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 October 1, 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 October 1, 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, and contralateral 2. Predominance of T-cell neurologic dysfunction infiltration of the CNS 3. Granzyme-B-mediated T-cell cytotoxic reaction West syndrome Epileptic spasms, hypsarhythmia, Multiple reported (mostly 1. Positive effect of steroid ‍21,​23,​30,​60,​61 developmental delay or structural, metabolic, or treatment regression genetic defects) 2. Auto-AB detected in some patients Landau-Kleffner syndrome Acquired aphasia, CSWS in Unknown 1. Positive effect of steroid ‍62–‍69 bilateral temporal regions treatment 2. Auto-AB or changes in levels of various circulating cytokines detected in some patients AEIMSE A group of likely related acute Unknown 1. Auto-AB rarely detected in ‍13,​22,​70–‍84 encephalopathies that present patients in childhood with status 2. Positive effect of IL-1 receptor epilepticus, including HHE, FIRES antagonist (anakinra) treatment in some FIRES patients Mesial temporal sclerosis linked Prolonged febrile seizures Unknown 1. Various cytokines detected in ‍85–‍90 with previous prolonged in infancy, subsequent serum or CSF of some patients febrile seizures identification of mesial after febrile seizures temporal lobe sclerosis 2. Involvement of genes coding for innate immune-response proteins AEIMSE, acute encephalopathy with immune-mediated status epilepticus; CSWS, continuous spike-waves during sleep; FIRES, febrile infection-related epilepsy syndrome; GluR, glutamate receptor; HHE, hemiconvulsion-hemiplegia-epilepsy syndrome.

–

seronegative (although it can be well-delineated epilepsy syndromes,40 59 T- and B-cell activation and auto-AB associated with glutamic acid 17 such as Rasmussen21,23,​ encephalitis,30,​– 60,​ 61​ ​ ‍ ‍ production, and innate mechanisms Specificdecarboxylase Pediatric [GAD] Epilepsies auto-ABs) or. West syndrome,​ ‍ 62‍ 69 ‍ Landau- of the CNS, like the increased Conditions in Which Auto-ABs or Kleffner syndrome,​ ‍‍ acute – production of cytokines by activated Dysimmune Features Have Been encephalopathy with immune-13,22,​ 70​ 84 glial cells observed in response to Reported mediated status epilepticus,​ ‍ ‍ ‍ ‍ various stimuli such as seizures. and mesial– temporal sclerosis linked The latter mechanism is a recently

with previous85 90 prolonged febrile identified process named neurogenic A majority of children who have seizures ‍ ‍ (Table 2). Detailed neuroinflammation, in which innate seizures share certain clinical pathophysiological mechanisms and adaptive inflammatory reactions features that likely reflect a remain to be understood. and vascular cell activation within the CNS are triggered by activity participation of the9 immune system Various Mechanisms Link Immune in their diseases. These include Activation and Seizures in primary afferent nerve94 fibers or– a change (mostly an increase higher-order neurons. On the91,94​ basis97 or, more rarely, a decrease) of 5 recent overview articles,​ ‍ ‍‍ in seizure frequency during It is generally accepted that the one can attempt to summarize the periods of infectious illnesses or activation of the immune system most important steps that link the a favorable response to certain can be both the consequence and immune system and seizures with the immunotherapeutic approaches. the cause of seizures, which in following: Some of the previously described both cases can induce permanent auto-ABs (as well as additional auto- functional changes in the CNS. – 1. An initial injury occurs, in the

ABs not primarily directed against These may themselves contribute91 93 CNS or in the periphery, and CNS targets), elevated cytokinesm, to generate epileptic seizures. ‍ ‍ provokes an activation of the and other nonspecific markers of Various pathways link the immune immune system in one or both an immune activation have been response and seizures. These include compartments (systemic or found in children with certain adaptive systemic responses, such as neuroinflammatory). Various Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 3, September 2017 3

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 events have been identified as intracellular kinase families, such in which BBB disruption may being able to play such a role, as inducing phosphorylation provoke chronic epilepsy remains including peripheral infections, of a subunit of glutamatergic incompletely understood. It has autoimmune diseases, CNS NMDA-R; the inhibition of the been hypothesized, for example, vascular disease (thrombosis, glutamate reuptake or the that acute BBB disruption after emboli, and hemorrhage), increase of glutamate release initial seizures cause prolonged vasculitis, neurotrauma, metabolic in the extracellular space by or permanent changes in brain disorders, CNS infections, seizures, astrocytes; the promotion of permeability, which forms the basis and status epilepticus. synaptic reorganization; and of chronic surrounding– neuronal

the dysfunction of ion channels. excitability106 108and further seizure 2. Inflammatory mediators are Animal research studies also genesis. ‍ ‍ Recent advances released in either compartment, showed that certain genes in the BBB disruption theory will or in both, depending on the that code for mediators of the likely help our understanding nature of the initial injury. inflammatory response, such of the process. Bargerstock et These mediators include various β 109 β as IL-1, IL-6 (and its receptor), al showed that S100B, an cytokines (such as interleukin α and IL-1 are upregulated in the astrocytic protein, is released in [IL]-1 , IL-6, and tumor acute phase that follows status the systemic circulation when the necrosis factor- ), complement epilepticus8,98​ or traumatic brain BBB endothelial tight-junctions proteins, so-called danger injury. ‍ are disrupted, for instance, during signals (molecules that alert the seizures. This release may in turn microenvironment to an ongoing All of these mechanisms increase neuronal excitability and lower induce a systemic autoimmune injury, such as high-mobility- reaction against the brain, which group box-1 and its activation of the seizure threshold, which creates a vicious cycle of increased underlies the development of toll-like receptor 4 in neurons chronic conditions in the CNS, such and glial cells), cell-adhesion seizure susceptibility. Animal research has provided details as epilepsy and Alzheimer disease. molecules, prostaglandins These results need confirmation. produced by the activation of regarding the various mechanisms for inflammation-induced the cyclooxygenase-2 signaling Therapeutic Approaches and pathway, and chemokines. The epileptogenesis. These include the Prognosis upregulation of these mediators abovementioned increased adhesion and their release by lymphocytes of activated peripheral leukocytes in the periphery, or by activated to endothelial cells followed by their Various drugs and molecules glial and neuronal cells, may infiltration into the CNS through99 with anti-inflammatory or in turn provoke blood-brain cytoskeletal reorganization. These immunomodulatory properties barrier (BBB) breakdown, cells generate free radicals and have been shown to decrease the adhesion and penetration of cytotoxic enzymes, which, in addition occurrence of additional seizures activated peripheral lymphocytes, to further production and secretion in acute clinical or experimental immunoglobulins and albumin of cytokines and chemokines, situations and– to prevent kindling into the brain (and, for the participate in neuronal dysfunction and epilepsy development in latter, subsequent activation or degeneration that contribute 98,110​ 117 β animals. ‍ ‍ ‍ Their mechanisms of the transforming growth to the appearance of a subsequent95 of action are summarized in Table factor- signaling pathway), chronic susceptibility to seizures. 3. As a general rule, situations increasing extracellular potassium On the other hand, a + in which neuronal auto-ABs are concentration, as well as neuroprotective role of CD3 T found and target surface antigens functional changes in neurons, cells of counterbalancing the innate – (eg, NMDA-R) have a much higher glial cells, and astrocytes. inflammation has been shown in mice therapeutic response rate than those that suffer from kainic-acid induced100 in which antigens118 are intracellular, 3. Neuronal functional changes seizures and lesioned hippocampi,​ such as GAD. Potential immune occur, which increase seizure thus leaving the question of the exact approaches for children in various role of the adaptive response open. susceptibility. Examples of these epileptic119, conditions120​ include– functional changes include the From another standpoint, the steroids,​ ‍ intravenous121 123 increased expression of IL-1R1 relation between the BBB and immunoglobulin (IvIg),​ ‍ plasma β 124,125​ (the target and mediator of the the occurrence– of epilepsy exchanges,​ ‍ rituximab (RTX),

