3] Childhood epilepsy carries a significant risk for a variety of problems involving cognition and behavior. The distribution of IQ scores of children with epilepsy is skewed toward lower values, [4,5] and the number of children experiencing difficulties in school because of learning disabilities or behavioral problems is greater than in the nonepileptic population. [6-9] Although children with poorly controlled seizures are at greatest risk for learning and behavioral abnormalities, even children with normal IQs and well-controlled seizures are at high risk for learning problems. [7] Childhood epilepsy is associated with a substantial risk of injury during the seizure, and sudden, unexplained death in children with epilepsy has been reported. [10] Even when seizures are controlled with AEDs, a significant number will have AED-induced adverse side effects. [11,12]

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• Epilepsy: Impact On The Life of The Child

Epilepsy: Impact on the Life of the Child

Parents of children with epilepsy describe many challenges that confront their children within the school system. In our experience, school personnel may have a basic understanding of seizures and related safety concerns, but are less well informed about how seizures and the child’s learning, emotional, behavioural and social adjustment are related. For example, genuine concern over a child’s physical safety in the schoolyard may supercede that of concern over his or her social integration. Furthermore, learning or behavioural issues specifically associated with epilepsy may not be clearly understood or are viewed as unrelated to the epilepsy, leading to inappropriate classroom management techniques, placement or inadequate support outlined in the individualized educational plan (IEP). The following paper provides a brief overview of the information we provide in a letter to schools (at the request of parents). In addition to this general information, we include in this letter specific information concerning the child: seizures [types, frequency, duration, emergency management, antiepileptic drugs (AEDs) ]; cognitive/psychological profile (if available); details of the child’s emotional or behavioural status and how problem areas might relate to an underlying brain abnormality, seizures or AED. Finally, we provide some suggestions to include in the child’s IEP that will optimize academic potential, as well as promote emotional well-being and social integration within the school setting.

Epilepsy is a disorder that involves a constellation of symptoms that vary in frequency and intensity from child to child. Of those children with epilepsy, approximately 25% continue to experience poor seizure control even with anti-epileptic drug therapy.1 In addition, it is well documented that epilepsy in children is associated with problems in multiple areas, including academic achievement, behavioural and emotional adjustment, and social competence.2-5 Even when seizures are well controlled with antiepileptic medications, these problems may persist6 because of abnormal brain formation or function, continuing epileptic activity in the brain (without symptoms), or side-effects from antiepileptic medications.

Learning/Academic Issues

Although overall intellectual ability in children with epilepsy is comparable to the normal childhood population7 they are at greater risk for learning problems and academic under achievement8. Even in those with normal intelligence, reports of deficits in specific areas related to thinking and learning abilities are common, particularly in the areas of attention and concentration, memory, organizational skills and academic achievement.9,10 Indeed, many children do not fit the typical school definition of learning disabilities, as their reading, spelling and math skills may be appropriately developed. Nonetheless, they do have significant challenges for learning due to the particular areas of weakness described above.

While some children with epilepsy have global learning problems (developmental delay) caused by extensive brain abnormalities, more often these children have a variety of specific learning problems that can be attributed to a focal brain abnormality. For example, children who have a scar in the middle part of the temporal lobe (mesial temporal sclerosis) may have permanent short term auditory or visual memory problems. Other factors such as seizures, AEDs and fatigue may also contribute to transitory learning problems. For example, seizures and post-seizure fatigue or confusion (post ictal state) can disrupt learning for minutes or hours. Although it is well known that visible seizures interrupt learning, there is some evidence that epileptiform discharges which occur in the brain between seizures (interictal activity) may also disrupt learning. This is referred to as Transient Cognitive Impairment (TCI).11 Finally, in our study of a group of children with poorly controlled epilepsy, children themselves frequently cited fatigue as an important factor that decreased their availability to learn in school12. It is likely that these transitory disruptions in learning account for parent and teacher reports that academic performance in these often children fluctuates from day-to-day. Teaching and learning strategies that take into account the dynamic learning profile of these children, for example intensive programmes that utilize repetitive instruction techniques, are critical to the child’s academic success.

Emotional and Behavioural Issues

Emotional and behavioural difficulties are also disproportionately high in children with epilepsy. For example, psychiatric disorders were identified in 34.6% of children with seizures compared to 6.6% in the general population and 11.6% in children with other chronic illnesses.1 Some of the more common emotional and behavioural difficulties seen in these children include increased anxiety, depression, irritability, hyperactivity, aggression, and in some cases, irrational periods of rage. In a more recent study 3 of behaviour in children in the 6 months before a first recognized seizure, 24.6 % of the children had higher than expected rates of behavioural problems (particularly attention difficulties). This finding suggests that epilepsy is a more complex disorder that may manifest itself with behavioural disturbances, as well as seizures.

In a small proportion of these children, verbal or behavioural aggression may occur spontaneously with minimal or no provocation. There is a paucity of research exploring intermittent spontaneous aggression in children with epilepsy and mechanisms underlying aggression in these children are poorly understood. Aicardi 13 proposed one causal mechanism for behavioural disturbances by suggesting that epileptiform discharges in the brain may produce disorganization of brain function that then affects behaviour. The authors of another paper14 suggest that behavioural aggression may be result from certain abnormal regions of the brain producing epileptic activity or may be aggravated by the effects of antiepileptic drug therapy.

Many parents in our clinical setting describe a variety of scenarios in which they have observed changes in their child’s mood accompanied by increased aggression. The most frequently cited complaint is that introduction or high doses of certain antiepileptic medications coincide with behavioural changes including irritability, verbal, or even physical aggression. For example, this might take the form of a younger child hitting other children. If the behavioral side effects are intolerable, reducing or discontinuing the antiepileptic medication while adding another medication may be necessary. Second, behavioral changes, such as increased irritability and verbal or physical aggression, often herald the onset of a seizure. These behavioral changes can occur minutes to days before a seizure. During this period, certain triggers (stimuli) may further irritate the child, producing increased frustration or aggression. Therefore, it may be prudent to reduce over stimulation in the school setting during this period, for example decreasing academic workload. The third scenario comprises a smaller group of children who experience sudden outbursts of verbal or physical aggression. These children present special challenges to the family, school and health professionals.

Characteristically, the episode of aggressive behaviour may appear with minimal or no provocation and can go on for some time. Our clinical observations, as well as conversations with children, parents, and teachers suggest a trajectory for episodic verbal or physical aggression. It seems that the child perceives a certain situation as noxious. For example, some children with epilepsy may have very sensitive hearing. Loud noises or a confusing number of noises in the classroom might precipitate explosive behaviour. Once the trigger stimulates an angry feeling, it is difficult for these children to ‘put on the brakes’. It is not that they ‘won’t’ control their aggression, rather, children tell us that they ‘cannot’ control the aggressive outbursts. Parents report that children often experience remorse following an aggressive outburst. They frequently berate themselves, for example, saying, “I’m a bad person”. Interventions that focus on immediately removing the stimulus/trigger, or removing the child from the stimulus, can sometimes diffuse their anger and outburst. It is our experience that these children do not respond to standard behavioural management strategies or restraint alone. Rather a combination of strategies, including assessment and follow-up by psychiatry, and interventions such as psychotropic medications and/or intensive behavioural therapy, may be warranted.

Social Issues

Participation in physical activities and social engagement with peers is particularly important during childhood development. Yet in our conversations with families of children with epilepsy, we frequently hear that seizures, and the associated secondary problems, often exclude children from full participation in academic, recreational and social experiences. Concern for the child’s safety may lead to restriction of normal school activities, which most children take for granted. This increases the child’s sense of social isolation. Isolation from these important social learning experiences further enhances a negative perception of self, informing the child, that he or she is ‘not normal’ at time in life when being ‘normal’, not ‘different’ is highly valued. It is important that parents advocate for extra support in the school to facilitate the child’s participation in school activities (e.g. playground, gym) that facilitate interactions with other children. Involvement in school activities is paramount to fostering a sense of emotional well-being well as, promoting social and physical development.

In practical terms, the stigma associated with epilepsy, and the insensitivity of others, are also stressors that affect the emotional and adaptive behavioural responses in these children. It is our experience that many of the children with whom we come in contact are excluded from activities with classmates; teased and bullied; and sometimes suspended from school because of behavioural issues. These factors further reinforce the child’s negative view of him/herself and alienate the child from the usual social and learning experiences that promote self-esteem and normal social development.

In summary, epilepsy is a complex disorder that has an impact on many aspects of a child's development and functioning. As a result, many of these children are at increased risk for unsuccessful school experiences; difficulties in social engagement with peers; inadequate social-skills; and poor self-esteem. It is, therefore, important that a partnership between educators, family members, and health care providers be instituted so that a plan for academic success as well as a plan for safety, management of emotional or behavioural dysregulation and active social integration be developed and evaluated on an ongoing basis.

References :

• Hauser WA & Hesdorffer DC. Remission, intractability, mortality, and comorbidity of seizures. In Wyllie E, editor. The treatment of epilepsy: principles and practice . Philidelphia. PA: Lippincott Williams and Wilkins, 2001. pp. 139-145.
• Bourgeois, B. F. D., Prensky, A. L., Palkes, H. S., Talent, B. K., & Busch, S. G. (). Intelligence in epilepsy: A prospective study in children . Annals of Neurology, 1983, 14: 438-444.
• Austin, J. K., Harezlak, J., Dunn, D. W., Huster, G. A., Rose, D. F., & Ambrosius, W. T. Behavior problems in children before first recognized seizures. Pediatrics , 2001, 107(1):115-122.
• Hoare P. The development of psychiatric disturbance among school children with epilepsy. Dev Med Child Neurol 1984, 26: 23-4.
• Seidenberg M, Beck N, Geisser M, Giordani B, Sackellares JC, Berent S et al. Academic achievement of children with epilepsy. Epilepsia 1986, 27: 753-759.
• Sillanpaa M., Jalava M, Kaeva P, Shinnar S, Long-term prognosis of seizures with onset in childhood , N Engl J Med 1998, l338:1715-22
• Rutter M. Graham P and Yule WA. Neuropsychiatric Study in Childhood . Philadelphia: J.B. Lippincott, 1970.
• Aldenkamp AP Learning disabilities in children with epilepsy. In: A.P. Aldenkamp, W.C.J. Alpharts, H. Meinardi, & G. Stores (Eds.). Education and epilepsy: Proceedings of an international workshop on education and epilepsy , 1987, 21-37. Berwyn, PA: Swets North America.
• Smith ML, Elliott IM, Lach L. Cognitive skills in children with intractable epilepsy: Comparison of surgical and non-surgical candidates. Epilepsia 2002, 43:631-7
• Williams J. Learning and behavior in children with epilepsy. Epilepsy & Behavior 2003, 4(2):107-111
• Rugland AL. ‘Subclinical’ Epileptogenic Activity . In: Sillanpaa M, Johannessen SI, Blennow G, and Dam M. eds. Paediatric Epilepsy. Wrightson Biomedical Publishing Ltd, 1990, pp. 217-224
• Elliott I, Lach L, Smith ML. Impact of intractable epilepsy on quality of life in children: child, adolescent and parent pre-surgical perspectives. Epilepsia 1999, 40 (Suppl 7): 112.
• Aicardi J. Epilepsy as a non-paroxysmal disorder. Acta Neuropediatr 1996, 2:249-257
• Juhasz C, Behen ME, Muzik O, Chugani DC, Chugani HT. Bilateral Medial Prefrontal and Temporal Neocortical Hypometabolism in Children with Epilepsy and Aggression. Epilepsia , 2001, 42(8):991-1001

Reprinted with permission from Epilepsy Canada . Lumina, Fall 2004;4-6.

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Epilepsy Case Studies

Pearls for Patient Care

• © 2021
• Latest edition
• William O. Tatum 0 ,
• Joseph I. Sirven 1 ,
• Gregory D. Cascino 2

Mayo Clinic, Department of Neurology, Jacksonville, USA

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Mayo Clinic, Department of Neurology, Rochester, USA

• Provides summary of differential diagnosis and treatment options
• Updated new edition with current terminology and up-to-date classification and references
• Offers a wide range of insightful clinical pearls and covers conditions relative to future research in epilepsy

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About this book

This book presents a case based approach to epilepsy management in both diagnostic challenges and treatment of complex cases. Cases reflect “real life” patient scenarios that practitioners encounter with up-to-date terminology and treatment approaches.

With 51 chapters, the book presents 51 unique, nuanced cases. Beginning with an initial presentation of a case history, the book opens with a basis for drawing in multiple aspects in the treatment of patients with epilepsy. Each chapter is organized into a clinical history, physical examination results, and ancillary testing to concentrate on differential diagnosis and focus on a definitive procedural approach to the final diagnosis. Subsequent information about the condition expands on the knowledge of the clinical features to a solution of common patient clinical scenarios as it affects people with epilepsy.

A comprehensive successor edition, Epilepsy Case Studies is an invaluable resource to clinicians ranging from those looking for a quick review of a topic present in the table of contents, to those crossing disciplines into medical areas where seizures are a symptom of disordered or dysfunctional brain.

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• comorbidities

Table of contents (51 chapters)

Front matter, epileptic spasms.

• Elaine Wirrell

Neonatal Seizures and Metabolic Epilepsies

• Anthony L. Fine, Lily C. Wong-Kisiel

Febrile Seizures

• Harry S. Abram

Childhood Absence Epilepsy

• Raj D. Sheth

Lennox-Gastaut Syndrome

• William O. Tatum, Raj D. Sheth

Self-Limited Epilepsies in Childhood

• Katherine Nickels

Genetics and Epilepsy

• Anthony L. Fine

Epileptic Encephalopaties and Developmental Disorders

• Keith Starnes, Raj D. Sheth

Autonomic Seizures and Panayiotopoulos Syndrome

• William O. Tatum, William P. Cheshire

Genetic Epilepsy with Febrile Seizures Plus

• William O. Tatum

Progressive Myoclonus Epilepsy

• Katherine Nickels, William O. Tatum

Autoimmune Epilepsies

• Matthew Hoerth

Electroclinical Localization and Treatment

Brain tumor-related epilepsy.

• Anteneh M. Feyissa

Head Trauma and Seizures

Gregory D. Cascino

First Seizure and Epilepsy

Starting antiseizure medication.

• Amy Z. Crepeau

Stopping Antiseizure Medication

Classification of epilepsy, editors and affiliations.

William O. Tatum, Joseph I. Sirven

About the editors

Bibliographic information.

Book Title : Epilepsy Case Studies

Book Subtitle : Pearls for Patient Care

Editors : William O. Tatum, Joseph I. Sirven, Gregory D. Cascino

DOI : https://doi.org/10.1007/978-3-030-59078-9

Publisher : Springer Cham

eBook Packages : Medicine , Medicine (R0)

Copyright Information : Springer Nature Switzerland AG 2021

Hardcover ISBN : 978-3-030-59077-2 Published: 20 December 2020

Softcover ISBN : 978-3-030-59080-2 Published: 20 December 2021

eBook ISBN : 978-3-030-59078-9 Published: 19 December 2020

Edition Number : 2

Number of Pages : XVII, 305

Number of Illustrations : 24 b/w illustrations, 50 illustrations in colour

Topics : Neurology , Internal Medicine

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Managing a Child with Epilepsy

The value of primary care and three-stage assessment.

Goel, Gargi; Mohan, Pavitra; Mohan, Sanjana Brahmawar

Basic Health Care Services, Udaipur, Rajasthan, India

Address for correspondence: Dr. Pavitra Mohan, Basic Health Care Services, 39, Krishna Colony, Bedla Road, Udaipur - 313 001, Rajasthan, India. E-mail: [email protected]

Received August 08, 2021

Received in revised form August 09, 2021

Accepted August 09, 2021

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

Epilepsy is defined as a condition characterized by recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause. It is estimated that, in India alone, about 10 million people suffer from epilepsy. The prevalence of epilepsy in rural areas is almost twice that seen in urban areas (1.9% vs. 0.6%).[ 1 ] However, it is estimated that almost 70%–90% of epileptic patients are either untreated, inadequately treated, or noncompliant.[ 1 ] Multiple factors contribute to this: nonrecognition that epilepsy is a medical illness, inability of families to access specialized care, challenges in managing epilepsy, and lack of coordination between primary care level and specialized health care.

