TheChristian M. Korff,Immune MD, a Russell C. Dale, MD,System PhDb in Pediatric Seizures and Epilepsies abstract The relation between the immune system and epilepsy has been studied for a long time. Immune activation may precede or follow the appearance of seizures. Depending on the situation, the innate and acquired immunity may be involved to various degrees. The intense, ongoing research has opened encouraging management and therapeutic perspectives for a significant number of patients suffering from seizures. These include the use of various drugs and less conventional approaches with anti-inflammatory or immunomodulatory properties. Data for children remain scarce, however, and the practical implications of recent discoveries in the field remain to be identified formally. The aim of this review is to present current knowledge of the role of immunity in relation to seizures, with a particular emphasis on clinical data available in childhood. More specifically, various autoantibodies involved in autoimmune encephalitis and epilepsy and general pathophysiological hypotheses on the role of immunity in seizure genesis are discussed, specific epilepsy syndromes in which autoimmune a components have been studied are summarized, workup recommendations Pediatric Neurology Unit, University Hospitals of Geneva, Geneva, Switzerland; and bThe Children’s Hospital at and therapeutic options are suggested, and finally, open questions and Westmead Clinical School, University of Sydney, Sydney, future needs are presented. New South Wales, Australia Drs Korff and Dale conceptualized and designed the study, drafted the initial manuscript, and approved 4 the final manuscript as submitted. The risk of new onset seizures is psoriasis. In some of these situations, DOI: https:// doi. org/ 10. 1542/ peds. 2016- 3534 particularly high during childhood. specific autoantibodies (auto-ABs) The average prevalence of nonfebrile have been involved in the development Accepted for publication Apr 17, 2017 recurrent seizures in developed of neurologic signs and symptoms, Address correspondence to Christian M. Korff, countries is between 3.5 and 5 per yet precise pathophysiological MD, Pediatric Neurology Unit, Child and Adolescent 1,2 Department, University Hospitals of Geneva, 6 Rue 1000 children, and the cumulative mechanisms remain to be identified. ∼ Willy-Donzé, CH 1211 Geneva 14, Switzerland. E-mail: incidence rate of epilepsy by age 15 In addition, immune function has [email protected] years old is 0.8%. Despite huge been intensively studied in numerous PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, advances in the field of imaging primary neurologic diseases, which 1098-4275). and genetics that have improved include the common epilepsies Copyright © 2017 by the American Academy of the understanding of underlying Pediatrics for which an underlying etiology5 pathophysiological mechanisms, remains to be discovered. The FINANCIAL DISCLOSURE: The authors have > 60% of seizure disorders remain3 acknowledgment of the importance indicated they have no financial relationships without an identifiable cause. of immunity in the pathophysiology relevant to this article to disclose. N In a recent, large population-based of the epilepsies is illustrated by the FUNDING: No external funding. study ( = 2518034), children with current intention of the International POTENTIAL CONFLICT OF INTEREST: The authors autoimmune diseases had an overall League Against Epilepsy to include have indicated they have no potential conflicts of interest to disclose. 5 times higher risk of epilepsy when 4 a new immune etiological category compared with age-matched controls. in its proposal for6 an Organization This risk was consistently heightened of the Epilepsies. Overall, the To cite: Korff CM and Dale RC. The Immune System in all of the 12 autoimmune diseases ongoing research in that field in Pediatric Seizures and Epilepsies. Pediatrics. 2017;140(3):e20163534 considered, including some not known opens encouraging management to affect central nervous system (CNS) and therapeutic perspectives for a function such as myasthenia gravis or significant number of adults with Downloaded from www.aappublications.org/news by guest on September 27, 2021 PEDIATRICS Volume 140, number 3, September 2017:e20163534 STATE-OF-THE-ART REVIEW ARTICLE Korff and Dale https://doi.org/10.1542/peds.2016-3534 September 2017 The Immune System in Pediatric Seizures and Epilepsies 3 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 1 Auto-ABs Against Neuronal Antigenic Targets Reported in Children With Seizures Intracellular Antigens Surface Antigens GAD Onconeural VGKC-complex NMDA-R AMPA-R Folate-R GABAA-R GABAB-R Glycine-R DPPX-6 (including Caspr-2) Suggestive LE, ataxia, LE, ataxia