biological response to IL-1 ) in has been studied101 105 extensively cyclophosphamide, and alternative neurons; the activation of various for years,​ ‍ but the way approaches such as the ketogenic Downloaded from www.aappublications.org/news by guest on October 1, 2021 4 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 3 Examples of Drugs and Treatments With Anti-Inflammatory or Immunomodulatory Properties That Have Shown Experimental or Clinical Efficacy in Seizure Treatment or Prevention of Epilepsy Development is that early therapy is more likely Mechanism of Action Examples of Drugs, Treatments to be effective than later treatment in autoimmune encephalitis, which BBB homeostasis control Steroids, ketogenic diet, hypothermia, vagal nerve stimulation, erythropoietin, magnesium sulfate, has been recently demonstrated in138 a rapamycin thorough review of the literature. Decreased leukocyte adhesion to BBB Natalizumab (integrin α-4 specific monoclonal AB), Practical Implications of steroids, IL-R antagonists Available Data and Current Immunosuppression Understanding in the Management Inhibition of auto-AB production Steroids, cyclophosphamide, RTX of Children With Seizures Inhibition of T cell response Tacrolimus, diazepam Inhibition of cytokine production and signaling Minozac, ICE-inhibitor (eg, VX-765, anakinra), levetiracetam When Should One Clinically Suspect Via NF-κB inhibition Valproate, propofol, thiopental, ketamine a Child With Seizures of Immune Removal of auto-AB IvIg, plasma exchanges Etiology? PTGS2 inhibition NSAIDs: celecoxib, parecoxib Microglia inactivation Erythropoietin, minocycline ICE, interleukin converting enzyme; NF, nuclear transcription factor; NSAID, nonsteroidal anti-inflammatory drug; PTGS2, 139 prostaglandin G/H synthase 2 (formerly COX-2, cyclooxygenase 2); R, receptor. Suleiman et al proposed a flowchart to approach children with

suspected autoimmune118 seizures. Likewise, Bien proposed a detailed diet, in which anti-inflammatory and on the basis of the presence of table of clinical and paraclinical neuroprotective– properties are likely at least 1 neural AB, personal features that should prompt the

to be major70,97,​ players126​ 128 in its mechanisms or family history or physical search for auto-ABs in patients with39 of action. ‍ ‍‍ stigmata of autoimmune disorders, epilepsy. More recently, Graus et al and frequent or refractory proposed a clinical approach to Two meta-analyses on the use seizures. Treatment with daily the diagnosis of autoimmune of IvIg or immunomodulatory infusions of 1 g of intravenous encephalitis, which emphasized that interventions overall in epilepsy methylprednisolone or 0.4 g/ clinical suspicion should result in concluded that, on the basis of kg IvIg for 3 to 5 days followed first-line immune therapy rather available data, their efficacy could 129,130​ by weekly infusions for 6 to 12 than wait for auto-AB results. Based not be demonstrated. ‍ Thus, weeks at the same dose (alone or on these proposals, we propose the question of whether anti- in combination) was administered. that immune function analyses inflammatory or immunomodulatory Eighteen patients responded with should be specifically considered in therapies should be added to classic a decrease in seizure frequency, children if 3 of these 5 criteria are antiepileptic drugs in autoimmune or which was sustained in the majority present (Fig 1): (1) unusually high even in all types of epilepsies remains of cases. The study brought class frequency of seizures from onset, open. 131 IV evidence that these therapeutic with early refractoriness to classic In a recent study, Irani et al options 132improved seizure antiepileptic drugs; (2) additional reported a rapid decrease and control. clinical signs of acute or subacute progressive total disappearance of onset, which are suggestive of diffuse faciobrachial dystonic seizures in the The role of agents that modify the CNS involvement (such as psychiatric 9 patients with ABs against leucine- innate immune system function and or behavioral troubles, disturbance of rich glioma inactivated 1 protein attenuate neuroinflammation, such as consciousness, abnormal movements, β who were treated with steroids in melatonin,– minocycline, or interferon or sleep problems); (3) the clinical addition to the initial antiepileptic -secreting133 136 mesenchymal stem presentation clearly orients to drugs to which seizures were cells,​ ‍‍ is emerging. In a recent a syndrome associated with the refractory. study, minocycline was shown to presence of specific auto-ABs; (4)

132 improve adaptive behaviors of certain presence of a personal or family Similarly, Toledano et al children with Angelman syndrome, history of autoimmune disease; and

selected 29 of 110 patients at although the exact mechanism 137of (5) the clinical presentation does their neuroimmunology clinic who action could be multifactorial. not orient to well-circumscribed presented with seizures as a major Whether these molecules have a and rapidly identifiable epilepsy complaint. Children as young as role to play in the management of syndromes, and structural lesions, 2 years old were included. These certain forms of epilepsy remains and infectious, metabolic, or toxic patients were suspected of having to be evaluated. Another major, diseases are excluded by history and seizures of an autoimmune etiology current theme in neuroimmunology initial investigation. Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 3, September 2017 5

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 FIGURE 1 Children with seizures of suspected immune etiology: suggestive clinical features and proposed stepwise diagnostic approach. FLAIR, fluid attenuation inversion recovery; T2, transverse relaxation time.