In this issue, we discuss the case study of a child from a rural area, who presented to our clinic with a history of seizures. The purpose of highlighting this case is to illustrate the value of primary care and three-stage assessment in managing children with epilepsy.

R, a 12-year-old girl, was brought to our clinic by her parents who resided in Morwal, a remote, rural village with no telephone connectivity, about 35 km from Udaipur city. Her presenting complaints were convulsions for 4 months; the episodes were associated with the loss of consciousness along with stiffening and jerky movements of the limbs, lasted for less than a minute, and occurred around 3–4 times/day. In between events, the child was alert, active, and had no difficulties in participating in her routine activities. There was no history of headaches, vomiting, fever, or ear discharge. There was no history of similar episodes, head injury, febrile illness with altered sensorium in the past, or febrile convulsions in childhood. She was born in a health center, had apparently attained all milestones at the appropriate age, and immunized. She had been living with her maternal aunt in the city for a year so that she could pursue her studies in class 6 in a school there but had been sent back to her village due to her illness. Her academic performance was average and was right-handed. Since coming home, she was spending a lot of time watching television or on the mobile. Menarche had not been attained. She was the second in birth order out of three siblings. There was no family history of epilepsy in the immediate family. Her father was an employee at the local liquor store, and her mother was a homemaker.

On examination, her height was 140 cm (−1.18 standard deviation [SD]), weight 28.9 kg (−1.52 SD), and body mass index 14.7 (−1.24 SD). Her vital parameters including blood pressure were normal. There was no overt dysmorphism or the presence of neurocutaneous markers. Her sensorium was normal and higher functions intact. There was no cranial nerve or focal neurological deficits or signs of meningeal irritation. Hearing and vision were normal.

We encouraged the family to seek a neurological consultation and to get an electroencephalogram (EEG) and magnetic resonance imaging (MRI) from a referral hospital. However, her father was unable to get leave for a few weeks. In view of these circumstances, a normal neurological examination, and the absence of history suggestive of any secondary illness, we kept a presumptive diagnosis of idiopathic generalized epilepsy and started her on sodium valproate. She was advised to limit her screen time. A few weeks later, an MRI of the brain (epilepsy protocol) revealed focal, abnormal, signal intensity in the right frontal lobe in the periventricular region that appeared hyperintense on T2-weighted and FLAIR images. An EEG showed paroxysms of generalized spike and wave, with an amplitude of 200–300 mV. The background activity was synchronous and symmetric, consisting of 8–9 Hz waves that were maximally seen over the posterior region. Hyperventilation and photic stimulation produced no significant changes. This confirmed our diagnosis, and she was asked to continue on the same dose of anticonvulsants and remain in close follow-up.

However, over the next few months, she was unable to visit regularly due to the distance, cost of travel, and inability of her father to get leave. This led to break in continuity in medication and poor seizure control. When she presented back to us 3 months later, she was still having 2–3 convulsions/day, each lasting for a few minutes. We decided to take over the prime responsibility of managing the child by ensuring the availability of antiepileptics and fortnightly follow-up visits to our clinic. With proper counseling and assurance that her antiepileptic drugs will be provided at the clinic (which was close to her home), her compliance improved, and seizure frequency decreased to one episode every 2–3 days.

A three-stage assessment was conducted to understand the family and social circumstances and determine factors that may have an impact on her condition.[ 2 ] This included the details that had been ascertained from her clinical assessment (history, examination, and established diagnosis), assessment of R (her thoughts, ideas, feelings, concerns, and fears), and contextual assessment (with respect to her family and home). R had been living away from her family, with her aunt in the city for a few months. Even after returning to the village, she was staying with her maternal grandmother and not her own family, due to a stressful environment at home. R felt that she was neglected because she was the second consecutive girl child. This resentment emerged in the form of anger and aggression directed at her family members. Her parents complained that she did not help with the household chores and that she had to be reprimanded often.

The clinic team and visiting physician consistently counseled and sensitized the family members individually about the condition and challenges that R faced. Extra efforts were obtained to actively listen to R and support her emotionally. Gradually, we noted that this resulted in her gaining more confidence and the family members becoming more aware of her emotional needs and displaying greater empathy toward her. Her compliance with the medication became absolute. Her screen time reduced significantly with gentle but repeated counseling at each visit. She has been seizure free for 6 months. Improved compliance, family support, and improvement in the home environment, all appear to have contributed to this. Her mood appears uplifted and her attitude positive when she comes to the clinic. She has resumed her studies. Her family reports that she is much calmer and helps out at home. The image on the front cover (social pediatrics) shows the child, her grandmother and one of our team members.

In the 21 st century India, the status of children with epilepsy in rural areas is just not acceptable. In 2015, the World Health Assembly passed a resolution to address the treatment gap in epilepsy and exhorted the member states to integrate epilepsy management in primary care.[ 3 ] This case study illustrates the value of primary care that is closer to the families, affordable, responsive to their needs, and understand their circumstances, with context to the management of epilepsy in children. In this case, the primary healthcare service (our clinic), was able to diagnose, treat, and follow-up R, in conjunction with the referral hospital. If the child had been dependent only on the latter, she would have remained inadequately treated. Better coordination between two levels (e.g., appropriate back-referral from the specialist care to primary care) can definitely improve the treatment course.

A three-level assessment is the basic principle and practice of family medicine and primary care. It includes clinical assessment (all aspects needed to establish the diagnosis), individual assessment (thoughts, ideas, feelings, concerns, and fears of the concerned patient), and contextual assessment (with respect to family and the work context). In this case, the three-level assessment revealed the identification of anger of the child as well as lack of understanding and empathy of the family toward her. Supporting the child and counseling the entire family helped us address the underlying household stress and likely contributed to the improvement in compliance to treatment and improved clinical outcomes. It is well-established that stress can trigger convulsions and hamper seizure control in epileptic patients.[ 4 ]

Moving ahead, to meet the treatment gap for childhood epilepsy, there is an urgent need to equip primary care providers with skills to identify and manage, to ensure the availability of antiepileptic drugs, and to improve the coordination between specialist care and primary care. It is a moral imperative for pediatricians and neurologists to decentralize the management of epilepsy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Conflicts of interest.

There are no conflicts of interest.

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• Published: 20 October 2021

Autoimmune epilepsy due to N -methyl- d -aspartate receptor antibodies in a child: a case report

• Jithangi Wanigasinghe   ORCID: orcid.org/0000-0002-9413-8363 1 &
• Thashi Chang 2  

Journal of Medical Case Reports volume  15 , Article number:  516 ( 2021 ) Cite this article

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Introduction

Seizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis. We report a child with “pure” autoimmune epilepsy followed up for 7 years to highlight long-term effects of this epilepsy and the importance of early initiation and appropriate escalation of immunosuppression to achieve a good long-term outcome.

Case presentation

A previously healthy 5-year-old Sri Lankan boy presented with acute, frequent, brief focal seizures of temporal-lobe semiology without clinical and investigatory findings suggestive of central nervous system infection, tumor, structural abnormality, or metabolic causes. His epilepsy showed poor response to increasing doses and combinations of antiseizure medications. Further investigations detected N -methyl- d -aspartate receptor antibodies in serum, but not cerebrospinal fluid. Treatment with intravenous methyl prednisolone and maintenance on mycophenolate resulted in a rapid reduction, with seizure freedom achieved within 5–6 weeks. He relapsed when immunotherapy and anti seizure medications were reduced after seizure freedom for 24 months. This, and subsequent relapses, showed poor response to modification of anti-seizure medications, but treatment with immunotherapy (methyl prednisolone and rituximab) achieved complete seizure freedom. At 7-years of follow-up, he remains free of seizure for over 3 years, and has average academic performance and satisfactory quality of life.

Conclusions

Autoimmune epilepsy is a recognized independent entity. Diagnostic criteria have been suggested for its early recognition and confirmation of diagnosis. Early diagnosis and initiation of immunosuppression, with prompt escalation of treatment when necessary, remains key to good patient outcome.

Peer Review reports

Antibodies targeting neuronal surface proteins (NSAbs) are increasingly recognized in autoimmune central nervous system (CNS) disorders in which seizures are the main or an important feature. N -methyl- d -aspartate receptor (NMDAR) encephalitis and NSAb-associated limbic encephalitis are the two leading syndromes within this group [ 1 ]. However, it has been increasingly recognized that seizures of autoimmune etiology may occur independent of or predate syndromes of encephalitis [ 2 , 3 ]. It is considered specifically in those with drug-resistant epilepsies and epilepsies of unknown etiology [ 4 ]. The International League Against Epilepsy (ILAE) in their 2017 classification identified autoimmunity as one of the etiological subcategories of epilepsy [ 5 ]. The potential for effective treatment with immune therapy calls for its consideration in all patients presenting with poorly controlled epilepsy without a known etiology or a recognized epilepsy syndrome. We reported the first case of NMDAR-antibody encephalitis in Sri Lanka in 2012 [ 6 ] and now report the first case of autoimmune epilepsy (AEp) from Sri Lanka, a resource-restricted setting. We discuss the initial presentation and subsequent long-term epilepsy and neurocognitive outcome over the 7-year follow-up. We wish to highlight the importance of early recognition and treatment, and document the need for prolonged therapy in some patients.

Case history

A 5-year-old, previously well, Sri Lankan boy presented in 2014 with recurrent seizures manifesting as staring episodes with behavioral arrest, progressively increasing from 10 to about 40 seizures a day. Some of the seizures were associated with autonomic features such as retching, vomiting, and tachycardia. In between seizures, his behavior fluctuated between normalcy, irritability, and increased sleepiness. Apart from two bouts of loose stools at the start of the illness, he remained afebrile without features of meningeal irritation such as neck stiffness or Kernig’s sign of papilledema. His cranial nerves, motor and sensory system, and cerebellar examination was normal. Glasgow Coma Scale score was 15/15. He did not have any abnormal movements or psychiatric manifestations. In between seizures, his pulse rate ranged from 90 to 100 beats per minute and blood pressure was 90/60 mmHg. His hematological and biochemical tests included full blood count (11.3 × 10 3  μ/L) with normal differential), C-reactive proteins (< 5.0 mg/L), erythrocyte sedimentation rate (10 mm/hour), calcium (9.2 mg/dL), magnesium (1.9 mg/dL), and serum sodium (136 mmol/L) and potassium (4.3 mmol/L). Renal, liver, and thyroid functions [serum glutamic pyruvic transaminase (SGPT) 14 U/L, serum glutamic oxaloacetic transaminase (SGOT) 33 U/L, and blood urea 14 U/L], serum creatinine (36 μmol/L), triiodothyronine (T3) (3.44 ng/dL), and thyroxine (T4) (1.2 ng/dL) were normal. In his very first electroencephalogram, only intermittent slowing with theta and delta activity over right temporal and occipital region was noted. Subsequent video monitoring identified seizures with staring, grimace, and versive head movements. Ictal recording showed bilateral attenuation of background, evolving to fast activity and rhythmic theta over temporal, and then frontal region over the right side. No delta brush was noted in these records. Computerized tomography and subsequent magnetic resonance imaging (MRI) of the brain were normal. Although he was afebrile, a lumbar puncture was performed considering the possibility of a CNS infection. Cerebrospinal fluid (CSF) analysis did not show a pleocytosis, and protein level was within normalcy (22/mm 3 lymphocytes, 1/mm 3 polymorphs, sugar of 3.9 mmol/L, and protein of 30 mg/dL); bacterial antigens were negative, and culture yielded no growth. Herpes simplex viral screen was negative. Stool analysis and culture were negative for infection. The initial electroencephalogram revealed intermittent slow background activity, particularly in the temporal and occipital regions. No focal or generalized epileptic discharges were recorded. No extreme delta brush was noted. He was the firstborn, with birth weight of 3.45 kg at 38 weeks. He did not have any major illness prior to this admission. There was no significant family history of note. He was only attending mainstream school in grade 2 at the time of onset of his illness.

He was initially treated with cefotaxime (50 mg/kg/dose 6-hourly) and aciclovir (250 mg/m 2 8-hourly), which were discontinued when the CSF findings were normal, including herpes simplex virus 1 (HSV-1= viral polymerase chain reaction (PCR) in CSF. He was commenced simultaneously on intravenous followed by multiple oral antiseizure medications (ASMs). These were phenobarbitone given intravenously (20 mg/kg) and levetiracetam, carbamazepine, and clobazam given in escalating doses gradually via oral route. The dosages were 30 mg/kg/day, 18 mg/kg/day, and 5 mg/day, respectively, the seizures progressively reduced in frequency and duration to 10–15 brief seizures per day. He was discharged from hospital after 2 weeks on three ASMs, albeit with infrequent seizure recurrences.

Although ASMs were increased in dose and in different combinations, there was no improvement in seizure control. Within the next 4 weeks, escalation up to 30–40 brief seizures per day, both with and without altered consciousness was noted. His serology at this point was negative for antinuclear, thyroglobulin, and thyroid peroxidase antibodies. Serum lactate level was 1.2 mmol/L. Facilities for advanced metabolic screening or genetic panels for epilepsy were unavailable. A repeat CSF analysis showed normal lactate and glucose values. However, examination of paired serum and CSF revealed presence of N -methyl- d -aspartate receptor (NMDAR) antibodies in serum but not in CSF (live cell-based assay, Oxford, UK). At this point, on retrospective analysis, we note that he fulfilled Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score of 4 in the proposed autoimmune epilepsy diagnostic criteria described in 2017, in which a score of ≥ 4 predicts has a sensitivity of 98% and a specificity of 85% for prediction of neural specific antibody seropositivity [ 7 ].

He was treated with intravenous methylprednisolone 30 mg/kg/day for 3 days, which resulted in significant reduction of seizure frequency after the first pulse, followed by complete freedom of seizures after the second pulse a month later. He was maintained on oral prednisolone (2 mg/kg/day), followed by transition to mycophenolate mofetil (MMF) at a starting dosage of 600 mg/m 2 twice daily. Serial ultrasonography excluded a testicular teratoma. On retrospective analysis, he can be considered to have demonstrated a Response to Immunotherapy in Epilepsy and Encephalopathy (RITE2) score of 8, which confirms his condition to be a definite autoimmune epilepsy.

He remained seizure free for 3 years and continued schooling with no concerns, and his behavior continued to be normal. Subsequent two electroencephalograms done annually showed no abnormality. However, he relapsed when attempting to tail off ASMs and MMF (March 2017). The repeat MRI of brain reviewed carefully remained normal without evidence of focal cortical dysplasia, and cortical or subcortical hyperintensities. The temporal lobes remained unchanged in hyperintensity or in size. Intensified treatment with levetiracetam (gradually up to 50 mg/kg/day), carbamazepine (20 mg/kg/day), and clobazam (10 mg/day) was ineffective, but pulsed intravenous steroids (methyl prednisolone 30 mg/kg/day for 3 days) given two times with 1-month interval resulted in complete resolution of seizures. One year later, while on regular MMF and ASMs, he relapsed with similar seizures (August 2018). Electroencephalography (EEG) at this point showed interictal epileptic activity over the right pericentral (C4) region and brief subclinical ictal activity consisting of rhythmic theta over the F4, Fz, and C4 region. Repeat serum and CSF examination detected persistence of NMDAR antibodies in low titers in the serum. Seizure resolution was achieved once again with pulsed high-dose intravenous steroids. To achieve longer remission, he was treated with rituximab (August 2019) given as four weekly doses of 375 mg/m 2 . Currently, he is 12 years old and has remained seizure-free for more than 2 years since last relapse in 2018 (Fig. 1 ). He schools in an age-appropriate grade with average academic performance comparable to his peers in school. His quality of life, assessed using the Sri Lankan Health Related Quality of Life Index for school children (SLHRQ-S), an age-specific, primary caregiver proxy rated, validated questionnaire for Sri Lankan children with epilepsy [ 8 ], demonstrated a mean score of 84.13. Individual scores were 83.3 (physical), 80.8 (psychological), and 88.3 (social) for the respective domains. These were within normal range of the validation scores.