LE, focal Psychiatric LE (limited Early-onset LE, multifocal LE (limited Stiff-person Prodromal associated type-1 (limited seizures, disturbance, data in refractory encephalitis data in syndrome, weight loss, features diabetes data in neuromyotonia movement children) seizures, (limited children) PERM, LE, gastrointestinal children) disorder, developmental data in focal dysmotility, sleep delay and/or children) encephalitis psychiatric difficulties, regression, manifestations, dysautonomia microcephaly brainstem involvement Prognosis in Unfavorable Unknown Favorable with Favorable with Unknown Unknown, may Unknown Unknown Favorable Favorable with children immune immune improve with immune therapy or therapy or with folinic immune therapy associated- associated- acid therapy tumor tumor (often removal ovarian) removal Important 12– 15 16 17– 23 24– 29 38 30– 32 11 33 34– 36 pediatric references Auto-ABs found predominantly in adults are not presented. ABs against leucine-rich glioma inactivated protein have not yet been reported in children with seizures. AMPA, α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid; DPPX-6, dipeptidyl-peptidase-like protein-6; GABA, γ aminobutyric acid; PERM, progressive encephalomyelitis with rigidity and myoclonus; R, receptor; VGKC, voltage-gated potassium channels. – 10 seizures,7 but data in children remain contributes to the protection of the this subject11 extensively38 . Current scarce. Because early identification brain from permanent damage after knowledge is summarized in and intervention is increasingly seizures; in certain circumstances, Table 1. shown to improve the general however, these immune8 processes outcome, alerting pediatricians about may be deleterious. In addition, Autoimmune encephalitis syndromes this specific topic is important. various auto-ABs have been are increasingly being defined by associated with acute or chronic their associated auto-AB biomarker, Accordingly, this article presents conditions in which seizures are such as N-methyl D-aspartate an overview of the current state a hallmark, but it is often unclear glutamate receptor (NMDA-R) of knowledge of the involvement whether they are pathogenic or if AB. However, many patients with of innate and adaptive immunity they simply represent markers of an suspected autoimmune encephalitis in epilepsies with an emphasis on underlying disease. do not have an associated biomarker, available pediatric data. Auto-ABs Related to Seizures in and so clinical syndromes remain IMMUNITY AND EPILEPSIES: RECENT Childhood important, the most important of PROGRESS IN THE UNDERSTANDING OF which being limbic encephalitis (LE). A COMPLEX RELATIONSHIP LE is an inflammatory encephalitis Numerous auto-ABs have been that predominantly affects the the subjects9 of study in epilepsy in limbic region with clinical memory An explosion of the number of past years. Two main categories change, temporal lobe seizures, and scientific studies on the relation of auto-ABs are usually identified psychiatric symptoms, and it is more between autoimmunity and epilepsy based on the location of their target common in adults than in children. has occurred since the early 1990s. antigens: intracellular (unlikely to MRIs typically show restricted In some circumstances, immune be pathogenic) or neuronal surface inflammation and swelling in the activation precedes and provokes (likely to be pathogenic). Their bilateral limbic regions, EEGs can the appearance of seizures. Animal presence has been demonstrated show localizing features, and CSF research data indicate that contrarily, in the serum or cerebrospinal may show features of inflammation. in other situations, the inflammatory fluid (CSF) of many patients with A set of diagnostic criteria for LE has cascade may be activated by the seizures, but the precise roles of been39 recently proposed by Graus seizures themselves. It is generally many auto-ABs remains to be fully et al. Unlike in adults, when LE is accepted that a certain degree of understood, especially in children. often associated with paraneoplastic immune reaction is favorable and A recent review article covers auto-ABs, LE in children is often Downloaded from www.aappublications.org/news by guest on September 27, 2021 2 KORFF and DALE Korff and Dale https://doi.org/10.1542/peds.2016-3534 September 2017 The Immune System in Pediatric Seizures and Epilepsies 3 140 Pediatrics 2017 ROUGH GALLEY PROOF TABLE 2 Pediatric Epilepsies or Epileptic Conditions in Which Dysimmune Features Have Been Reported Disease Disease Characteristics Underlying Cause Major Elements Indicating Ref. No(s). Immune Activation Rasmussen encephalitis Refractory focal epilepsy, Unknown 1. Peripheral T cells stimulated 40–59 progressive hemispheric by GluRε2 atrophy,