In addition, certain infections are seizure variability or multifocality and ligand imaging studies will known to trigger encephalitis and and history of neoplasia have been certainly improve our ability to epilepsy in children. Some of them related to autoimmune epilepsy identify CNS inflammation in the directly infect the brain and cause in adults, and they should also be future. a primary viral encephalitis; on the considered as suggestive features in We suggest that targeted blood other hand, certain micro-organisms children. It is important to note that analyses for the most likely auto-ABs can induce a secondary autoimmune the absence of these features cannot according to clinical presentation, the encephalitis, such as herpes– simplex definitively rule out autoimmune use of biochips (mosaics of cells that or varicella zoster-induced anti- epilepsy. 140 142 display various antigens, such as NMDA-R encephalitis. ‍ ‍ In some 118 Also, certain patients with those described in Table 1),​ of these infectious or postinfectious autoimmune encephalitis do not and a cerebral MRI with transverse encephalitis syndromes, there is exhibit any clinical symptoms besides relaxation time and fluid attenuation evidence of autoimmunity and 146 the seizures. These observations inversion recovery sequences should specific biomarkers (such as NMDA-R are likely to be rare, particularly in be the minimal procedures performed AB), whereas in other syndromes, childhood, and we do not believe all initially in children with seizures of a there is no specific biomarker, and children presenting with seizures suspected immune etiology. Because the exact inflammatory mechanism is should be investigated for an blood investigations may bring unclear. Studies of postencephalitic immune etiology in the absence nonspecific (positive or negative) epilepsy showed that herpes simplex of other clinical or investigational results, a lumbar puncture should and mycoplasma have the highest features that are suggestive of be performed to look for increased potential to result in ongoing 143,144​ inflammation. protein or cell counts, oligoclonal epilepsy. In these studies, bands, and intrathecal production of severe clinical indicators such as These limitations emphasize the fact auto-ABs. A standard EEG may bring status epilepticus were risk factors that the spectrum of autoimmune forward additional clues in specific for subsequent drug-resistant epilepsy is yet to be defined, and situations, such as when NMDA-R epilepsy. Recently, auto-AB against novel CSF or blood biomarkers are δ encephalitis is suspected and a pattern leimodin-1, an intracellular protein needed. How Should a Child With Seizures of extreme brush is present (although that is expressed in smooth muscle 26,147​ of a Suspected Immune Etiology Be this feature has low sensitivity). ‍ tissue and the thyroid but also in Investigated? An extended blood, CSF, and urine the cytoplasm of neurons, have workup for systemic autoimmune been found in the serum and CSF diseases should also be considered, of certain children from eastern There have been major advances especially in those with multiorgan Africa with nodding syndrome, a in our understanding of the roles involvement (Table 4). This workup thus far unexplained and epidemic Onchocerca of auto-ABs as mediators and includes liver- and kidney-function epileptic disorder that is associated volvulus biomarkers in autoimmune epilepsy, markers, erythrocyte sedimentation with the parasitic worm 145 but it is likely that many syndromes rates, complement proteins, various . have dominant cellular or innate- auto-ABs encountered in systemic Responsiveness to immune therapy immune mechanisms that are poorly lupus erythematosus or vasculitides, is indicative of autoimmune epilepsy, recognized. Broader biomarker as well as auto-ABs associated with but this is only possible to determine profiles including cytokine and/or autoimmune thyroid disease (which in retrospect. Intraindividual chemokine, molecular techniques, one has to remember represents Downloaded from www.aappublications.org/news by guest on October 1, 2021 6 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 4 Proposed Investigation of Seizures and Epilepsy of Suspected Immune Etiology Test Grouping Specific Tests or prednisolone at 1 to 2 mg/kg Specific auto-ABs associated with autoimmune Cell-based assay, such as Eurimmun biochip per day for 2 to 4 weeks and a slow epilepsy (see Table 1) Anti-NMDA-R AB 118,139,​ 153​ taper. ‍ ‍ This approach should Anti-GABAA-R AB Anti-MOG AB (if CNS demyelination) be considered as soon as suspicion Anti-GAD of autoimmune etiology arises,39 be it Other auto-ABs rarely found in children: LGI-1, in chronic or acute situations–. As Caspr2, GABA -R, DPPX-6, neurexin 3a, AMPA-R B specifically demonstrated in conditions Evidence of peripheral inflammation or immune Complete blood cell count 153 155≥ dysregulation Erythrocyte sedimentation rate like NMDA-R encephalitis,​ ‍‍ CRP aggressive treatment 118including 4 to IgG, IgM, IgA 10 plasma exchanges followed by C3, C4, CH50 IvIg at 2 g/kg divided by 2 to 5 doses Evidence of systemic autoimmunity or Antinuclear AB (or IvIg followed by plasma exchanges vulnerability to autoimmunity Rheumatoid factor 156 Antiphospholipid AB after a minimal 2-week interval) Antineutrophil cytoplasmic AB and various combinations of Anti-DNA AB immunosuppressive drugs (including – 2 AB to extractable nuclear antigens: Anti-Sm, intravenous RTX at 375 mg/m every Anti-Jo1, antihistones, anti-scl70, anti-SSA/SSB, week, 2 4 times; and intravenous antiribonucleoproteins,​ – 2 antithyroid peroxidase AB, anti-TSH receptor AB cyclophosphamide at 750118 mg/m Evidence of (nonspecific) immune activation, Microscopy, protein count, CSF oligoclonal bands, monthly for 3 6 months) should be inflammation, or CNS infection neopterin rapidly considered in conjunction with AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; anti-SSA, anti–Sjögren’s-syndrome-related antigen A; steroids in severe disease. anti-SSB, anti-Sjögren’s syndrome type B; anti-TSH, antithyrotropin receptor Caspr2, contactin-associated protein; CRP, c-reactive protein; DPPX-6, dipeptidyl-peptidase-like protein-6; GABA, γ aminobutyric acid; IgA, immunoglobulin A; IgG, Importantly, this treatment scheme immunoglobulin G; IgM, immunoglobulin M; LGI, leucine-rich glioma inactivated 1 protein; MOG, myelin oligodendrocyte has been proposed for autoimmune glycoprotein; NMDA-R, N-methyl D-aspartate glutamate receptor. epilepsy and/or encephalitis and may not be effective in other dysimmune epilepsy syndromes. Given the fact a predisposition to autoimmunity protein 18 kDa, was demonstrated that immune activation in the CNS can and autoimmune thyroid disease ipsilaterally and contralaterally to be protective, the best therapeutic approach for patients with suspected rather than a pathogenic marker seizure foci, which suggests150 ongoing of autoimmune epilepsy). Tumor diffuse inflammation. In another but not confirmed immune-mediated searches should be performed study, the attempt to detect specific epilepsy remains uncertain. In Fig according to the potential finding EEG features in patients with epilepsy 2, we propose an immune-therapy trial scheme that could be followed in of auto-ABs specifically associated and various antineuronal ABs failed151 with malignancies, such as ovarian to define discriminating features. future prospective studies of suspected138,157​ teratomas in girls with the NMDA-R However, there are acute EEG immune or autoimmune epilepsy. ‍