The temporal profile of seizure frequency since presentation and its response to immunotherapy. The x -axis indicates the time course from presentation (red arrow) to last review (red star) with time points of relapses. Time points of immunotherapy (black arrows, intravenous methylprednisolone; orange arrow, rituximab) are indicated above the graph

This report narrates the progression of a child with poorly controlled epilepsy, subsequently confirmed a definitive diagnosis of autoimmune epilepsy without encephalopathy, treated with progressive courses of immunotherapy resulting in normal childhood and intellectual growth with satisfactory quality of life. Early institution of immunotherapy and its timely escalation to achieve long-term remission is emphasized.

In the 2017 ILAE concept paper, “Epilepsy of immune aetiology” was considered for persons in whom “epilepsy was directly from an immune disorder in which the seizures are a core symptom of the disorder” [ 5 ]. Criteria and supportive features to diagnose AEp are presented in Table 1 [ 9 ]. Those with supportive criteria for AEp are divided into four groups: “definite,” “possible,” “probable,” and “unlikely” [ 10 ], which was subsequently modified to include a fifth category as “unknown AEp” [ 2 ]. In our patient, the diagnosis fulfilled “definite” criteria. Subsequent description of a predictive model in 2017 aided diagnosis, treatment, and prognostication of autoimmune epilepsy [ 11 ]. In this, an RITE2 score of ≥ 7 is associated with definite diagnosis of autoimmune epilepsy, with sensitivity of 88% and specificity of 84%; our patient had scored 8.

The role of immunity in epileptogenesis is related to different types of immunity [ 12 ]. A specific role has been shown for innate immunity, where activation of glial cells occurs owing to release of inflammatory molecules in brain injury, convulsive events, and some genetic epilepsies [ 13 ]. Similarly, the peripheral immune system mediated by lymphocytes has been shown to play a role in disruption of the blood–brain barrier [ 14 ]. Additionally, an increasing number of clinical and neuropathological observations have shown that activation of inflammatory processes occurs in a variety of focal epilepsies without infectious or immune-mediated etiology [ 12 ].

In our patient, it is the adoptive immunity that plays a role in epileptogenicity. There has been a massive expansion of knowledge, particularly over the past two decades, with demonstration of causality between autoimmunity and several seizure-related diseases [ 13 , 15 ]. Antibodies described in AEp include antibodies directed against intracellular proteins, such as glutamic acid decarboxylase 65-kilodalton isoform (GAD65), and NSAb directed against voltage-gated potassium channel (VGKC)-complex proteins, glutamate [NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)], and gamma-amino butyric acid-A (GABAA) and gamma-amino butyric acid-B (GABAB) receptors [ 13 , 16 ]. Antibody-negative AEp has been reported in about 36% of patients [ 17 ]. AEp was initially described as part of a syndrome of encephalitis, but has now been recognized as an entity of its own, as seen in our patient who did not develop encephalitis over a period of 7 years of follow-up. It could be argued that early initiation of immunotherapy may have prevented the progression to encephalitis, but this appears less likely given the long follow-up and quiescent disease during periods of waning immunotherapy.

Immunotherapy-responsive, CSF-negative but serum-positive NMDAR-antibody encephalitides have been previously reported, with the observation that serum antibodies were always higher than CSF in paired samples, and that, with time, previously present CSF antibodies may diminish with preserved serum antibodies [ 18 , 19 ]. Indeed, this may have been the case in our patient, in whom NMDAR antibodies were tested late during the first presentation, while in the second presentation the serum antibody response being of low titer may have had a paired CSF titer that was not detectable. Furthermore, it has been hypothesized that immunoprecipitation of the antibody at the blood–brain barrier may account for this discrepancy of seropositive but CSF-negative autoimmune encephalitis in some patients [ 20 ].

Features that would suggest an autoimmune etiology in epilepsy include young age at onset, previous normal health, multiple focal seizures occurring several times a day, temporal lobe semiology, and some specific seizure semiologies such as faciobrachial dystonia and paroxysmal dizzy spells, poor response to ASM, and negative brain imaging [ 17 , 21 ]. Seizure semiologies suggesting AEp include usually brief, focal seizures, with or without retained awareness, rapid recovery with minimal post-ictal features, and occur with higher frequency in sleep. They may be multifocal and may have changing semiologies [ 21 ]. Other factors to suspect AEp include personal or family history of autoimmune disorders, or recent or past neoplasia [ 21 ]. Literature on specifics of treatment of AEp and its long-term outcome are rare but immunotherapy, if instituted early, has shown to result in good outcomes in epilepsies associated with NSAbs [ 21 ]. Type of therapy is mostly guided by recommendations available for autoimmune encephalitis, that is, steroids, plasmapheresis, and intravenous immunoglobulins as first-line immunotherapy; rituximab, cyclophosphamide, MMF, and azathioprine as second line; and tocilizumab and bortezomib as third-line therapy [ 22 ]. Treatment strategies for new-onset refractory status epilepticus (NORSE) have been described. Prospective studies are needed for establishing treatment algorithms specific for autoimmune epilepsy. Initiation of immune therapy early for AEp (within 6 months of disease onset) is shown to result in favorable seizure control [ 11 ]. This was the case in our patient. Larger reports of long-term outcomes will be useful to understand the disease evolution and its behavior with immune therapy.

Our case report highlights the importance of early diagnosis of AEp, early treatment with immunotherapy, long-term clinical follow-up, and timely escalation and continuation of immunotherapy in achieving a good patient outcome, retaining intellectual development, and quality of life.

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Acknowledgements

We thankfully acknowledge Prof. Angela Vincent, Professor of Immunology, Nuffield Department of Clinical Neurosciences, University of Oxford, UK, for facilitating the immunodiagnostic assays.

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Jithangi Wanigasinghe

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JW—pediatric neurologist responsible for diagnosis and follow-up of the patient and writing up the case history. TC—neurologist contributed towards the follow-up of the patient and writing up the case history. Both the authors read and approved the final manuscript.

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Correspondence to Jithangi Wanigasinghe .

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Wanigasinghe, J., Chang, T. Autoimmune epilepsy due to N -methyl- d -aspartate receptor antibodies in a child: a case report. J Med Case Reports 15 , 516 (2021). https://doi.org/10.1186/s13256-021-03117-5

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First Child Brain Implant for Epilepsy Appears Successful

Summary: A groundbreaking implantable device has significantly reduced the frequency and severity of seizures in children with severe epilepsy, according to a new UK clinical trial.

The rechargeable device, attached to the skull, delivers constant electrical stimulation to the brain, allowing patients like Oran to experience dramatic improvements in quality of life.

This trial, known as the CADET pilot, is the first to measure this treatment for pediatric epilepsy and shows promise for broader applications. Further research will expand to more patients, aiming for a new standard in epilepsy treatment.

• Seizure Reduction : The device has significantly reduced seizure frequency and severity.
• Innovative Design : Mounted on the skull and rechargeable, it avoids frequent surgeries.
• Clinical Trial : The first UK trial to test this type of treatment for children with epilepsy.

Source: UCL

Oran, who had been having severe epileptic seizures for eight years and often needed resuscitation, was the first child in the UK to have this device implanted at Great Ormond Street Hospital in October 2023, when he was 12 years old.

Now eight months on, his seizures have dramatically reduced in frequency and severity thanks to the device.

The rechargeable device is mounted onto the skull and is attached to electrodes deep in the brain to reduce seizure activity. This is the first UK clinical trial measuring this type of treatment for children with epilepsy.

The CADET pilot (Children’s Adaptive Deep brain stimulation for Epilepsy Trial) will now recruit three additional patients with Lennox-Gastaut syndrome, which is funded by the Royal Academy of Engineering, before 22 patients take part in the full trial, which is being funded by GOSH Charity and LifeArc. The study is sponsored by UCL.

Martin Tisdall, (Honorary Associate Professor at UCL and Consultant Paediatric Neurosurgeon at GOSH), said: “Every single day we see the life-threatening and life-limiting impacts of uncontrollable epilepsy. It can make school, hobbies or even just watching a favourite TV show utterly impossible.

“For Oran and his family, epilepsy completely changed their lives and so to see him riding a horse and getting his independence back is absolutely astounding. We couldn’t be happier to be part of their journey. 

“Deep brain stimulation brings us closer than ever before to stopping epileptic seizures for patients who have very limited effective treatment options. We are excited to build the evidence base to demonstrate the ability of deep brain stimulation to treat paediatric epilepsy and hope in years to come it will be a standard treatment we can offer.” 

Oran’s story

Oran’s seizures started two weeks after his third birthday and up until the trial he hadn’t had a single day without a seizure.  

Many of his family all have a mutation in the SCNIB gene and have all dealt with seizures and epilepsy but all now have control of their seizures. 

Unfortunately, Oran’s epilepsy became more severe, and often meant he stopped breathing and needed resuscitation. This means Oran needed round-the-clock care, as seizures could happen at any time of day, and he was at a significantly increased risk of Sudden Unexpected Death in Epilepsy (SUDEP).   

Oran’s Mum Justine said: “Before the seizures began Oran was hitting all his milestones but as seizures became more severe, we lost more and more of Oran. From being a happy, energetic three-year-old, he struggled to engage in the world due to his medication and seizures – but he has still got his sense of humour.

“We’ve tried everything, but this is the first real shot we’ve been given in years, there has been no ‘what next’ until now.  

“Unless somebody takes the first step on a trial like this, there is never going to be a better and there has to be a better for our family.”

Oran had surgery in October 2023 to insert the device and once he had recovered from the procedure the device was “switched-on”, delivering constant electrical stimulation to Oran’s brain. Since then Oran and his family’s life has completely changed.

Oran’s Mum Justine said: “We’ve been switched on since December and we’ve seen a big improvement, seizures have reduced and are less severe. That’s been great but the quality of life improvement has been invaluable for Oran. 

“He’s a lot more chatty, he’s more engaged. He’s turned 13 and I definitely now have a teenager – he’s happy to tell me no. But that adds to his quality of life, when he can express himself better. 

“The team really do have your back. We never felt alone, from last August [when we joined the trial]. We were made to feel part of the team and so was Oran.

“The future looks hopeful which I wouldn’t have dreamed of saying six months ago. For Oran, having hope brings excitement. It makes the future brighter and more attainable even. I’m really pleased that Oran gets to experience that.” 

The CADET Pilot and Trial

Deep Brain Stimulation (DBS) is a treatment involving surgery to insert a small device which stimulates specific parts of the brain.

Unlike other DBS devices which are mounted on the chest with wires running up the neck to the brain, this device is mounted on the skull meaning the leads are less likely to break or erode as the child grows.  

This device is also rechargeable through wearable headphones, which can be used while watching a video or interacting with a tablet. This also means it does not require surgery to replace it every three to five years.

Professor Tim Denison, University of Oxford and Royal Academy of Engineering Chair in Emerging Technologies, lead engineer said:   “Our mission is to design pioneering research systems for exploring the treatment of intractable health conditions such as paediatric epilepsy. Oran is the first child in the world to receive this device and we are extremely pleased that it has had such a positive benefit for him and his family.”

The device targets the thalamus, which is a hub for electrical signals in the brain. It is hoped that the device will block electrical pathways and consequently stop seizures from spreading. The device also has settings for optimisation towards seizure patterns, which although not utilised in this trial, could be used in the future for patients with LGS.  

Funding: The CADET Pilot is funded by the Royal Academy of Engineering and sponsored by UCL. It is a collaboration between UCL, GOSH, King’s College London, the University of Oxford and a UK-based company: Amber Therapeutics.

The second phase of the trial will be jointly funded through GOSH Charity and LifeArc’s Translational Research Accelerator Grants.

About this deep brain stimulation and epilepsy research news

Author: Poppy Tombs Source: UCL Contact: Poppy Tombs – UCL Image: The image is credited to Neuroscience News

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• Published: 02 January 2024

Impact of prenatal, neonatal, and postnatal factors on epilepsy risk in children and adolescents: a systematic review and meta-analysis

• Imen Ketata   ORCID: orcid.org/0000-0002-3057-8028 1 , 2 ,
• Emna Ellouz   ORCID: orcid.org/0000-0002-2180-9445 1 , 2 &
• Rahil Mizouri 1 , 3  

Acta Epileptologica volume  6 , Article number:  1 ( 2024 ) Cite this article

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Epilepsy is a common, long-term neurological condition. Several previous case-control, cohort and cross-sectional studies have highlighted the role of prenatal, delivery and postnatal factors in the onset of epilepsy. In this systematic review, we evaluate the impact of these factors on the development of epilepsy in children and adolescents.

We searched PubMed and Google Scholar for literature on the relationship between prenatal, delivery and postnatal factors and the occurrence of epilepsy. The research was performed according to the PRSIMA 2020 flowchart and checklist. Data were extracted and pooled according to the ReviewManager 5.3 software using a random-effects model. Sensitivity analysis and subgroup analysis were used to evaluate the source of heterogeneity.

We identified 25 reports, including 45,044 cases with confirmed epilepsy and 2,558,210 controls. Premature birth is significantly associated with the risk of epilepsy (pooled OR = 4.36 [95% CI: 1.26–15.09], P  = 0.02). Smoking during pregnancy significantly increases this risk by 28% (pooled OR = 1.28 [95% CI:1.1–1.49], P  = 0.002). Furthermore, maternal epilepsy confers a pooled OR of 2.06 [95% CI:1.26–3.36]. Eclampsia is linked to a 16.9-fold increased risk of epilepsy. In addition, both pregnancy metrorrhagia and maternal infection are significantly associated with the epilepsy risk (pooled OR = 2.24 [95% CI: 1.36–3.71] and 1.28 [95% CI: 1.17–1.41], respectively). For delivery conditions, cord prolapse (pooled OR = 2.58 [95% CI: 1.25–5.32]), prolonged labor (> 6 h) (OR = 6.74 [95% CI: 3.57–12.71]) and head trauma (pooled OR = 2.31 [95% CI: 1.54–3.48]) represent a meaningful risk of epilepsy occurrence. Moreover, birth complications (OR = 3.91 [95% CI: 2.43–6.29]), low birth weight (pooled OR = 1.83 [95% CI: 1.5–2.23]) and male birth (pooled OR = 1.18 [95% CI: 1.06–1.32]) are associated with an elevated risk of epilepsy in childhood and adolescence.

Conclusions

Epilepsy in children and adolescents can be attributed to a multitude of intricate factors, notably those during pregnancy, delivery and the postnatal period. These findings highlight the crucial role of prenatal and postnatal care in reducing the impact of these factors on epilepsy occurrence.