auto-AB. Searching for nonspecific indicators of poor152 outcome in children Conclusions markers of immune activation in with encephalitis. Thus, EEG can the CNS, such as CSF neopterin Halsoow beShould useful a in Child terms With of prognosis.Seizures or oligoclonal148,149​ bands, may also be of Demonstrated (or Strongly It is now clear that inflammation helpful. ‍ Suspected) Immune Etiology be and autoimmunity play important Treated? roles in childhood seizures and There is an urgent need to develop epilepsies. These immune reactions reliable markers of CNS immune can be the cause of seizures, such activation, which are currently lacking The classic treatment schemes used as when auto-ABs against various or not broadly available. These will in other autoimmune neurologic CNS targets involved in neuronal likely include CSF cytokines and diseases may also be applied to activation are produced. On the chemokines and EEG or imaging seizures and epilepsy of immune other hand, various CNS and

features. An example of the11 latter was etiology. Current recommendations peripheral immune responses are provided recently by an c-acetate for autoimmune encephalitis, such activated after seizures. The latter positron emission tomography as NMDA-R AB encephalitis, include mechanisms are encompassed in scan study of 23 adult patients with intravenous methylprednisolone the recently described concept of ≤ epilepsy arising from the temporal at 30 mg/kg per day for 3 to 5 days neurogenic neuroinflammation, lobe in which increased binding of ( 1 g) followed by ongoing, monthly which can result in the activation one of these markers, translocator pulsed steroids, oral prednisone, of an anti-inflammatory cascade Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 3, September 2017 7

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 References 1. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34(3):453–468 2. Ber g AT, Jallon P, Preux PM. The epidemiology of seizure disorders in infancy and childhood: definitions and classifications. Handb Clin Neurol. 2013;111:391–398 3. Hauser WA. Epidemiology of epilepsy in children. In: Pellock JM, Nordli DR Jr, Sankar R, Wheless JW, eds. Pellock’s Pediatric Epilepsy: Diagnosis and Therapy. New York, NY: Demos Medical Publishing; 2017:177–205 4. Ong MS, Kohane IS, Cai T, Gorman MP, Mandl KD. Population-level evidence for an autoimmune etiology of epilepsy. JAMA Neurol. 2014;71(5):569–574 5. Bien CG, Scheffer IE. Autoantibodies and epilepsy. Epilepsia. 2011; 52(suppl 3):18–22 FIGURE 2 6. Korff CM, Scheffer IE. Epilepsy A guide to immune therapy trial. The duration of the immune trial is dependent on the clinical classification: a cycle of evolution scenario. In general, the therapeutic trial needs to be long enough to determine effect, and in more and revolution. Curr Opin Neurol. severe conditions, the trial should be sustained or even redosed.138,‍157​ Steroids should be considered 2013;26(2):163–167 for all patients with suspected autoimmune epilepsy. In strongly suspected cases or cases with proven steroid responsiveness and/or dependence, other immune therapies such as IvIg, RTX, 7. Bien C. Immune-mediated pediatric cyclophosphamide, and steroid-sparing agents like mycophenolate mofetil should be considered. epilepsies. In: Dulac O, Lassonde M, Sarnat H, eds. Handbook of Clinical Neurology: Pediatric Neurology Part 1. Acknowledgments Amsterdam, Netherlands: Elsevier B.V.; 2013:521 531 and homeostatic mechanisms with – 8. Choi J, Koh S. Role of brain subsequent neuroprotection and We address our warmest thanks interruption of seizures or the inflammation in epileptogenesis. to Dr Douglas R. Nordli Jr, in Los Yonsei Med J. 2008;49(1):1–18 perpetuation of a maladaptive and Angeles for his useful suggestions in 9. Korff C. Autoimmunité, épilepsies, neurotoxic immune response as the94 the initial stages of the manuscript. basis of further epilepsy genesis. et encéphalopathies chez l’enfant. Epileptologie. 2014;31:26–31 Important questions that remain Abbreviations open include the understanding of 10. Suleiman J, Dale RC. The recognition the precise timing and sequence of and treatment of autoimmune epilepsy elements of the immune response in children. Dev Med Child Neurol. auto-AB: autoantibody 2015;57(5):431 440 to seizures, the detection of – BBB: blood-brain barrier reliable diagnostic biomarkers 11. Petit-Pedrol M, Armangue T, Peng X, CNS: central nervous system of CNS inflammation in children et al. Encephalitis with refractory CSF: cerebrospinal fluid with epilepsies, the identification seizures, status epilepticus, and GAD: glutamic acid antibodies to the GABAA receptor: of specific clinical, radiologic, decarboxylase a case series, characterisation of and electrophysiological features IL: interleukin the antigen, and analysis of the that may allow early suspicion IvIg: intravenous effects of antibodies. Lancet Neurol. of immune epilepsy, and the immunoglobulin 2014;13(3):276–286 development of optimal therapeutic LE: limbic encephalitis 12. Korff CM, Parvex P, Cimasoni L, et al. strategies and molecules targeted NMDA-R: N-methyl D-aspartate Encephalitis associated with glutamic against the various inflammatory glutamate receptor acid decarboxylase autoantibodies in mediators described above through RTX: rituximab prospective-controlled studies. Downloaded from www.aappublications.org/news by guest on October 1, 2021 8 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 a child: a treatable condition? Arch school-age children (FIRES). Dev Med 31. Bonkowsky JL, Ramaekers VT, Neurol. 2011;68(8):1065–1068 Child Neurol. 2011;53(11):1053–1057 Quadros EV, Lloyd M. Progressive encephalopathy in a child with 13. Specchio N, Fusco L, Claps D, Vigevano 23. Suleiman J, Wright S, Gill D, et al. cerebral folate deficiency syndrome. F. Epileptic encephalopathy in Autoantibodies to neuronal antigens J Child Neurol. 2008;23(12):1460 1463 children possibly related to immune- in children with new-onset seizures – mediated pathogenesis. Brain Dev. classified according to the revised ILAE 32. Hasselmann O, Blau N, Ramaekers VT, 2010;32(1):51–56 organization of seizures and epilepsies. Quadros EV, Sequeira JM, Weissert 14. Olson JA, Olson DM, Sandborg C, Epilepsia. 2013;54(12):2091–2100 M. Cerebral folate deficiency and Alexander S, Buckingham B. Type 1 24. Poloni C, Korff CM, Ricotti V, et al. CNS inflammatory markers in diabetes mellitus and epilepsia partialis Severe childhood encephalopathy Alpers disease. Mol Genet Metab. continua in a 6-year-old boy with elevated with dyskinesia and prolonged 2010;99(1):58–61 anti-GAD65 antibodies. Pediatrics. cognitive disturbances: evidence for 33. Kruer MC, Hoeftberger R, Lim KY, et al. 2002;109(3). Available at: www.​pediatrics.​ anti-N-methyl-D-aspartate receptor Aggressive course in encephalitis org/cgi/​ content/​ full/​ 109/​ 3/​ E50​ encephalitis. Dev Med Child Neurol. with opsoclonus, ataxia, chorea, 2010;52(5):e78–e82 15. lin JJ, Lin KL, Hsia SH, Wang HS, and seizures: the first pediatric 25. florance NR, Davis RL, Lam C, et al. Chou IJ, Lin YT; CHEESE Study Group. case of γ-aminobutyric acid type B Antiglutamic acid decarboxylase Anti-N-methyl-D-aspartate receptor receptor autoimmunity. JAMA Neurol. (NMDAR) encephalitis in children antibodies in children with 2014;71(5):620–623 encephalitis and status epilepticus. and adolescents. Ann Neurol. Pediatr Neurol. 2012;47(4):252–258 2009;66(1):11–18 34. Damásio J, Leite MI, Coutinho E, et al. Progressive encephalomyelitis 16. Honnorat J, Didelot A, Karantoni E, et al. 26. Armangue T, Titulaer MJ, Málaga I, et al; with rigidity and myoclonus: the Autoimmune limbic encephalopathy Spanish Anti-N-methyl-D-Aspartate first pediatric case with glycine and anti-Hu antibodies in children Receptor (NMDAR) Encephalitis Work receptor antibodies. JAMA Neurol. without cancer. Neurology. Group. Pediatric anti-N-methyl-D- 2013;70(4):498–501 2013;80(24):2226–2232 aspartate receptor encephalitis- clinical analysis and novel findings 35. Carvajal-González A, Leite MI, Waters 17. Haberlandt E, Bast T, Ebner A, et al. in a series of 20 patients. J Pediatr. Limbic encephalitis in children P, et al. Glycine receptor antibodies 2013;162(4):850–856.e2 and adolescents. Arch Dis Child. in PERM and related syndromes: characteristics, clinical features 2011;96(2):186–191 27. Granerod J, Ambrose HE, Davies NW, et al; UK Health Protection Agency (HPA) and outcomes [published correction 18. Kr ll-Seger J, Bien CG, Huppertz HJ. ö Aetiology of Encephalitis Study Group. appears in Brain. 2014;137(pt 12): Non-paraneoplastic limbic encephalitis Causes of encephalitis and differences e315]. Brain. 2014;137(pt 8): associated with antibodies to in their clinical presentations in 2178–2192 potassium channels leading to England: a multicentre, population- bilateral hippocampal sclerosis in 36. Wuerfel E, Bien CG, Vincent A, Woodhall based prospective study. Lancet Infect a pre-pubertal girl. Epileptic Disord. M, Brockmann K. Glycine receptor Dis. 2010;10(12):835–844 2009;11(1):54–59 antibodies in a boy with focal epilepsy 28. Gable MS, Sheriff H, Dalmau J, Tilley and episodic behavioral disorder. 19. Suleiman J, Brenner T, Gill D, et al. DH, Glaser CA. The frequency of J Neurol Sci. 2014;343(1 2):180 182 Immune-mediated steroid-responsive – – autoimmune N-methyl-D-aspartate epileptic spasms and epileptic receptor encephalitis surpasses that 37. Tobin WO, Lennon VA, Komorowski L, encephalopathy associated with VGKC- of individual viral etiologies in young et al. DPPX potassium channel antibody: complex antibodies. Dev Med Child individuals enrolled in the California frequency, clinical accompaniments, Neurol. 2011;53(11):1058 1060 – Encephalitis Project. Clin Infect Dis. and outcomes in 20 patients. Neurology. 2014;83(20):1797 1803 20. lin JJ, Lin KL, Hsia SH, Wang HS, Chiu 2012;54(7):899–904 – CH; CHEESE Study Group. VGKC complex 29. Byrne S, Walsh C, Hacohen Y, et al. 38. Ganor Y, Goldberg-Stern H, Lerman- antibodies in pediatric severe acute Earlier treatment of NMDAR antibody Sagie T, Teichberg VI, Levite M. encephalitis: a study and literature encephalitis in children results in a Autoimmune epilepsy: distinct review. Brain Dev. 2013;35(7):630 635 – better outcome. Neurol Neuroimmunol subpopulations of epilepsy patients 21. Suleiman J, Brenner T, Gill D, et al. Neuroinflamm. 2015;2(4):e130 harbor serum autoantibodies to either VGKC antibodies in pediatric glutamate/AMPA receptor GluR3, 30. Steele SU, Cheah SM, Veerapandiyan encephalitis presenting with glutamate/NMDA receptor subunit A, Gallentine W, Smith EC, Mikati status epilepticus. Neurology. NR2A or double-stranded DNA. Epilepsy MA. Electroencephalographic and 2011;76(14):1252 1255 Res. 2005;65(1–2):11–22 – seizure manifestations in two patients 22. Illingwor th MA, Hanrahan D, Anderson with folate receptor autoimmune 39. Graus F, Titulaer MJ, Balu R, et al. CE, et al. Elevated VGKC-complex antibody-mediated primary cerebral A clinical approach to diagnosis of antibodies in a boy with fever-induced folate deficiency. Epilepsy Behav. autoimmune encephalitis. Lancet refractory epileptic encephalopathy in 2012;24(4):507–512 Neurol. 2016;15(4):391–404