Epilepsy is a common chronic neurological disorder marked by a pathological tendency toward recurring and unprovoked seizures [ 1 ]. Epilepsy poses a burden for parents, children, and medical doctors. The annual incidence of epilepsy is 61.4 per 100,000 persons [ 2 ]. Notably, the incidence of epilepsy is highest in the first year of life, with a rate of ~ 150 cases/100,000 persons per year [ 3 ]. Additionally, the occurrence of repeated and unprovoked seizures in childhood reaches 0.8% by the age of 15 [ 3 ]. For those aged under 20, epilepsy can affect 1% of the population [ 4 ]. The etiology of epilepsy can be divided into three types: cryptogenic, symptomatic, and idiopathic [ 1 ]. Meanwhile, the underlying risk factors for epilepsy in childhood and adolescence vary from those associated with epilepsy in adults [ 1 ]. A risk factor for epilepsy is defined as a situation that increases the occurrence of epilepsy [ 5 ]. Although certain risk factors are well documented, such as infection in the central nervous system and metabolic disorders, others remain poorly understood, notably those associated with pregnancy characteristics [ 5 ]. In fact, 20% of epilepsy cases have no identifiable causes [ 6 ]. While extensive research has been conducted to understand the etiology and management of epilepsy, there is a growing interest in investigating the roles of prenatal factors, delivery conditions, and postnatal factors in the development and progression of epilepsy. Understanding the risk factors can help prevent epilepsy onset, decrease epilepsy prevalence in children and adolescents as well as its associated comorbidities, and aid healthcare professionals in identifying high-risk populations and making plausible preventive strategies. Hence, the impacts of prenatal factors, delivery condition and postnatal factors on epilepsy are still a subject of debate, with different studies yielding conflicting results. In this systematic review, we aim to establish the relationships of prenatal characteristics, newborn delivery situations and postnatal conditions with the risk of epilepsy.

Study design

This systematic review and meta-analysis was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 [ 7 ]. It has not been recorded or registered in any registry site. The checklist is provided as a supplementary material .

Literature search

We searched for literatures on the relationship between perinatal/postnatal characteristics and the risk of epilepsy development in children and adolescents in PubMed and Google Scholar using the MeSH (Medical Subject Heading) terms with the assistance of the HeTOP site ( https://www.hetop.eu/hetop/ ). The terms identified were combined by Boolean search operators, and we used the following phrases for the search: “Epilepsy” AND (“prenatal” OR “prenatal care” OR “prenatal injuries” OR “pregnancy” OR “postnatal” OR “postnatal care” OR “postpartum” OR “postpartum care” OR “postnatal injuries”) AND (“child” OR “children” OR “childhood” OR “adolescent” OR “infant” OR “adolescence”). We specifically looked for case-control, cohort and cross-sectional studies. The last search was made in September 2023. No language or date restrictions were set during the search. Only studies in humans and full-free papers were included. The title and abstract of the collected papers were reviewed by two investigators to assess whether the records covered risk factors for epilepsy, and then the full-texts were evaluated for eligibility. In the event of a disagreement, a third author would rejudge the article.

Eligibility criteria

The inclusion criteria for literature are listed as below: (1) case-control, cohort or cross-sectional papers aiming to establish epilepsy risk factors in children or adolescents according to prenatal factors, newborn delivery conditions and postnatal characteristics; (2) free full-text; (3) reporting cases aged 0 to 20 years; (4) reporting epilepsy cases with normal birth without stroke, cerebral palsy, malformation or encephalopathy; and (5) reporting cases of confirmed epilepsy regardless of the seizure type (two or more unprovoked seizures or one seizure with abnormal electroencephalogram). Reports that included adult seizures or reported only one seizure with normal electroencephalogram or with hypoglycemia as a cause of neonatal seizure or febrile seizure were excluded.

We considered the following prenatal factors: maternal age, gestational age, maternal infection regardless of the type of infection, preeclampsia, gestational hypertension, gestational diabetes, eclampsia, smoking during pregnancy, maternal epilepsy, and pregnancy metrorrhagia regardless of the term. The factors that were considered to occur during newborn delivery conditions are as follows: cesarean section, forceps, breech presentation, cord prolapses, prolonged labor and meconium. Finally, the following factors were incorporated into the category of postnatal factors: birth complications (infection excluding nervous central system infection, respiratory distress, feeding or crying or breathing complications, Apgar < 6), male newborn (male gender), weight at birth under 2.5 kg and head trauma.

Quality of studies

The validated Newcastle-Ottawa quality assessment scale (NOS) was applied to assess the quality of reports [ 2 ]. Two investigators independently screened the quality of articles based on three key aspects: (i) participant selection, (ii) comparability of groups, and (iii) determination of the exposure of interest for a case-control study and the outcome of interest for a cohort study.

Data extraction

For each report, the following information was retrieved: first author, year of publication, country or region of the paper, study design, gender, number of cases, number of control groups, number of evaluated perinatal/postnatal factors in cases and controls and the odds ratio (OR) and 95% confidence interval (95% CI).

Statistical analysis

The ReviewManager 5.3 software developed by the Cochrane Collaboration was used to analyze the data and pooled the odds ratio. For the pooled effect, statistical significance was set at P  < 0.05. Meanwhile, when P  = 0.05, we defined it as statistical significant when the 95% CI did not contain 0. OR was combined for dichotomous data and DerSimonian and Laird's general inverse variance technique [ 8 ] was used to estimate the between-study variance, in which each study's weight was inversely proportional to its variance. Given the possibility of high variability among studies due to differences in study origins and populations, we chose a random-effects model over a fixed-effects model. To analyze the heterogeneity across the different studies, the Cochran Q test ( P  < 0.1 was deemed significant) and I 2 statistic were used. The heterogeneity was categorized as minimal ( I 2 value, 0–25%), low (25–50%), moderate (50–75%), and severe (> 75%). If considerable heterogeneity was found, a sensitivity analysis was performed by eliminating studies one by one to determine the likely causes of this heterogeneity. We ran a subgroup analysis if the sensitivity analysis failed to identify the source of heterogeneity. Because there were fewer than 10 combined studies in each risk factor analysis, it remained unnecessary to study the bias risk by funnel plot or Begg test, and Egger test [ 9 , 10 ].

Characteristics of the studies and evaluation of their quality

The initial search identified 6296 records from PubMed and Google Scholar. After screening the title, abstract, and full-text for eligibility, we identified 25 reports [ 5 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Figure  1 illustrates the flowchart of the selection procedure. Overall, we collected 45,044 cases with confirmed epilepsy and 2,558,210 controls. Epilepsy was confirmed by clinical criteria (two or more unprovoked seizures) or one seizure coupled with an abnormal electroencephalogram.

PRISMA flowchart showing the processes of literature search and screening for systematic review and meta-analysis

Each of the case-control studies included was evaluated using the NOS. One study received a score of 4 and another had a score of 5. Seven reports had a score of 6, 11 had score of 7 and four had a score of 8. Only one study had a score of 9. Table 1 summarizes the features of the included studies.

Meta-analysis

The number and the type of prenatal, newborn delivery and postnatal risk factors varied among studies. Some risk factors could not be pooled for analysis since their association with epilepsy was only reported in one study (alcohol consumption during pregnancy, vacuum extraction delivery, cephalic presentation and breastfeeding). Overall, we analyzed 20 factors (10 prenatal factors, 6 newborn delivery factors and 4 postnatal factors) for epilepsy occurrence in children or adolescents (age < 20).

• Prenatal factors

Gestational age (< 37 weeks or > 42 weeks)

Gestational age < 37 weeks or > 42 weeks was not significantly associated with the risk of epilepsy in children or adolescents with significant heterogeneity (pooled OR = 2.58 [95% CI: 0.68–9.73], P  = 0.16, I 2  = 100%, Cochran's Q test < 0.00001) (Fig.  2 a). Sensitivity analysis by excluding studies one-by-one showed no decrease in heterogeneity. Subgroup analysis revealed that premature birth was significantly associated with the risk of epilepsy (pooled OR = 4.36 [95% CI: 1.26–15.09], P  = 0.02). Meanwhile, the heterogeneity was also significant ( I 2  = 100%, Cochran's Q test < 0.00001). Furthermore, postterm was not linked to the risk of epilepsy (OR = 0.52 [95% CI: 0.16–1.77], P  = 0.3) (Fig.  2 b). The study by Attumalil et al. was excluded because it combined preterm and postterm births into a single variable [ 25 ].

Forest plot of the associations of gestational age, smoking, maternal epilepsy and eclampsia with the epilepsy risk. a Forest plot of the association between gestational age and the epilepsy risk. b Forest plot of the association between gestational age and the epilepsy risk after subgroup analysis. c Forest plot of the association between smoking during pregnancy and the epilepsy risk. d Forest plot of the association between smoking during pregnancy and the epilepsy risk after sensitivity analysis. e Forest plot of association between maternal epilepsy and the epilepsy risk. f Forest plot of the association between maternal epilepsy and the epilepsy risk after sensitivity analysis. g Forest plot of the association between eclampsia and the epilepsy risk. h Forest plot of the association between eclampsia and the epilepsy risk after subgroup analysis

Smoking during pregnancy was associated with an increased prevalence of epilepsy in children or adolescents with significant heterogeneity (37% vs 31.1%, pooled OR = 1.91 [95% CI: 1.01–3.61], P  = 0.05, I 2  = 84%, Cochran's Q test = 0.002) (Fig.  2 c). Meanwhile, after sensitivity analysis by excluding the study by Attumalil et al. [ 25 ], smoking during pregnancy was shown to significantly increase the risk of epilepsy in children or adolescents by 28%, with insignificant and negligible heterogeneity (38% vs 31.1%, pooled OR = 1.28 [95% CI:1.1–1.49], P  = 0.002, I 2  = 0%, Cochran's Q test = 0.6) (Fig.  2 d).

Maternal epilepsy

Maternal epilepsy significantly elevated the risk of epilepsy in children or adolescents, with significant heterogeneity (1.32% vs 0.4%, pooled OR = 2.62 [95% CI: 1.42–4.84], P  = 0.002, I 2  = 57%, Cochran's Q test = 0.03) (Fig.  2 e). After sensitivity analysis by excluding the study by McDermott et al. [ 16 ], this risk factor was significantly associated (1.15% vs 0.5%) with the epilepsy occurrence (pooled OR = 2.06 [95% CI:1.26–3.36], P  = 0.004, I 2  = 0%, Cochran's Q test = 0.64) (Fig.  2 f).

Eclampsia was not significantly associated with the risk of epilepsy in childhood or adolescence (0.6% vs 0.02%, pooled OR = 3.46 [95% CI: 0.13–89.52], P  = 0.45, I 2  = 82%, Cochran's Q test = 0.004) (Fig.  2 g). Sensitivity analysis by excluding studies one-by-one did not show a decrease in heterogeneity. Subgroup analysis revealed that study design (cohort study/cross-sectional study or case‒control study) represented the source of heterogeneity ( I 2  = 81.9%, Cochran's Q test = 0.02). Additionally, subgroup analysis showed that eclampsia was associated with a 16.9- fold increase of the risk of epilepsy in children/adolescents with insignificant heterogeneity in cohort/cross-sectional studies (prevalence of epilepsy, 0.85% vs 0.02%, pooled OR = 16.9 [95% CI: 2.05–139.53], P  = 0.009, I 2  = 48%, Cochran's Q test = 0.16) (Fig.  2 h).

Pregnancy metrorrhagia

Pregnancy metrorrhagia, regardless of the term, was significantly associated with the risk of epilepsy occurrence in children or adolescents (prevalence of epilepsy, 2.8% vs 0.8%, pooled OR = 2.24 [95% CI: 1.36–3.71], P  = 0.002, I 2  = 0%, Cochran's Q test = 0.83). The heterogeneity was low and insignificant (Fig.  3 a).

Forest plot of the associations of pregnancy metrorrhagia, infection, preeclampsia, gestational diabetes and hypertension, maternal age, and cord prolapse with the epilepsy risk. a Forest plot of the association between pregnancy metrorrhagia and the risk of epilepsy. b Forest plot of the relationship between maternal infection and the risk of epilepsy in children or adolescents. c Forest plot of association between gestational diabetes and the epilepsy risk. d Forest plot of the association between gestational hypertension and the epilepsy risk. e Forest plot of the association between gestational hypertension and the epilepsy risk after sensitivity analysis. f Forest plot of the association between preeclampsia and the epilepsy risk. g Forest plot of the association between maternal age and the epilepsy risk. h Forest plot of the association between maternal age and the epilepsy risk after sensitivity analysis. i Forest plot of the association between cord prolapse and the epilepsy risk

Maternal infection

Maternal infection was shown to raise the risk of developing epilepsy by 28% with negligible and insignificant heterogeneity (26.2% vs 22.1%, pooled OR = 1.28 [95% CI: 1.17–1.41], P  < 0.001, I 2  = 18%, Cochran's Q test = 0.29) (Fig.  3 b).

Other factors

Gestational diabetes (Fig.  3 c), hypertension (Fig.  3 d,e), preeclampsia (Fig.  3 f), and maternal age (Fig.  3 g,h) were not related to an increased risk of epilepsy in childhood or adolescence.

Newborn delivery factors

Cord prolapse.

Children/adolescents with epilepsy had a significantly higher prevalence of cord prolapse than the control groups (2.1% vs 0.3%) (pooled OR = 2.58 [95% CI: 1.25–5.32], P  = 0.01, I 2  = 0%, Cochran's Q test = 0.88) (Fig.  3 i).

Prolonged labor > 6 h

Prolonged labor > 6 h was not significantly connected to the risk of epilepsy in childhood or adolescence with significant heterogeneity (37% vs 35.5%, pooled OR = 3.4 [95% CI: 0.78–14.75], P  = 0.1, I 2  = 93%, Cochran's Q test < 0.00001) (Fig.  4 a). Sensitivity analysis by eliminating the study of Whitehead et al. [ 20 ] revealed a significant decrease in heterogeneity ( I 2  = 0%, Cochran's Q test = 0.71). Prolonged labor (> 6 h) was associated with a 6.74-fold increase of epilepsy risk (34.3% vs 7% pooled OR = 6.74 [95% CI: 3.57–12.71], P  < 0.001, I 2  = 0%, Cochran's Q test = 0.71) (Fig.  4 b).

Forest plot of the associations of prolonged labor, cesarean section, forceps use, and breech presentation with the risk of epilepsy. a Forest plot of the association between prolonged labor and the epilepsy risk. b Forest plot of the association between prolonged labor and the epilepsy risk after sensitivity analysis. c Forest plot of the association between cesarean section and the epilepsy risk. d Forest plot of the association between cesarean section and the epilepsy risk after sensitivity analysis. e Forest plot of the association between forceps use and the epilepsy risk. f Forest plot of the association between breech presentation and the epilepsy risk. g Forest plot of the association between breech presentation and the epilepsy risk after sensitivity analysis

Cesarean section (Fig.  4 c, d), forceps (Fig.  4 e), breech presentation (Fig.  4 f, g) and meconium (Fig.  5 a) were not associated with the risk of epilepsy in children or adolescents.

Forest plots of the associations of meconium, head trauma, birth complications, low birth weight and male gender with the epilepsy risk. a Forest plot of the association between meconium and the epilepsy risk. b Forest plot of the association between head trauma and the epilepsy risk. c Forest plot of the association between head trauma and the epilepsy risk after sensitivity analysis. d Forest plot of the association between birth complications and the epilepsy risk after subgroup analysis. e Forest plot of the association between low birth weight and the epilepsy risk. f Forest plot of the association between epilepsy risk and male newborns g Forest plot of the association between male gender and the epilepsy risk after sensitivity analysis

• Postnatal factors

Head trauma

Head trauma was correlated with an elevated likelihood of epilepsy in children or adolescents (9.5% vs 3.8%, pooled OR = 3.39 [1.84–6.25], P  < 0.001, I 2  = 74%, Cochran's Q test = 0.0007) (Fig.  5 b). The sensitivity analysis showed that after excluding the study by Cansu et al. [ 23 ], there remained a significant association between head trauma and epilepsy during childhood or adolescence, but with insignificant heterogeneity (9.5% vs 5.1%, pooled OR = 2.31 [95% CI: 1.54–3.48], P  < 0.001, I 2  = 33%, Cochran's Q test = 0.19) (Fig.  5 c).

Birth complications

Birth complications including feeding complications, crying, respiratory complications, infection (excluding central nervous system infection) and Apgar < 6, were significantly associated with a higher risk of epilepsy (12.4% vs 8.3%, pooled OR = 3.91 [95% CI: 2.43–6.29], P  < 0.001). Meanwhile, the heterogeneity was high and significant ( I 2  = 90%, Cochran's Q test < 0.00001). Sensitivity analysis did not show any decrease in heterogeneity. Subgroup analysis showed that the complication type (infection, respiratory distress) was not the source of heterogeneity across studies ( I 2  = 0%, Cochran's Q test = 0.41). Figure  5 d shows that the most significant risk factor was infection (OR = 19.49 [95% CI: 1.03–368.71], P  = 0.05]).

Low birth weight (< 2.5 kg)

Low birth weight significantly increased the risk of epilepsy in childhood or adolescence by 83% (18.2% vs 10.7%, pooled OR = 1.83 [95% CI: 1.5–2.23], I 2  = 0%, Cochran's Q test = 0.57) (Fig.  5 e).

The male gender was not associated with the risk of epilepsy with high heterogeneity (28.6% vs 50.7%, pooled OR = 0.7 [95% CI: 0.2–2.45], P  = 0.58, I 2  = 99%, Cochran's Q test < 0.00001) (Fig.  5 f). After sensitivity analysis by excluding the study by McDermott et al. [ 16 ], this risk factor was significant with negligible and insignificant heterogeneity (56% vs 50.7%, pooled OR = 1.18 [95% CI: 1.06–1.32], P  = 0.003, I 2  = 0%, Cochran's Q test = 0.41) (Fig.  5 g).

Table 2 provides a concise overview of the variables associated with epilepsy occurrence in childhood and adolescence, categorized by prenatal, delivery, and postnatal periods.

The present systematic review and meta-analysis is the first to evaluate factors associated with epilepsy occurrence in childhood or adolescence. Meta-analysis based on the 25 studies revealed that the prenatal risk factors for epilepsy included preterm birth (< 37 weeks), smoking during pregnancy, maternal epilepsy, eclampsia, pregnancy metrorrhagia regardless of the term, and maternal infection regardless of the term. Newborn delivery factors that increase the risk of epilepsy were cord prolapse, head trauma and prolonged labor > 6 h. Regarding postnatal factors, the risk of epilepsy was significantly elevated with birth complications, low-weight birth (< 2.5 kg), and male gender.

Prenatal factors were more commonly studied in various papers [ 16 , 18 , 19 , 20 , 21 , 28 , 33 ]. Of the studies addressing the relationship between preterm/postterm birth and the risk of epilepsy, we identified six case-control studies [ 14 , 16 , 24 , 25 , 28 , 33 ] and four cohort studies [ 19 , 20 , 21 , 33 ]. It is worth noting that these studies had comparable weights in terms of their impact on the overall results of the meta-analysis. Subgroup analysis and sensitivity analysis indicated that preterm birth doubled the risk of epilepsy in children or adolescents. The study conducted by Li et al. was in line with our findings, in which the risk was 2.16 times higher in preterm groups [ 35 ]. However, post-term birth was not associated with the risk of epilepsy. Several studies have indicated the association between preterm birth and epilepsy onset at a younger age is mediated by white matter gliosis and hypoxic-ischemic brain injury [ 13 , 36 ]. However, in our study, by excluding cerebral palsy and stroke, we emphasize alternative hypotheses. In fact, hippocampal sclerosis, impaired development of brain structure and a higher risk of infection in preterm groups have been reported to contribute to this association [ 13 ]. Given the limited data on the risk of epilepsy occurrence in children and adolescents with preterm, full-term, or post-term births, we were unable to compare the risk of epilepsy between those with preterm and full-term births, and between those with postterm and full-term births.

Our results showed that smoking during pregnancy significantly increased epilepsy occurrence by 28%. Smoking during pregnancy has been identified as the first environmental risk factor for epilepsy worldwide. Furthermore, it doubles the risk of seizures in children [ 37 ]. Among the few studies exploring the association of smoking at pregnancy with epilepsy onset at an early age, smoking has been found to induce placental inflammation, placenta damage, decreased blood flow in the placenta, remodeling of the uterine vasculature, low birth weight and fetal growth restriction [ 38 , 39 , 40 ], which may underlie the increased risk of epilepsy [ 38 , 39 , 40 ]. Additionally, tobacco contains various chemicals with proconvulsant effects such as ammonia, hexane, toluene and arsenic; however, it remains unknown whether these chemicals can cross the placental barrier to induce epileptic seizures in children [ 40 ]. Furthermore, some studies have reported brain structural changes associated with maternal smoking, such as cortical thinning in the lateral and perisylvian occipital cortices and a significantly smaller frontal lobe [ 40 , 41 ]. Moreover, maternal smoking affects the expression of many genes that are related with epilepsy [ 42 ]. Further research is required to elucidate the pathophysiology of smoking during pregnancy and the risk of epilepsy in children or adolescents.

In our study, children/adolescents born to epileptic mothers were 2.06 times more likely to have epilepsy. Out of the 6 studies that examined the association of maternal epilepsy with epilepsy onset in children or adolescents, two were cross-sectional and case-control studies [ 11 , 12 ], three were case-control studies [ 27 , 30 , 32 ] and one was a cohort study [ 20 ]. Notably, the two studies that exerted the most significant influence on the overall results were those by Ngugi et al. (2013) and Whitehead et al. (37.5% and 30.6% respectively) [ 12 , 20 ]. This finding was similar to those reported in various other studies [ 12 , 16 , 43 ]. In fact, maternal epilepsy was associated with an ~ 45% increased risk of epilepsy in the offspring [ 43 ]. Additionally, antiepileptic drug use during pregnancy is not an explanation for epilepsy occurrence in children/adolescents [ 44 ]. Another hypothesis that can explain this relationship is the genetic origin of epilepsy. In fact, epilepsy can be inherited from the mothers [ 43 ]. Additional studies are needed to fully establish the mechanism behind the association between maternal epilepsy and the risk of epilepsy in children and adolescents.

While preeclampsia was not identified as a risk factor for epilepsy, eclampsia was strongly associated with this risk and conferred an OR of 16.9. The variation in study design has been identified as the origin of heterogeneity in this analysis. Specifically, we integrated two cohort studies [ 19 , 20 ] along with one case-control study [ 32 ]. The research conducted by Whitehead et al. carried the greatest significance in the analysis, accounting for 40.1% of the total weight [ 20 ]. Eclampsia is a serious complication that can lead to epilepsy in children/ adolescents through various pathways. In fact, mothers can experience hypoxia, which can affect the normal development of the fetal brain and increase the risk of epilepsy. Rocca et al. showed that eclampsia increases the risk of generalized tonic-clonic seizures, partial seizures and absence seizures by 2 folds; however, this relationship is not significant [ 45 ]. This association may be explained by placental dysfunction, biological changes during eclampsia, premature birth and low-weight birth. Meanwhile, the exact mechanism remains unknown. As preeclampsia precedes eclampsia, prompt diagnosis and treatment of preeclampsia are needed to prevent eclampsia onset and its associated complications.

In our meta-analysis, we found that maternal infection, regardless of the type or term, is the leading cause of epilepsy in children and adolescents. Sun et al. showed that prenatal exposure to maternal cystitis, pyelonephritis, persistent diarrhea, coughing, and vaginal yeast infections is linked to an elevated risk of juvenile epilepsy [ 13 ]. Additionally, Casetta et al. found that maternal illness, notably upper respiratory infections, is linked to an elevated incidence of cryptogenic and idiopathic partial epilepsy [ 46 ]. While the pathophysiological mechanisms remain unclear, a plausible explanation is that the immune response and cytokines might potentially induce placental abnormalities and fetal brain damage. This finding highlights the importance of antenatal care to prevent infection and other pregnancy-related issues. Other factors related to epilepsy occurrence are prolonged labor and cord prolapse. These results could also be explained by the increased risk of infection. Cord prolapses can also lead to oxygen deprivation inducing brain injury [ 47 ]. Glass et al. showed a positive association between cord prolapses and seizure occurrence in children with an OR of 6.9 [95% CI: 5.9–8.1] [ 47 ].

The occurrence of epilepsy following head trauma has been extensively studied in both children/adolescents and adults [ 45 , 48 ]. We found that children/adolescents with a history of head trauma had a 2.31-fold increased risk of epilepsy. This finding aligns with the results of previous studies. In fact, this association can be linked to neuroinflammation, glial scars and brain injuries induced by head trauma.

After sensitivity analysis by excluding the study of McDermott et al. [ 16 ], the risk of epilepsy occurrence was shown to be higher in male newborns (56% vs 50.7%, pooled OR = 1.18 [95% CI: 1.06–1.32]). We excluded this particular study because it was the primary source of variations of results. Our findings are consistent with those of other studies [ 49 , 50 ]. Two potential explanations for our findings are as follows: sex differences in cerebral connectivity and in astrocyte structure [ 51 , 52 , 53 ]. The male brain typically has a larger amygdala and thalamus, while the female brain features a larger hippocampus, caudate nuclei, regional gray matter, and cortices [ 54 ]. Studies have shown that men exhibit stronger right-side connectivity in the amygdala, while women display more prominent left-side connections [ 54 ]. These sex-related distinctions in brain development, influenced by steroid hormones, impact the susceptibility to seizures [ 54 ]. Additionally, astrocyte structural variations may contribute to the sex difference in epilepsy, as cultured astrocytes and microglia from male and female rats display distinct functional responses and inflammatory marker expression [ 52 , 53 ]. Further research is needed to uncover the structural and neuroendocrine factors contributing to the sex differences in epilepsy.

In our study, birth complications including feeding complications, crying, respiratory complications, infection (excluding central nervous system infection) and Apgar < 6, are significantly associated with a higher risk of epilepsy occurrence (pooled OR = 3.91 [95% CI: 2.43–6.29]). This discovery aligns with previous research. Indeed, the presence of respiratory complications and an Apgar score below 6 increase the likelihood of neurodevelopmental issues and the risk of epilepsy development [ 55 ]. Hypoxia can result in energy depletion, oxidative stress, and inflammation, ultimately causing cellular death, which can contribute to the development of cerebral palsy and epileptic lesions [ 56 ]. Additionally, Frederik et al. discovered that the likelihood of an epilepsy diagnosis is elevated not only after central nervous system infections but also after a wide variety of peripheral infections [ 57 ]. Some infections can enhance the likelihood of experiencing seizures, particularly in individuals who already have a pre-existing susceptibility to epilepsy [ 58 ]. Infections, particularly those linked to inflammation, have the potential to alter the immune responses in the brain and disrupt the equilibrium of neurotransmitters [ 59 ], which may potentially elevate the likelihood of epilepsy development [ 58 ]. Conversely, adequate nutrition is essential for healthy brain development. Insufficient intake of vital nutrients can have adverse effects on brain growth and development, increasing the vulnerability to various neurological disorders, including epilepsy [ 59 ]. Moreover, difficulties with feeding can give rise to metabolic imbalances, such as hypoglycemia or disruptions in electrolytes. These metabolic irregularities can impact brain function and potentially provoke seizures [ 59 ].

We assume that multiple factors during the prenatal, delivery and postnatal periods interact synergistically and dynamically, elevating the risk of epilepsy in children or adolescents. For instance, eclampsia can contribute to premature birth and low-weight birth, which, in turn, can lead to frequent newborn infections and complications. Additionally, maternal infection can be linked to cord prolapse and prolonged labor. A better understanding of these factors is critical for advancing effective preventive and treatment measures to reduce the likelihood of epilepsy.

While our study is novel and represents the first meta-analysis on prenatal, delivery and postnatal factors, it has some limitations. First, our research included 25 studies with various study designs. Second, some data were unavailable, such as the exact term and the quantity or severity of pregnancy metrorrhagia, which prevented us from establishing a stronger relationship between these factors and epilepsy onset. Furthermore, the inclusion and exclusion criteria varied across the studies. The age of children/adolescents included in different studies ranged from 0 to 20 years, potentially introducing bias. Third, our study only examined children and adolescents, excluding adults. It is essential to acknowledge that the factors we examined may have implications for epilepsy in adulthood [ 60 , 61 ].

Epilepsy onset in children or adolescents is related to multiple and complex factors, according to the pregnancy and postnatal characteristics. Among these factors, eclampsia is the strongest prenatal risk factor, prolonged labor is the strongest delivery factor and child infection is the most influential postnatal factor. These findings call for improved awareness about these factors. Further studies are required to understand the physiological mechanisms underlying each of these factors.

Availability of data and materials

Data are available from the corresponding author upon reasonable request.

Abbreviations

Newcastle-Ottawa quality assessment scale

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

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Ketata, I., Ellouz, E. & Mizouri, R. Impact of prenatal, neonatal, and postnatal factors on epilepsy risk in children and adolescents: a systematic review and meta-analysis. Acta Epileptologica 6 , 1 (2024). https://doi.org/10.1186/s42494-023-00143-2

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Epilepsy in Children: From Diagnosis to Treatment with Focus on Emergency

Carmelo minardi.

1 Department of Anesthesiology, AOU Policlinico—Vittorio Emanuele, University of Catania Via S. Sofia, 78, 95123 Catania, Italy; [email protected] (C.M.); moc.liamg@illepacanimatrebor (R.M.); moc.liamg@78portsalav (P.V.); [email protected] (F.V.); moc.liamg@58pfos (S.P.); ti.ilacsit@ramtsa (M.A.); ti.ilacsit@otibarumoloap (P.M.)

Roberta Minacapelli

Pietro valastro, francesco vasile, sofia pitino, piero pavone.

2 Department of Pediatrics, AOU Policlinico—Vittorio Emanuele, University of Catania Via S. Sofia, 78, 95123 Catania, Italy; ti.tcinu@enovapp

Marinella Astuto

Paolo murabito.

Seizures are defined as a transient occurrence of signs and symptoms due to the abnormal, excessive, or synchronous neuronal activity in the brain characterized by abrupt and involuntary skeletal muscle activity. An early diagnosis, treatment, and specific medical support must be performed to prevent Status Epilepticus (SE). Seizure onset, especially in the child population, is related to specific risk factors like positive family history, fever, infections, neurological comorbidity, premature birth, mother’s alcohol abuse, and smoking in pregnancy. Early death risk in children without neurological comorbidity is similar to the general population. Diagnosis is generally based on the identification of continuous or recurrent seizures but Electroencephalogram (EEG) evaluation could be useful if SE condition is suspected. The main goal of therapy is to counteract the pathological mechanism which occurs in SE before neural cells are irreversibly damaged. According to the latest International Guidelines and Recommendations of seizure related diseases, a schematic and multi-stage pharmacological and diagnostic approach is proposed especially in the management of SE and its related causes in children. First measures should focus on early and appropriate drugs administration at adequate dosage, airway management, monitoring vital signs, Pediatric Intensive Care Unit (PICU) admission, and management of parent anxiety.

1. Introduction

The emergency department generally is the place where children affected by seizures receive first treatment and medical support. Proper skills of physicians are essential for early diagnosis, treatment, and adequate communication with the parents.

Seizures are defined as a transient occurrence of signs and symptoms due to the abnormal, excessive, or synchronous neuronal activity in the brain characterized by abrupt and involuntary skeletal muscles activity. The adjective “transient” in the definition, indicates a time frame with a clear onset and remission [ 1 ]. Status epilepticus (SE) is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of a mechanism, which leads to abnormally, prolonged seizures (for a time period of 5 min or more). It is a condition, which can have long-term consequences (especially if its duration is more than 30 min) including neuronal death, neuronal injury, and alteration of neuronal network, depending on the type and duration of seizures [ 1 ]. Febrile seizures are defined as critical seizures which occurs in children aged between 1 month and 6 years with temperature rise over 38 °C and without signs of infectious disease of the central nervous system (CNS) [ 2 ].