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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 40. Rasmussen T, Olszewski J, Lloydsmith 50. Varadkar S, Bien CG, Kruse CA, 60. Montelli TC, Soares AM, Peraçoli D. Focal seizures due to chronic et al. Rasmussen’s encephalitis: MT. Immunologic aspects of West localized encephalitis. Neurology. clinical features, pathobiology, and syndrome and evidence of plasma 1958;8(6):435–445 treatment advances. Lancet Neurol. inhibitory effects on T cell function. Arq 2014;13(2):195 205 Neuropsiquiatr. 2003;61(3B): 41. Bien CG, Granata T, Antozzi C, et al. – 731 737 Pathogenesis, diagnosis and treatment 51. Owens GC, Erickson KL, Malone CC, – of Rasmussen encephalitis: a et al. Evidence for the involvement of 61. Tekgul H, Polat M, Tosun A, European consensus statement. Brain. gamma delta T cells in the immune Serdaroglu G, Kutukculer N, Gokben S. 2005;128(pt 3):454–471 response in Rasmussen encephalitis. Cerebrospinal fluid interleukin-6 levels in patients with West syndrome. Brain 42. Rogers SW, Andrews PI, Gahring J Neuroinflammation. 2015;12(1): Dev. 2006;28(1):19 23 LC, et al. Autoantibodies to 134 – glutamate receptor GluR3 in 52. Takahashi Y, Mogami Y, Mine 62. landau WM, Kleffner FR. Syndrome Rasmussen’s encephalitis. Science. J, et al. Genetic variations of of acquired aphasia with convulsive 1994;265(5172):648–651 immunoregulatory genes associated disorder in children. Neurology. 1957;7(8):523 530 43. Watson R, Jiang Y, Bermudez I, with Rasmussen syndrome. Epilepsy – et al. Absence of antibodies to Res. 2013;107(3):238–243 63. Buzatu M, Bulteau C, Altuzarra C, glutamate receptor type 3 (GluR3) in 53. Cepeda C, Chang JW, Owens GC, Dulac O, Van Bogaert P. Corticosteroids Rasmussen encephalitis. Neurology. et al. In Rasmussen encephalitis, as treatment of epileptic syndromes 2004;63(1):43–50 hemichannels associated with with continuous spike-waves 44. Mantegazza R, Bernasconi P, Baggi microglial activation are linked to during slow-wave sleep. Epilepsia. F, et al. Antibodies against GluR3 cortical pyramidal neuron coupling: 2009;50(suppl 7):68–72 peptides are not specific for a possible mechanism for cellular 64. Connolly AM, Chez MG, Pestronk A, hyperexcitability. CNS Neurosci Ther. Rasmussen’s encephalitis but are Arnold ST, Mehta S, Deuel RK. Serum also present in epilepsy patients 2015;21(2):152–163 autoantibodies to brain in Landau- with severe, early onset disease and 54. O’Rourke DJ, Bergin A, Rotenberg Kleffner variant, autism, and other intractable seizures. J Neuroimmunol. A, et al. Rasmussen’s encephalitis neurologic disorders. J Pediatr. 2002;131(1–2):179–185 presenting as focal cortical dysplasia. 1999;134(5):607–613 Epilepsy Behav Case Rep. 2014;2: 45. Takahashi Y, Mori H, Mishina M, et al. 65. Connolly AM, Chez M, Streif EM, et al. 86 89 Autoantibodies to NMDA receptor – Brain-derived neurotrophic factor and in patients with chronic forms of 55. frigeri T, Hemb M, Paglioli E, et al. autoantibodies to neural antigens in epilepsia partialis continua. Neurology. Bilateral Rasmussen’s encephalitis sera of children with autistic spectrum 2003;61(7):891–896 associated with type II focal cortical disorders, Landau-Kleffner syndrome, and epilepsy. Biol Psychiatry. 46. Takahashi Y, Mori H, Mishina M, dysplasia: dormant ‘second’ 2006;59(4):354 363 et al. Autoantibodies and cell- epileptogenic zone in contralateral – mediated autoimmunity to NMDA- disease. Epilepsy Behav Case Rep. 66. Boscolo S, Baldas V, Gobbi G, et al. Anti- type GluRepsilon2 in patients with 2013;1:66–68 brain but not celiac disease antibodies Rasmussen’s encephalitis and 56. Wang D, Blümcke I, Gui Q, et al. in Landau-Kleffner syndrome and chronic progressive epilepsia partialis Clinico-pathological investigations related epilepsies. J Neuroimmunol. continua. Epilepsia. 2005;46(suppl of Rasmussen encephalitis suggest 2005;160(1–2):228–232 5):152–158 multifocal disease progression and 67. Nevsímalová S, Tauberová A, Doutlík associated focal cortical dysplasia. 47. farrell MA, Droogan O, Secor DL, S, Kucera V, Dlouhá O. A role of Poukens V, Quinn B, Vinters HV. Epileptic Disord. 2013;15(1):32–43 autoimmunity in the etiopathogenesis Chronic encephalitis associated 57. Ravindra VM, Mazur MD, Mohila of Landau-Kleffner syndrome? Brain with epilepsy: immunohistochemical CA, Sweney MT, Hersh A, Bollo Dev. 1992;14(5):342–345 and ultrastructural studies. Acta RJ. Rasmussen encephalitis 68. van den Munckhof B, de Vries EE, Neuropathol. 1995;89(4):313 321 – with dual pathology in a patient Braun KP, et al. Serum inflammatory 48. li Y, Uccelli A, Laxer KD, et al. Local- without seizures: case report and mediators correlate with disease clonal expansion of infiltrating T literature review. Childs Nerv Syst. activity in electrical status epilepticus lymphocytes in chronic encephalitis 2015;31(11):2165–2171 in sleep (ESES) syndrome. Epilepsia. of Rasmussen. J Immunol. 58. Bauer J, Bien CG. Encephalitis and 2016;57(2):e45–e50 1997;158(3):1428 1437 – epilepsy. Semin Immunopathol. 69. Cole AJ, Andermann F, Taylor L, et al. 49. Bien CG, Bauer J, Deckwerth TL, et al. 2009;31(4):537–544 The Landau-Kleffner syndrome of Destruction of neurons by cytotoxic T 59. Har tman AL, Cross JH. Timing of acquired epileptic aphasia: unusual cells: a new pathogenic mechanism in surgery in rasmussen syndrome: clinical outcome, surgical experience, Rasmussen’s encephalitis. Ann Neurol. is patience a virtue? Epilepsy Curr. and absence of encephalitis. 2002;51(3):311–318 2014;14(suppl 1):8–11 Neurology. 1988;38(1):31–38