In 2014 the International League Against Epilepsy (ILAE) Task Force proposed the operational (practical) clinical definition of epilepsy, intended as a disease of the brain defined by any of the following conditions:

• At least two unprovoked (or reflex) seizures occurring >24 h apart
• One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years
• Diagnosis of an epilepsy syndrome

Epilepsy is considered to be resolved for individuals who had an age-dependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years [ 3 ].

The incidence of epilepsy varies between industrialized countries and developing ones. In Western countries, new cases per year are estimated to be 33.3–82/100,000, [ 4 ] in contrast to the maximum incidence of 187/100,000 estimated in developing countries [ 4 , 5 ]. In particular, recent studies showed that the maximum incidence occurs in the first year of age with a rate of 102/100,000 cases per year, just like the age range from 1 to 12 [ 4 ]; in children from 11 to 17 years old incidence is 21–24/100,000 cases [ 4 , 5 ]. Previous studies suggest that the total incidence of epilepsy is constant from 25 years, showing a slight increase in males [ 4 ].

In Italy, epilepsy incidence is 48.35/100,000 new cases per year and it is comparable with data recorded in the other industrialized countries. The peak of incidence occurs in children younger than 15 years old (50.14/100,000 new cases per year) and especially in the first year of life with an incidence of 92.8/100,000 new cases per year. In this regard, it should be taken into due account that the child’s immature CNS is more susceptible to seizures and at the same time refractory to the consequences of an acute attack. Finally, incidence is higher in males than in females [ 6 ].

From 2015 to 2017 the ILAE Task force revised concepts, definition, and classification of seizures, epilepsy, and Status Epilepticus. In the classification of seizures ( Table 1 ) levels can be skipped.

Classification of seizure types-expanded version [ 7 ].

Moreover, the diagnosis of epilepsy has become a multilevel process, which is designed to allow the classification of epilepsy in different clinical environments, meaning that different levels of classification will be possible depending on the available resources. After the presentation of seizures in a patient, the clinician makes a diagnosis working through several critical steps, excluding, however, any other possible causes for the clinical condition (epilepsy-imitators [ 8 ]). Indeed, the classification includes three levels: seizure types, epilepsy type, epilepsy syndrome ( Table 2 ). Where possible, a diagnosis at all three levels should be sought as well as the etiology of the individual’s epilepsy [ 9 ].

Classification of the epilepsies [ 9 ].

On SE, the most common causes in children are fever and infections of the CNS. Other causes include hyponatremia, accidental ingestion of toxic agents, abnormalities of the CNS, genetic and metabolic disorders (phenylketonuria, hypocalcemia, hypoglycemia, hypomagnesemia).

The pathophysiological course of SE in children depends on the absence of anatomical abnormalities and pre-existing predisposing conditions of CNS.

SE is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms which lead to abnormally prolonged seizures (after time point t 1 ). It is a condition that can have long-term consequences (after time point t 2 ), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures [ 1 ].

This definition is conceptual, with two operational dimensions: the first is the length of the seizure and the time point (t 1 ) at which the seizure should be regarded as an “abnormally prolonged seizure.” The second time point (t 2 ) is the time of ongoing seizure activity beyond which there is a risk of long-term consequences.

1.1. Classification of SE

Status Epilepticus is classified according to the International League Against Epilepsy (ILAE) guidelines [ 1 ] into four categories: semiologic ( Table 3 ), etiologic ( Table 4 ), EEG pattern ( Table 5 ), age-related ( Table 6 ).

Semeiologic classification of Status Epilepticus (SE).

Etiologic classification of SE.

Electroencephalogram EEG related SE classification.

Seizure age-related classification.

1.2. Risk Factors

The principal risk factors for seizures in children are correlated with: positive family history [ 10 ], high temperature [ 11 ], mental disability [ 12 ], delayed discharge from NICU or premature birth [ 10 ], mother’s alcohol abuse and smoking in pregnancy doubles the risk of seizure incidence [ 13 ]. Moreover in 30% of children in which the first episode of seizures occurs, the probability of recurrent episodes is increased.

Instead risks factors of recurrent febrile seizures include: small age and duration of first episode of seizures, low temperature during the first episode, positive familiar history for febrile seizures in a first degree relative, short timeframe from temperature elevation, and seizure onset [ 10 ].

Patients with all these risk factors show more than 70% probability of a recurrent episode of seizures; in contrast patients with none of them have a probability of a recurrent episode of seizure lower than 20% [ 14 , 15 ].

1.3. Mortality

The mortality rate in people affected by epilepsy is 2–4 times higher than the rest of the population, and 5–10 times higher in children.

Early death risk in children without neurological comorbidity is similar to the general population and lots of deaths are not related to seizures themselves but to the neurological preexisting disability.

This risk increase is a consequence of: lethal neuro-metabolic alterations, systemic complications (consequence of neuro-disability), death directly related to seizures.

This group includes sudden unexpected death in epilepsy (SUDEP), that represents the most common cause of death related to epilepsy in children: it is uncommon but death risk increases if epilepsy persists until the young-adult age [ 12 , 13 ].

Other causes of death could be: seizure related (ab-ingestis), natural causes related (brain tumors), non-natural causes (suicide or accidental death).

Global mortality rates are between 2.7 and 6.9 death per 1000 children every year; SUDEP related mortality in children is about 1.1–2 cases/10,000 children per year [ 13 ].

1.4. Pathophysiology

The exact mechanism of seizure onset is unknown. There could be either a deficit of neuronal inhibition or an excess of excitatory stimuli. Most authors suggest that the onset of seizures depends on a deficit in the neuronal inhibition, in particular γ-Aminobutyric acid (GABA) deficit [ 16 ], the most important neurotransmitter of CNS; alternatively it depends on the alteration of the GABA function which determines a prolonged and high intensity stimulation.

Other studies, in experimental animal models, demonstrated that N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid, both glutamate receptors, the most important excitatory receptor of CNS, are involved in seizure physiopathology [ 16 ]. Febrile seizures occur in young children whose convulsive threshold is lower.

Children are more exposed to frequent infections like: respiratory high tract infections, otitis media, viral infection where children present high temperature [ 17 , 18 ]. Animal models suggest the central role of inflammatory mediators like IL-1 that could cause an increase in neuronal stimulation and the onset of febrile seizures [ 17 ].

Preliminary studies in children seem to confirm this hypothesis but its clinical and pathological meaning is still unknown. Febrile seizures could underline a severe pathological process like meningitis, encephalitis, and cerebral abscess [ 17 ].

Viral infections seem to be involved in the pathogenesis of seizures. Recent studies show that HHSV-6 (Human herpes simplex virus-6) and Rubivirus could be found in 20% of patients affected by febrile seizures for the first time [ 18 , 19 ]. Finally, other reports also suggest that Shigella related gastroenteritis has been associated with febrile seizures [ 20 ].

2. Diagnosis

The most challenging condition, which happens to be treated during an emergency, is the status epilepticus. Because of this, diagnosis and treatment sections are focused on this clinical state.

Clinical presentation in status epilepticus varies. It depends on the type of seizures, stage, and previous state conditions of the pediatric patient. Diagnosis is based on the identification of continuous or recurrent seizures, and it is easy to recognize during the clinical manifestation.

After persisting status epilepticus, despite disappearance of motor manifestations, it is difficult to exclude non-epilepticus continuous status.

A complete instrumental evaluation can be requested in case of first clinical presentation of SE, or in case of complicated SE, comorbidity, and in infants [ 21 ].

Literature suggests that in pediatric age routine, serologic examinations are not justified, because of the low frequency of abnormal values. The only abnormal test in more than 20% of patients is hypoglycemia [ 21 ].

In patients with status epilepticus and body temperature above 38.5 °C, a lumbar puncture could be considered, when infectious etiology is suspected. Temperature, leukocytosis, and pleocytosis in cerebro-spinal fluid may be present in SE even if infections in the central nervous system are absent.

American Association of Pediatrics (AAP) guidelines in medical management of pediatric patients with febrile seizures do not suggest performing diagnostic tests routinely, including lumbar puncture, except if it is requested by the state of the condition [ 19 ].

A lumbar puncture is firmly recommended in all patients under one-year age that present temperature and seizures [ 14 ].

American College of Emergency Physician (ACEP) guidelines suggest that the lumbar puncture should be requested in cases of immune-compromission, clinical signs of meningitis, persisting seizures, and recent CNS infections [ 19 ].

Computerized Tomography (CT) is requested during the first clinical presentation of seizures and in clinical conditions that could increase the risk of complications.

An encephalic CT without contrast media is the first test recommended to diagnose neoformations, head injury, hemorrhages, and/or cerebral infarcts. A CT with contrast media could be necessary to confirm suspected diagnosis of brain tumors or subdural hematoma.

A study has shown that pediatric patients with complex febrile seizures and normal clinical examination, and pediatric patients with febrile seizures without evident acute cause in anamnesis rarely have a positive CT. So this examination could be postponed [ 14 ].

The use of EEG in the emergency room is restricted to differential diagnosis. EEG should be considered every time SE is suspected.

Research of SE causes should proceed in parallel with treatment, and good knowledge is required because optimal treatment includes the prevention of recurrent SE.

3. Treatment of SE

The main goal in therapy during SE is to stop seizures before neural cells are irreversibly damaged. SE is difficult to control as the duration increases; for this reason, it is important to start an early target pharmacological treatment.

The most important thing in pharmacological treatment is rapid implementation of a clear protocol, adjusting doses to the weight of the patient. Therefore, in the case of refractory SE the treatment should be as fast as possible.

The 2017 ILAE recommendations [ 22 ] relate pharmacological treatment to time. So three time-points are described here:

• T1 is the period in which the emergency treatment of SE should be started.
• T2 is the period after which seizures could result in neural cell death, modifications in neural networks, and functional deficiency.
• T3 is characterized by refractory SE: SE continues despite the treatment. In this case, hospitalization and PICU admission are recommended.

There is also a period called T4. It is characterized by a super refractory SE, that continues for more than 24 h. In this case, it is necessary to have advanced life support.

3.1. General Support Measures

The first approach in SE should focus on airway management and adequate ventilation and circulation. It is important to safeguard patients from injuries caused by uncontrolled movement. It is also important to place the patient in a lateral position to prevent inhalation, and position a peripheral venous catheter.

Monitoring vital signs (heart rate, blood pressure, oxygen saturation, and temperature) is essential to evaluate the course of SE. A rapid blood test should be done to recognize hypoglycemia or poisoning [ 23 ].

Most of the drugs used to treat SE suppress respiratory drive. Therefore, it is important to take precautions to recognize and treat their side effects.

3.2. Anticonvulsant Drugs in Emergency

Guidelines in the treatment of SE give the basis to manage SE optimally in the emergency room; 80% of patients with simple convulsion respond to initial treatment, including those who will develop an SE.

The most important factor is to use effective drugs at the appropriate dosages. Therapy can be optimized by choosing the correct sequence of drugs ( Table 7 ).

Pharmacological therapy.

Benzodiazepines are considered the first choice in the initial treatment of seizures and SE in pre-hospital emergency care. They increase inhibition of GABA receptors, have rapid onset and are effective in 79% of patients in SE.

Barbiturates increase inhibition of GABA receptors. Fenobarbital is one of the most commonly used. However, it is difficult to manage because of its long half time.

Phenobarbital and Phenytoin are considered second-class drugs to treat seizures and SE, and they are usually administrated when benzodiazepines fail. Side effects are: sedation, respiratory depression, and hypotension. So airway management and cardiovascular treatment should be considered as priority [ 24 ].

Phenobarbital is the antiepileptic drug often used in neonatal seizures, although Phenytoin is equally effective.

Valproic acid is important in refractory SE (stage 2 in 2017 ILAE recommendations) [ 22 ].

Propofol is an anesthetic agent with anticonvulsant activity. It is used in refractory SE. The disadvantages are the short half-life and rapid metabolism that can make convulsions worse. The main side effects are respiratory depression and hypotension because of myocardial depression [ 25 , 26 ]. High doses of Propofol in continuous rate infusion should be limited to a short period, generally no more than 24–48 h in order to prevent Propofol infusion syndrome [ 27 ].

4. Remarks on Convulsions and Pediatric SE

Pediatric patients with head injury and 3–8 Glasgow Coma Scale (GCS) risk developing seizures and it is recommended to prevent them by prophylaxis. Most seizures in pediatric patients and teenagers can be treated by oral valproic acid. In particular, juvenile myoclonic epilepsy (JME) can take advantage of it. Young adults that do not sleep much and drink alcohol can show generalized seizures in the morning [ 28 ]. In these patients, valproic acid is a very good drug to use in emergency [ 29 ].

5. Parents Training for the Future

Parents must be prepared to know what to do if their children show seizures. They should call the emergency number if seizures persist for more than 10 min, and if the post convulsive state lasts longer than 30 min. Moreover, they should be informed about the benign nature of febrile seizures. In fact they are not connected to neurological problems or physically slow development. Parents must pay particular attention to their sons, because studies have proved that febrile seizures are inclined to be recurrent in a family [ 30 ].

6. Conclusions

Pediatric seizures and SE are emergencies that request early and effective treatment. Everyone is aware that for all this the patients outcome can be improved using antiepileptic drugs at the appropriate dose. Further studies should focus on the management of a pediatric patient’s convulsions or SE through improvement of treatment taking into due account that airway management is priority in pediatric patients with seizures or SE; children with febrile seizures in anamnesis must be evaluated through neurological examination and monitoring of mental development, causes of fever must always be investigated and treated, other causes of seizures must be excluded, and parent anxiety must be controlled.

Author Contributions

C.M., R.M., P.V., F.V., S.P., P.P., M.A., P.M. reviewed the literature, critically discussed various aspects of epilepsy in pediatric patients and read the manuscript; C.M. and P.M. wrote the manuscript and prepared the tables.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

• Adam L. Numis   ORCID: orcid.org/0000-0002-1594-9812 1 , 2 ,
• Gilberto da Gente 1 ,
• Elliott H. Sherr 1 , 2 &
• Hannah C. Glass 1 , 2 , 3  

Pediatric Research volume  91 ,  pages 896–902 ( 2022 ) Cite this article

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The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known.

Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches.

Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy.

Conclusions

In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy.

We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures.

Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy.

Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

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Introduction.

Neonatal seizures due to brain injury (acute symptomatic seizures) are typically self-limited in the neonatal period, but as many as 25% of survivors will later develop recurrent unprovoked seizures (epilepsy) and approximately 10% of survivors are diagnosed with infantile spasms (IS). 1 , 2 , 3 , 4 Known risk factors for epilepsy after acute symptomatic seizures include severity of neonatal encephalopathy, low birth weight, low blood pH on the first day of life, abnormal neuroimaging, multifocal (versus focal) seizures, >1 medicine to control neonatal seizures, status epilepticus, persistently abnormal electroencephalogram (EEG) background, and seizure spread to the contralateral hemisphere. 5 , 6 , 7 Yet, not every neonate with risk factors will develop epilepsy, and the most vulnerable children cannot be prospectively identified. Furthermore, little is known about the pathophysiologic mechanisms of epileptogenesis following neonatal brain injury.

Next-generation sequencing has transformed our understanding of epilepsy genetics; hundreds of genes have potential association with recurrent seizures. Pathogenic variants can result in syndromes with epilepsy as the core symptom (e.g., SCN1A and Dravet syndrome), cause brain malformations and other physical or developmental anomalies associated with epilepsy (e.g., TSC1 / TSC2 and tuberous sclerosis complex), or alter inherent seizure susceptibility (e.g., CACNA1H ). 8 , 9 Whereas the utility of whole-exome sequencing (WES) with targeted gene analysis has been important for establishing diagnosis and prognosis of severe early-onset epileptic encephalopathies, 10 , 11 the contribution of gene variants to epileptogenesis after acute symptomatic neonatal seizures is not known, but we hypothesize that genetic risk factors play a role.

In this pilot case–control study, we examined WES in family trios from children affected by acute symptomatic neonatal seizures with and without post-neonatal epilepsy to determine whether there is an increased incidence of de novo and inherited loss-of-function mutations in known genes associated with epilepsy versus genes in an unrelated group of disorders, in this case those associated with coronary artery disease (CAD). We evaluated remaining WES variants using pathway analysis to evaluate differential enrichment of functional biologic processes in those with and without post-neonatal epilepsy. We hypothesize that de novo and inherited mutations in established and candidate genes that may alter risk of epilepsy after acute symptomatic neonatal seizures have a higher prevalence in children with epilepsy after acute symptomatic seizures compared to children without post-neonatal epilepsy.

This was a case–control study of WES family trios including a proband with a history of acute symptomatic seizures and aged at least 2 years and their biological mother and father. Ten children who developed epilepsy in childhood (cases) were compared with 10 children who remained free from epilepsy until at least 2 years of age (controls). All participants were recruited from the University of California, San Francisco (UCSF) Benioff Children’s Hospital. First, we recruited among participants enrolled in the Neonatal Seizure Registry at UCSF (NCT02789176), a multicenter prospective cohort study of neonates with acute symptomatic seizures. 12 Additional cases of children with epilepsy after neonatal acute symptomatic seizures were enrolled from a clinic-based convenience sample of patients seen at the UCSF Pediatric Epilepsy Center of Excellence or the Neuro-Intensive Care Nursery follow-up program from 3/2019 to 5/2019. We included children with a history of acute symptomatic seizures with onset <44 weeks postmenstrual age. Seizure etiology included, but was not limited to, hypoxic–ischemic encephalopathy (HIE), ischemic stroke, or cerebral hemorrhage. 13 We excluded children with risk for epilepsy independent of seizures and underlying brain injury (including, but not limited, to inborn errors of metabolism or brain malformations), as well as transient cause for seizures (e.g., mild hypoglycemia, hyponatremia, hypocalcemia with normal neuroimaging), and neonatal-onset epilepsy syndromes. The study protocol was approved by the UCSF Committee on Human Research and both biologic parents of each child provided written informed consent.

Clinical data abstraction

Hospital records were reviewed to determine demographic data, seizure etiology, continuous video EEG results, neuroimaging results, and antiseizure medication (ASM) use. Neonatal seizure etiology was determined by a pediatric neurologist (A.L.N. and H.C.G.) after reviewing clinical and imaging records and was classified as follows: HIE, ischemic stroke, intracranial hemorrhage, infection, hypoglycemia, or other. Seizure classification (clinical, electroclinical, or electrographic only) and burden in the Neuro-Intensive Care Nursery was determined by a review of the clinical report by a board-certified clinical neurophysiologist (A.L.N.). A neonate was considered to have seizures without EEG confirmation (i.e., clinical seizures) if they had paroxysmal events with a semiology consistent with neonatal seizures warranting treatment with an ASM before EEG monitoring was initiated. Subclinical or electrographic only seizures were defined as sudden, abnormal EEG events with repetitive and evolving pattern with amplitude ≥2 μV and duration ≥10 s without a clinical correlate. 14 Seizure burden was defined as follows: (1) no electrographic seizures, (2) rare electrographic seizures (less than seven), (3) many isolated electrographic seizures (seven or more), (4) frequent recurrent seizures not meeting criteria for status epilepticus, and (5) status epilepticus. 15

Outpatient follow-up records from primary care, neurology clinic, subspecialty visits, and the Intensive Care Nursery Follow Up Program were reviewed to determine the presence of seizures after the neonatal period. The primary outcome, post-neonatal epilepsy, was defined per International League Against Epilepsy (ILAE) 2014 criteria. 16 IS was defined according to ILAE criteria as seizures characterized by “epileptic spasms… a sudden flexion, extension, or mixed extension–flexion of predominantly proximal and truncal muscles” occurring in clusters and during infancy. Intractable epilepsy was defined as failure of two appropriate ASMs.

Genetic sampling, whole-exome capture, and sequencing

Participants were contacted for participation from 5/2019 to 8/2019. After consenting to participate in this study, families were mailed validated self-collection and assisted saliva-based collection kits (DNA Genotek OGR-500 and OGR-575). Samples was returned and stored at 4 °C until processing at the UCSF Institute for Human Genetics Genomics Core. DNA was isolated using the Qiagen Gentra Puregene system. DNA was fragmented using a Covaris LE220 to a size range of ~350 bases and assembled into a library constructed with unique dual indexes compatible with NovaSeq. As previously described, exome sequencing was performed using the NimbleGen Human SeqCap EZ Exome (v3.0) Kit according to the manufacturer’s protocol in 12/2019. 17 Libraries were pooled into a capture reaction that contains biotinylated oligonucleotide probes to target specific regions of interest. The biotinylated probe/target hybrids were pulled down by streptavidin-coated magnetic beads to obtain libraries highly enriched for the target regions. WES was performed using the Illumina NovaSeq 6000. Sequencing data were transferred using gzipped fastq format for analysis.

Exome data analysis

In our primary analysis, we restricted WES data to 200 genes found in commercially available epilepsy gene panels (GeneDx “Comprehensive epilepsy panel,” Gaithersburg, MD; and, Invitae “Epilepsy Panel,” San Francisco, CA; Table  S1 ). These panels include the eight genes curated by the Clin Gene Epilepsy Gene Curation Expert Panel in 2018 as having definitive or strong evidence of an epilepsy association ( ALG13 , CHD2 , DNM1 , KCNA2 , KCNQ2 , KCNT1 , SCN8A , and STXBP1 ) as well as eight genes with limited or disputed evidence ( CACNA1H , CACNB4 , EFHC1 , GRIN2D , MAGI2 , RYR3 , as well as SCN9A , and SRPX2 ). 18 The remaining genes in these panels have varying, at times contradictory, levels of evidence for an epilepsy association; however, we included these genes in our analyses given our exploratory aim and hypothesis that established and candidate epilepsy association genes, more so than genes associated with an epilepsy syndrome (i.e., SCN1A , KCNQ2/3 ), will increase the risk of epilepsy after neonatal acute symptomatic seizures. As a sensitivity analysis, we restricted WES data to a subset of 89 non-overlapping genes associated with CAD as previously described. 17 In a secondary analysis, we analyzed the complete WES dataset.

Our analytic pipeline followed “The Broad Institute’s Best Practices” guidelines for discovering putative variants and utilizes the Genome Analysis Toolkit (software version 2014.23.1.7-10) in combination with BWA-mem, Picard Tools, and SAM Tools as previously described. 19 In brief, after aligning the DNA read sequences to the GRCh37 reference build using BWA-mem, Picard Tools were used to identify and remove PCR duplicates, add read group information, and sort alignment files using modules Mark Duplicates, SortSam, and AddOrReplaceReadGroups, respectively. All variants were compared to parental samples to determine whether they were de novo or inherited from the biological mother or father.

For all analyses, variants were required to be within the transcript region (identified as a missense/nonsense single-nucleotide variant or out-of-frame small insertion or deletion (indel)) or within 3 base pairs of a splice site, be below a population frequency of 0.1% (as determined by 1000 Genomes and the Exome Variant Server 6500), a CADD score of >20, and genotype quality (GQ) of >50. For de novo analyses, all variants had a minimum of 10 reads with at least 3 showing the alternate variant in addition to an allelic balance >0.25. In targeted gene sets, allelic balance requirement was lowered to 0.1. In both analyses, parents were required to have a minimum GQ of 50 with no reads showing the alternate variant. For inheritance analysis in targeted gene panels, variants were separated into subgroups of transmitted (passed from parent to child) or non-transmitted (not passed from parent to child).

Variant classification

Each variant was annotated against a reference transcript. In silico modeling with Polyphen-2 (HumDiv and HumVar) was used to assess protein structure/function and evolutionary conservation. Variants were classified as “pathogenic,” “likely pathogenic,” “benign,” “likely benign,” or a “variant of uncertain significance” (VUS), according to the American College of Medical Genetics and Genomics (ACMG) guidelines. 20 Pathogenic variants were confirmed with visual inspection in IGV. The biological relevance of all affected variants was evaluated using the Online Mendelian Inheritance in Man database, ClinVar, gnomAD, and Uniprot. 21 , 22 , 23 , 24

KEGG pathway enrichment analysis

De novo pathogenic, likely pathogenic, and VUS identified in the complete WES dataset were analyzed for functional properties using Kyoto Encyclopedia of Genes and Genomes (KEGG) searches. 25 , 26 , 27 Given the limitations of power with sample size, we limited pathway analysis to KEGG orthology and excluded categorization of human disease (09160) and organismal systems (09150) apart from the nervous system (09156).

Statistical analyses

Statistical analyses were performed using the Stata 15.1 software. Chi-square test was used to compare categorical variables and t test for continuous variables. Significance was determined as p  < 0.05.

We conducted WES in 20 trios, of whom 10 probands developed post-neonatal epilepsy at a median age of 16 months (interquartile range (IQR) 5–24 months). Among 26 potential participants enrolled in the Neonatal Seizure Registry at UCSF, 2 of 3 (67%) with post-neonatal epilepsy and 10 of 23 (44%) without post-neonatal epilepsy enrolled in this investigation. 28 The remaining cases of children with post-neonatal epilepsy were identified in a clinic-based convenience sample, with 8 of 10 (80%) consecutive patients enrolling. Median age of follow-up in children without epilepsy at the time of enrollment into this study was 3.2 years (IQR 2.5–3.8 years), with 70% of children having >3 years of follow-up and no child having >5 years of follow-up. The median age at the time of WES was 3.5 years (IQR 2.4–17.8 years). Children with post-neonatal did not differ from those without epilepsy with regards to duration of follow-up at the time of enrollment ( p  = 0.51) or at the age when next-generation sequencing was performed ( p  = 0.50).

In children with post-neonatal epilepsy, five were diagnosed with IS, of whom two had HIE, one had ischemic stroke, one had intracranial hemorrhage, and one had infection as cause of their acute symptomatic neonatal seizures. Children with and without post-neonatal epilepsy did not differ by sex, mode of delivery, gestational age, birth weight, neonatal seizure burden, or seizure treatment in the neonatal period (Table  1 ). The underlying etiologies for neonatal seizures were similar between groups, with HIE, ischemic stroke, and intracranial hemorrhage accounting for the majority in children with and without post-neonatal epilepsy.

Targeted gene analysis (epilepsy gene panel)

Among the 200 established and candidate epilepsy association genes, we identified 29 variants: 4 de novo variants in 3 genes and 25 inherited variants in 23 genes. Six (21%) of the 29 variants were classified as pathogenic or likely pathogenic in 6 participants (Table  2 ), 17 (58%) as benign or likely benign, and the remaining 6 (21%) as VUS (Table  S2 ). All inherited variants were also found in a parent without a history of epilepsy. There was no difference in variant type (missense, nonsense, frameshift, splice site) between children with and without post-neonatal epilepsy.

The six pathogenic/likely pathogenic variants in epilepsy-associated genes were more common among children with post-neonatal epilepsy (5/10 children, 50%) as compared to those without (1/10, 10%). Children with epilepsy had 9.0 times the odds of having a pathogenic/likely pathogenic variant compared to those without post-neonatal epilepsy (95% confidence interval (CI) 0.6–472, p  = 0.05). In contrast, in a similar analysis using known CAD genes, one child with post-neonatal epilepsy and one child without epilepsy had a pathogenic/likely pathogenic variant identified (odds ratio (OR): 1.0, 95% CI: 0.01–87, p  = 1.0, Table  S3 ). Similarly, there was no difference in the number of families with non-transmitted pathogenic or likely pathogenic variants in epilepsy or CAD genes (in each analysis, one parent of a child with epilepsy and no parent of a child without epilepsy had pathogenic variants identified; Table  S4 ).

Among children with post-neonatal epilepsy, two pathogenic/likely pathogenic variants and two VUS were in candidate genes that may alter susceptibility to epilepsy ( CACNA1H , CASK , RBFOX3 , and RYR3 ), 9 , 29 , 30 , 31 and three pathogenic/likely pathogenic variants were in established and candidate genes that are associated with epilepsy syndromes with incomplete penetrance and variable expressivity ( KCNT1 , MAGI2 , and PRRT2 ). 32 , 33 , 34 Three of the five children with IS had pathogenic/likely pathogenic variants. Among the children without post-neonatal epilepsy, the one pathogenic variant identified was in CPA6 , a candidate gene that may result in epilepsy with onset through 12–18 years of age, outside the window of follow-up in this cohort. 32 , 35 , 36 , 37

WES analysis with KEGG orthology

Seventeen de novo pathogenic/likely pathogenic variants or VUS were found in genes without a known association with epilepsy (Table  3 ). Seven of the variants were found in 6 children with post-neonatal epilepsy and 10 of the variants were found in 6 children without post-neonatal epilepsy (OR 1.0, 95% CI 0.11–8.4, p  = 1.0). There was no difference between groups with respect to variant type (missense, nonsense, frameshift, splice site). An exploratory KEGG orthology analysis demonstrated that children who developed post-neonatal epilepsy had a relative enrichment in variants associated with the nervous system, including synaptic transmission, and those without epilepsy had a relative enrichment of variants associated with cell growth and death, in particular the ubiquitin system (Fig.  1 ).

KEGG orthology categorization of pathogenic variants on whole exome.

In this pilot case–control study of 20 trios of children with a history of acute symptomatic seizures with and without subsequent epilepsy, WES with targeted analysis of established and candidate epilepsy-associated genes identified six de novo or inherited pathogenic/likely pathogenic variants in six children. Children with epilepsy had increased odds of having a pathogenic/likely pathogenic variant compared to those without post-neonatal epilepsy. There was no difference in the odds of having a pathogenic/likely pathogenic variant in CAD genes, or a difference in the odds non-transmitted variants in epilepsy or CAD genes between groups, suggesting that the findings are related to the development of epilepsy. We propose that the “double hit” of a pathogenic/likely pathogenic variant in an established or candidate epilepsy association gene and acute symptomatic seizures in the neonatal period increases risk of epilepsy more than acute symptomatic seizures alone. Our findings add to the growing literature about the use of genetic testing to understand epilepsy. Targeted gene panels and WES are considered important for defining diagnosis and understanding prognosis of a wide range of non-acquired epilepsies from severe early-onset epileptic encephalopathies to focal epilepsies in adulthood. 10 , 11 , 38 If replicated in a larger cohort, our findings suggest that genetic testing may also enable us to better predict the subsequent risk of epilepsy after acute neonatal symptomatic seizures.

Identification of variants in established and candidate epilepsy association genes may also inform ASM management. For example, in our cohort, two children with intractable post-neonatal epilepsy had variants in the CASK and CACNA1H genes. The CASK gene encodes the protein calcium/calmodulin-dependent serine protein kinase regulating alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking. 39 , 40 Perampanel is a selective, non-competitive AMPA agonist and with potential to rescue CASK-mediated disruption. The CACNA1H gene encodes a subunit of the voltage-dependent calcium channel complex. CACNA1H-associated epilepsy has demonstrated responsiveness to lamotrigine or ethosuximide therapy. 9 , 41 In our cohort, children with variants in these genes have at least weekly seizures, have failed three or more ASMs to control their seizures, and had not yet trialed possible precision medicine therapies. Targeted gene analysis may inform providers regarding ASM selection, providing an individualized approach to epilepsy management.