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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 70. Nabbout R, Vezzani A, Dulac O, repetitive partial seizures. Brain Dev. pathophysiology. Epilepsy Curr. Chiron C. Acute encephalopathy 2012;34(9):763–767 2014;14(suppl 1):3–7 with inflammation-mediated 81. Milh M, Villeneuve N, Chapon F, et al. 92. Vezzani A, R egg S. The pivotal role of status epilepticus. Lancet Neurol. ü New onset refractory convulsive immunity and inflammatory processes 2011;10(1):99 108 – status epilepticus associated with in epilepsy is increasingly recognized: 71. Sethi NK, Tenney JR. Child neurology: serum neuropil auto-antibodies introduction. Epilepsia. 2011;52(suppl hemiconvulsion-hemiplegia- in a school aged child. Brain Dev. 3):1–4 epilepsy syndrome. Neurology. 2011;33(8):687–691 2012;79(24):2367; author reply 93. Vezzani A, French J, Bartfai T, Baram TZ. 82. Okanishi T, Mori Y, Kibe T, et al. The role of inflammation in epilepsy. 2367–2368 Refractory epilepsy accompanying Nat Rev Neurol. 2011;7(1):31–40 72. Nabbout R. FIRES and IHHE: delineation acute encephalitis with multifocal of the syndromes. Epilepsia. cortical lesions: possible autoimmune 94. Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory 2013;54(suppl 6):54–56 etiology. Brain Dev. 2007;29(9):590–594 CNS reactions in response to 73. Sakuma H, Fukumizu M, Kohyama 83. Gall CR, Jumma O, Mohanraj R. Five neuronal activity. Nat Rev Neurosci. J. Efficacy of anticonvulsants on cases of new onset refractory status 2014;15(1):43–53 acute encephalitis with refractory, epilepticus (NORSE) syndrome: repetitive partial seizures (AERRPS) outcomes with early immunotherapy. 95. Xu D, Miller SD, Koh S. Immune [in Japanese]. No To Hattatsu. Seizure. 2013;22(3):217–220 mechanisms in epileptogenesis. Front Cell Neurosci. 2013;7:195 2001;33(5):385–390 84. Kenney-Jung DL, Vezzani A, Kahoud RJ, 74. Saito Y, Maegaki Y, Okamoto R, et al. et al. Febrile infection-related epilepsy 96. friedman A, Dingledine R. Molecular Acute encephalitis with refractory, syndrome treated with anakinra. Ann cascades that mediate the influence repetitive partial seizures: case Neurol. 2016;80(6):939–945 of inflammation on epilepsy. Epilepsia. 2011;52(suppl 3):33 39 reports of this unusual post- 85. Stafstrom CE. The incidence and – encephalitic epilepsy. Brain Dev. prevalence of febrile seizures. In: 97. Marchi N, Granata T, Janigro D. 2007;29(3):147 156 – Baram TZ, Sihinnar S, eds. Febrile Inflammatory pathways of seizure 75. Wilder -Smith EP, Lim EC, Teoh HL, et al. Seizures. San Diego, CA: Academic disorders. Trends Neurosci. The NORSE (new-onset refractory Press; 2002:1–25 2014;37(2):55–65 status epilepticus) syndrome: defining 86. Choy M, Dub CM, Ehrengruber M, 98. Pitk nen A, Lukasiuk K. Mechanisms a disease entity. Ann Acad Med é ä Baram TZ. Inflammatory processes, of epileptogenesis and potential Singapore. 2005;34(7):417 420 – febrile seizures, and subsequent treatment targets. Lancet Neurol. 76. Mikaeloff Y, Jambaqué I, Hertz- epileptogenesis. Epilepsy Curr. 2011;10(2):173–186 Pannier L, et al. Devastating epileptic 2014;14(suppl 1):15–22 99. Greenwood J, Etienne-Manneville S, encephalopathy in school-aged Adamson P, Couraud PO. Lymphocyte children (DESC): a pseudo encephalitis. 87. Dubé C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta migration into the central nervous Epilepsy Res. 2006;69(1):67–79 contributes to the generation of system: implication of ICAM-1 77. Kramer U, Chi CS, Lin KL, et al. experimental febrile seizures. Ann signalling at the blood-brain barrier. Febrile infection-related epilepsy Neurol. 2005;57(1):152–155 Vascul Pharmacol. 2002;38(6):315–322 syndrome (FIRES): pathogenesis, 100. Zattoni M, Mura ML, Deprez F, et al. treatment, and outcome: a multicenter 88. Dubé CM, Ravizza T, Hamamura M, et al. Brain infiltration of leukocytes study on 77 children. Epilepsia. Epileptogenesis provoked by prolonged experimental febrile seizures: contributes to the pathophysiology of 2011;52(11):1956–1965 mechanisms and biomarkers. temporal lobe epilepsy. J Neurosci. 78. van Baalen A, H usler M, Plecko- ä J Neurosci. 2010;30(22):7484–7494 2011;31(11):4037–4050 Startinig B, et al. Febrile infection- 101. Marchi N, Angelov L, Masaryk T, et al. related epilepsy syndrome without 89. Hu MH, Huang GS, Wu CT, et al; CHEESE Seizure-promoting effect of blood- detectable autoantibodies and Study Group. Analysis of plasma brain barrier disruption. Epilepsia. response to immunotherapy: multiplex cytokines for children 2007;48(4):732 742 a case series and discussion with febrile seizures and severe – of epileptogenesis in FIRES. acute encephalitis. J Child Neurol. 102. Cornford EM, Oldendorf WH. Epilepsy Neuropediatrics. 2012;43(4):209–216 2014;29(2):182–186 and the blood-brain barrier. Adv Neurol. 1986;44:787 812 79. Specchio N, Fusco L, Claps D, et al. 90. Emsley HC, Appleton RE, Whitmore – Childhood refractory focal epilepsy CL, et al. Variations in inflammation- 103. Cornford EM. Epilepsy and the following acute febrile encephalopathy. related genes may be associated with blood brain barrier: endothelial cell Eur J Neurol. 2011;18(7):952–961 childhood febrile seizure susceptibility. responses to seizures. Adv Neurol. Seizure. 2014;23(6):457 461 1999;79:845 862 80. Wakamoto H, Takahashi Y, Ebihara T, – – et al. An immunologic case study of 91. Vezzani A. Epilepsy and inflammation 104. Janigro D. Blood-brain barrier, acute encephalitis with refractory, in the brain: overview and ion homeostatis and epilepsy:

Downloaded from www.aappublications.org/news by guest on October 1, 2021 PEDIATRICS Volume 140, number 3, September 2017 11