WES with gene set enrichment analysis to compile an individual’s genetic variant burden in pathways that are over- or under-represented can inform exploration of molecular processes that may facilitate or suppress epileptogenesis. 42 , 43 In our secondary analysis, WES analysis demonstrated a similar number of de novo variants throughout the exome among those with and without epilepsy after acute symptomatic neonatal seizures. Exploratory KEGG orthology analysis revealed differences in the relative enrichment of variants in key molecular processes between groups. Notably, those with post-neonatal epilepsy had enrichment of variants associated with synaptic transmission while those without post-neonatal epilepsy had enrichment of variants in cell growth and death pathways, in particular the ubiquitin pathway. This finding is compelling, given that epilepsy is caused by an imbalance between neuronal excitation and inhibition and alterations in synaptic transmission contribute to the disease process, although the impact of the pathogenic variants in our cohort is not known. Ubiquitin is a regulatory protein associated with neurologic disease through its effects on neural development and maintenance via post-translational modifications and resultant protein degradation. 44 Levels of the brain-enriched enzyme ubiquitin C-terminal hydrolase-L1 can predict neuronal injury after traumatic brain injury, ischemic brain injury, and neonatal HIE. 45 , 46 These data, while under-powered, can inform future evaluation of single-nucleotide polymorphisms that alter function within these pathways with the aim of improving our understanding mechanism of epileptogenesis after brain injury. 47

This single-center study has limitations. First, the small sample size limits immediate generalizability. Second, although we only studied children whose epilepsy onset was before age 2 years, the duration follow-up for children without epilepsy was relatively short (2–5 years), and so these children may yet develop epilepsy. 48 , 49 For example, the pathogenic variant in the CPA6 gene identified in our control group (children without epilepsy through at least 2 years of age) can increase epilepsy susceptibility into late childhood; 38 , 39 , 41 longer duration of follow-up could result in re-classification of this proband. Third, gene sequencing has inherent limitations in predicting the consequences of DNA variants on protein function. While our methods use ACMG criteria for variant classification so as to use best practices and limit future re-categorization, these are only applicable to the six genes with definitive or strong evidence for an epilepsy association. 18 , 20 By applying these methods to candidate epilepsy genes, we may be incorrectly categorizing variants as “pathogenic” or “likely pathogenic” for an epilepsy association and biasing our results.

If the role of targeted gene analysis to predict post-neonatal epilepsy after acute symptomatic seizures is supported with future studies, epilepsy gene panels could enhance established prediction paradigms that currently incorporate clinical, EEG, and radiologic data, allowing for improved counseling of providers and families. 6 , 7 , 13 , 48 , 49 Future investigations of genetic sequencing in larger cohorts, perhaps leveraging existing databases of neonates with acute symptomatic seizures with longer follow-up duration, may test this hypothesis with multivariate modeling of genetic data along with known risk factors of post-neonatal epilepsy. WES in larger cohorts also will allow robust bioinformatic analysis and hierarchical clustering to visualize and explore functional pathways associated with epilepsy after acute symptomatic seizures. 50 , 51

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Acknowledgements

The authors thank Renée Shellhaas, MD for her review of the manuscript and Rebecka Craig for her contributions to the investigation. This study was supported by a Marcus Program Seeding Bold Ideas Award.

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Adam L. Numis, Gilberto da Gente, Elliott H. Sherr & Hannah C. Glass

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Adam L. Numis, Elliott H. Sherr & Hannah C. Glass

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Numis, A.L., da Gente, G., Sherr, E.H. et al. Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures. Pediatr Res 91 , 896–902 (2022). https://doi.org/10.1038/s41390-021-01509-3

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Epilepsy surgery found to reverse cognitive decline in children

13 September 2024

There is a significant improvement in the cognition of children who have undergone brain surgery for epilepsy, finds a new study by UCL researchers.

The study, published in Brain , retrospectively analysed the records of 500 children who had undergone epilepsy surgery at Great Ormond Street Hospital (GOSH) between the years of 1990 and 2018.

Information was extracted from IQ tests and tests of academic attainment performed many years before and after surgery. Most children studied had shown declines in all areas of neuropsychological functioning, in comparison with their healthy peers, in the time leading up to surgery.

A range of factors have been attributed as causes of cognitive impairments in children with epilepsy, including the underlying cause of their epilepsy, ongoing seizures, and use of antiseizure medication.

The researchers found that children were on a downward cognitive trajectory in the years before they underwent surgery (losing on average 1-4 IQ points per year). Based on this observation, it could be expected that, without intervention, they would have continued on this downward trajectory.

However, the researchers found that the surgery not only stopped the downward trajectory of neuropsychological functioning for children who became seizure free, but also reversed it. These children continued to show improvements in cognitive functioning over the course of their long-term follow-up. There was an additional benefit in that children were able to be weaned off anti-seizure medication.

Lead author, Dr Maria Eriksson said: “We have known for many years that brain surgery for drug-resistant epilepsy can be transformative in achieving seizure freedom for children, but we have known less about how surgery impacts cognition, particularly in the long-term.

“This study shows us the extent to which children’s cognition can continue to improve in the years after surgery, allowing them to catch-up with their peers.

“We hope this knowledge will support clinicians and help to empower children and their families when making an informed decision on whether to proceed with brain surgery for epilepsy.”

This is the first study of its kind to have measured changes in cognitive ability over such a long-term period – more than 10 years before and 15 years after surgery – and across all types of epilepsy.

In previous studies, where analysis was only conducted directly before and directly after surgery, cognitive ability appeared unchanged in children. However, lead scientist Dr Maria Eriksson and the team at UCL Great Ormond Street Institute of Child Health found that when children were followed up many years after surgery, freedom from seizures because of surgery led to an uplift in children’s cognition, including problem-solving, memory and academic performance.

The study was supported by the National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre (NIHR GOSH BRC).

Researchers and scientists who took part in the study have received support and funding from GOSH Charity, the Child Health Research Studentship (funded by NIHR GOSH BRC), the Sigrid Jusélius Foundation, the Rosetrees Trust, Epilepsy Research UK and Wellcome.

• Research in  Brain
• Dr Maria Eriksson's academic profile
• UCL Great Ormond Street Institute of Child Health
• UCL Population Health Sciences
• Credit:  Thitima Uthaiburom  on iStock

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Poppy tombs.

E: p.tombs [at] ucl.ac.uk

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Global development and adaptive behaviour in children with early-onset epilepsy: a population-based case-control study

Affiliations.

• 1 Research Department, Young Epilepsy, Lingfield, Surrey, UK.
• 2 UCL Great Ormond Street Institute of Child Health (ICH), London, UK.
• 3 Child Development Centre, Crawley Hospital, Crawley, West Sussex, UK.
• 4 Great Ormond Street Hospital for Children NHS Trust, London, UK.
• 5 Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden.
• 6 Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, VT, USA.
• PMID: 29862505
• DOI: 10.1111/dmcn.13926

Aim: There are limited population-based data on global development and adaptive behaviour in children with early-onset epilepsy. The aims of this study were: (1) to identify the prevalence of deficits in global development and adaptive behaviour experienced by children with early-onset epilepsy; (2) to identify factors associated with such deficits; and (3) to compare the relationship between measures of neurodevelopment in the group with epilepsy to a group without epilepsy who had other neurological or neurodevelopmental difficulties.

Method: The Sussex Early Epilepsy and Neurobehaviour study is a prospective, community-based study involving children (1-7y) with epilepsy. We undertook comprehensive psychological assessment with participants, including measures of global development and adaptive behaviour. We compared the children with epilepsy with a sex, age, and developmentally-matched group of children without epilepsy who had neurodevelopmental or neurological difficulties using correlation matrices.

Results: Forty-eight children (91% of the eligible population) with epilepsy underwent assessment. Seventy-one per cent of children displayed delayed global development (<2SD) and 56% showed significant deficits (<2SD) in adaptive behaviour. Our analysis revealed that non-white ethnicity and use of polytherapy were independently associated with decreased scores on measures of global development and adaptive behaviour. The correlations between measures of developmental functioning were higher in children with epilepsy than in those without.

Interpretation: Children with early-onset epilepsy frequently have difficulties with global development and adaptive behaviour. The higher correlations between neurodevelopmental measures in children with epilepsy suggest that the profile in children with epilepsy is different. This may have significant implications for both neuropathology and interventions.

What this paper adds: Children with early-onset epilepsy are at significant risk of intellectual disability. Developmental impairment is associated with use of polytherapy but not with any seizure parameters. Developmental profiles in young children with epilepsy differ from other conditions.

© 2018 Mac Keith Press.

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• Global development and adaptive functioning in children with epilepsy. Kirsch AC, Zaccariello MJ. Kirsch AC, et al. Dev Med Child Neurol. 2019 Feb;61(2):110-111. doi: 10.1111/dmcn.13941. Epub 2018 Jun 21. Dev Med Child Neurol. 2019. PMID: 29926470 No abstract available.

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Landmark study reveals epilepsy surgery reverses cognitive decline in children

First-of-its-kind study

A first-of-its-kind study, led by researchers from GOSH and the UCL Great Ormond Street Institute of Child Health (UCL GOS ICH) has found that brain surgery for epilepsy is linked to significant improvement in children’s cognition.

The team, many of whom are funded by Great Ormond Street Hospital Charity (GOSH Charity), reveals that surgery not only halts but in fact reverses the decline in neuropsychological functioning for these children.

The study retrospectively analysed the records of children with drug-resistant epilepsy who received surgery at GOSH. It is the first time a study has measured changes in cognitive ability over such a long-term period — more than 10 years before and 15 years after surgery — and across all types of epilepsy.

Exploring the findings

In previous studies, where analysis was only conducted directly before and directly after surgery, cognitive ability appeared unchanged in children. However, this study reveals that when children were followed up many years after surgery, becoming seizure free as a result of surgery led to an uplift in children’s cognition, including problem-solving, memory and academic performance, which continued to improve over time.

The research team analysed the data of 500 children who had undergone epilepsy surgery at GOSH between the years 1990 and 2018. Information was taken from IQ tests and tests of academic attainment performed many years before and after surgery.

Most children studied had shown declines in all areas of neuropsychological functioning in the time leading up to surgery. However, those who became seizure-free through surgery showed higher neuropsychological performance post-operation and continued to show improvements in cognitive functioning over their long-term follow-up.

“We hope this will empower children and their families.”

Honorary Research Fellow at UCL Great Ormond Street Institute of Child Health, Dr Maria Eriksson said:

“We have known for many years that brain surgery for drug-resistant epilepsy can be transformative in achieving seizure freedom for children, but we have known less about how surgery impacts cognition, particularly in the long-term.

This study shows us the extent to which children’s cognition can continue to improve in the years after surgery, allowing them to catch up with their peers. We hope this knowledge will support clinicians and help to empower children and their families when making an informed decision on whether to proceed with brain surgery for epilepsy.”

GOSH Charity’s Director of Impact and Charitable Funding, Dr Aoife Regan, said:

“This promising new research demonstrates the enormous impact that world-class treatment for conditions like epilepsy can have on a child’s life.

“At GOSH Charity, we do everything we can to give seriously ill children the best chance and the best childhood possible and are proud to have supported many of the researchers who have contributed to this important study in their work to transform the lives of children with epilepsy.”

Will’s story

Will was a healthy, intelligent child who was in the top sets at school. A talented sailor, he had his sights set on the Olympics and was competing in national and international events.

However, shortly before Will’s thirteenth birthday he experienced a tonic seizure while on holiday in Paris. After spending some time at hospitals in France, Will was repatriated by ambulance to GOSH.

Will said: “My consultant Martin Tisdall said I’d experienced a brain injury caused by a burst cavernoma, which are abnormal clusters of vessels containing bubbles filled with blood.

“At that point it felt like I couldn’t do anything anymore. I was paranoid I would have another seizure, and if I did who would be there to help me? The tiredness was really annoying. I would do an hour in school, come home, sleep and then get up and do another hour.”

Mum Cherie adds: “Will completely lost his childhood. He didn’t go out, go to the park or cinema and didn’t go to prom. He became a recluse. There were talks about sending him back a year at school. I think it’s fair to say it sent him into quite a dark place.”

One of the biggest frustrations for Will was how his condition had impacted his sailing. Luckily, Sailability, a sailing organisation for disabled people, gave Will the chance to get back on the water.

Will said: “We found Sailability and I even ended up sailing with the Invictus team. My risk assessment said I had to wear a helmet and collared life jacket so that if I had a seizure and fell in the water I’d be able to float on my back. I found sailing harder because I was always so tired. The eight-hour days became near impossible as I needed a nap in the middle.”

"The surgery was transformational."

Clinicians and Will’s family agreed to wait before considering surgery, but Will soon decided that life as he knew it was too difficult and wrote to GOSH about how he was feeling. He was scheduled in for surgery 10 weeks later.

Will said: “Martin Tisdall talked it over in a fashion that I understood and the fact that they would be removing the cavernomas, as well as a section of my temporal lobe. He was great and honest about the risks.”

Cherie said: “The surgery was transformational, even in the shortest time. By the end of the day his bandage was off, and the following day he got up and walked. We were all flabbergasted.”

Will, now considered previously epileptic adds: “I wasn’t allowed to sail for a while but within six weeks I was back on the boat. It felt weird the first time as I had lost my confidence and balance. My brain still had to re-knit and I could feel little air bubbles in my brain.

“At school I struggled at first because I’d forgotten bits. I had a reader and scribe in my exams and that really helped me. I was better able to function, and my recall was better. I am expecting my A Level results this August and have an offer from Bournemouth Uni, Brighton Uni and Surrey Uni for paramedic science. I’m hoping to go to Bournemouth.”

Cherie said: “What we’re seeing now I couldn’t have envisaged three years ago. We’re living with the new Will, living his best life. He passed his driving test in six weeks, he’s one of the youngest power boat instructors and at one point was the youngest day skipper in the country. There are minor challenges but if you consider how challenging life was versus life now, it’s amazing.”

Will said: “Sailing is my safe space. When I’m having a bad day and I go sailing, it’s just me, the water and the boat. Sailing is now my hobby — I teach sailing and power boating courses on the weekend to earn pocket money, and I’m going to keep it like that. The America’s Cup have paramedics on their safety boats. That would be my dream job.”

Aaron’s story

Aaron was a few months old when he experienced his first seizure.

Mum Christina said: “He started shaking – I'd never seen anything like it. I called an ambulance and they told me he was having baby convulsions, but over time it got a lot worse. It was an awful time. When you look back you don’t realise how you got through it. I feel for any parent going through that.”

He was later transferred to GOSH, and the family spent a large part of his childhood travelling back and forth between the hospital and their home in Kent.

“At school, Aaron was always behind others his own age and struggled quite a bit. He also missed so much school due to his seizures.”

Aaron said: “Before surgery I had around five or more seizures a day and often couldn’t go out and play with my friends. It was the worst time of my life. I never wanted to leave home and after every seizure it would take me such a long time to get over it. I couldn’t live life the way I was.” Aaron’s worst seizure left him in a coma, which Christina described as “terrifying”.

"I’m so glad I had the surgery."

The family was told that Aaron was eligible for brain surgery to treat his epilepsy, and in 1993 he underwent his first operation.

Christina said: “When we were told about the surgery we were as frightened as you could be, but we knew we had to do it. Waiting for the operation to end felt like a lifetime. The first operation went well, but it was decided that a second procedure was necessary, and that took place a few years afterwards. We couldn’t have imagined a better outcome.”

Aaron said: “I’m so glad I had the surgery. Life is so much better and I feel so happy. I can do so much more – I’ve got a job at a gym and have barely missed a day of work since I started my first job aged 17. I have a season ticket for Fulham FC and regularly go and watch matches with my friends.”

Christina said: “Aaron’s cognition has come on so much. His memory is incredible, he’s so dedicated to his job and has a lovely group of friends - he's so sociable. I can’t describe how much epilepsy surgery has changed our lives – not just Aaron’s life, but the entire family's.”

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