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 possible implications towards rapamycin reduces epileptogenesis 126. Viaccoz A, Laive P. Autoimmune the understanding of ketogenic and blood-brain barrier leakage but epilepsie: treatment overview. diet mechanisms. Epilepsy Res. not microglia activation. Epilepsia. Epileptologie. 2014;31:31–38 1999;37(3):223 232 2012;53(7):1254 1263 – – 127. Viaccoz A, Honnorat J. Paraneoplastic 105. van Vliet EA, da Costa Araújo S, 116. Beghi E, Shorvon S. Antiepileptic drugs neurological syndromes: general Redeker S, van Schaik R, Aronica E, and the immune system. Epilepsia. treatment overview. Curr Treat Options Gorter JA. Blood-brain barrier leakage 2011;52(suppl 3):40–44 Neurol. 2013;15(2):150–168 may lead to progression of temporal 117. Janigro D, Iffland PH II, Marchi N, 128. zkara , Vigevano F. Immuno- and lobe epilepsy. Brain. 2007;130(pt Ö Ç Granata T. A role for inflammation antiinflammatory therapies in epileptic 2):521–534 in status epilepticus is revealed disorders. Epilepsia. 2011;52(suppl 106. Janigro D. Are you in or out? Leukocyte, by a review of current therapeutic 3):45–51 ion, and neurotransmitter permeability approaches. Epilepsia. 2013;54(suppl 129. Walker L, Pirmohamed M, Marson AG. across the epileptic blood-brain 6):30–32 barrier. Epilepsia. 2012;53(suppl Immunomodulatory interventions for 118. Bien CG. Value of autoantibodies focal epilepsy syndromes. Cochrane 1):26–34 for prediction of treatment response Database Syst Rev. 2013;(6):CD009945 107. Oby E, Janigro D. The blood-brain in patients with autoimmune barrier and epilepsy. Epilepsia. epilepsy: review of the literature 130. Geng J, Dong J, Li Y, et al. Intravenous 2006;47(11):1761–1774 and suggestions for clinical immunoglobulins for epilepsy. management. Epilepsia. 2013;54(suppl Cochrane Database Syst Rev. 108. Seiffer t E, Dreier JP, Ivens S, et al. 2):48 55 2011;(1):CD008557 Lasting blood-brain barrier disruption – induces epileptic focus in the rat 119. Kurian M, Korff CM. Steroids in 131. Irani SR, Stagg CJ, Schott JM, et al. somatosensory cortex. J Neurosci. pediatric epilepsy: infantile spasms Faciobrachial dystonic seizures: 2004;24(36):7829–7836 and beyond…. Epileptologie. the influence of immunotherapy on 2011;28:15–20 seizure control and prevention of 109. Bar gerstock E, Puvenna V, Iffland P, cognitive impairment in a broadening 120. Verhelst H, Boon P, Buyse G, et al. et al. Is peripheral immunity regulated phenotype. Brain. 2013;136(pt by blood-brain barrier permeability Steroids in intractable childhood 10):3151–3162 changes? PLoS One. 2014;9(7): epilepsy: clinical experience and e101477 review of the literature. Seizure. 132. Toledano M, Britton JW, McKeon A, et al. 2005;14(6):412–421 Utility of an immunotherapy trial in 110. Ravizza T, Balosso S, Vezzani A. evaluating patients with presumed 121. Geva-Dayan K, Shorer Z, Menascu S, Inflammation and prevention of autoimmune epilepsy. Neurology. epileptogenesis. Neurosci Lett. et al. Immunoglobulin treatment for 2014;82(18):1578–1586 2011;497(3):223–230 severe childhood epilepsy. Pediatr Neurol. 2012;46(6):375–381 133. Pinato L, da Silveira Cruz-Machado 111. Marchi N, Granata T, Alexopoulos A, S, Franco DG, et al. Selective Janigro D. The blood-brain barrier 122. Billiau AD, Witters P, Ceulemans B, Kasran A, Wouters C, Lagae L. protection of the cerebellum hypothesis in drug resistant epilepsy. against intracerebroventricular Brain. 2012;135(pt 4):e211 Intravenous immunoglobulins in refractory childhood-onset epilepsy: LPS is mediated by local melatonin 112. fabene PF, Navarro Mora G, effects on seizure frequency, synthesis. Brain Struct Funct. Martinello M, et al. A role for EEG activity, and cerebrospinal 2015;220(2):827–840 leukocyte-endothelial adhesion fluid cytokine profile. Epilepsia. 134. Calvo JR, González-Yanes C, Maldonado mechanisms in epilepsy. Nat Med. 2007;48(9):1739–1749 MD. The role of melatonin in the cells 2008;14(12):1377–1383 123. Mikati MA, Kurdi R, El-Khoury Z, Rahi A, of the innate immunity: a review. 113. Marchi N, Granata T, Freri E, et al. Raad W. Intravenous immunoglobulin J Pineal Res. 2013;55(2):103–120 Efficacy of anti-inflammatory therapy therapy in intractable childhood 135. Henry CJ, Huang Y, Wynne A, in a model of acute seizures and in a epilepsy: open-label study and review et al. Minocycline attenuates population of pediatric drug resistant of the literature. Epilepsy Behav. lipopolysaccharide (LPS)-induced epileptics. PLoS One. 2011;6(3):e18200 2010;17(1):90–94 neuroinflammation, sickness behavior, 114. Noe FM, Polascheck N, Frigerio F, 124. lousa M, Sanchez-Alonso S, Rodriguez- and anhedonia. J Neuroinflammation. et al. Pharmacological blockade Diaz R, Dalmau J. Status epilepticus 2008;5:15 of IL-1 /IL-1 receptor type 1 axis β with neuron-reactive serum antibodies: 136. Hou Y, Heon Ryu C, Jun JA, Kim during epileptogenesis provides response to plasma exchange. SM, Jeong CH, Jeun SS. Interferon neuroprotection in two rat models of Neurology. 2000;54(11):2163–2165 -secreting mesenchymal stem temporal lobe epilepsy. Neurobiol Dis. β 125. Palcoux JB, Carla H, Tardieu M, et al. cells combined with minocycline 2013;59:183–193 Plasma exchange in Rasmussen’s attenuate experimental autoimmune 115. van Vliet EA, Forte G, Holtman L, et al. encephalitis. Ther Apher. encephalomyelitis. J Neuroimmunol. Inhibition of mammalian target of 1997;1(1):79–82 2014;274(1–2):20–27

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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 137. Grieco JC, Ciarlone SL, Gieron-Korthals and antibody-associated encephalitis 151. Baysal-Kirac L, Tuzun E, Altindag E, M, et al. An open-label pilot trial of in childhood: clinical and etiologic risk et al. Are there any specific EEG minocycline in children as a treatment factors. Epilepsia. 2016;57(1):e7–e11 findings in autoimmune epilepsies? for Angelman syndrome. BMC Neurol. Clin EEG Neurosci. 2016;47(3): 144. lin JJ, Hsia SH, Wu CT, Wang HS, Lin 2014;14:232 224 234 KL. Mycoplasma pneumoniae-related – 138. Nosadini M, Mohammad SS, postencephalitic epilepsy in children. 152. Mohammad SS, Soe SM, Pillai Ramanathan S, Brilot F, Dale RC. Epilepsia. 2011;52(11):1979–1985 SC, et al. Etiological associations and outcome predictors of acute Immune therapy in autoimmune 145. Johnson TP, Tyagi R, Lee PR, et al. electroencephalography in childhood encephalitis: a systematic Nodding syndrome may be an encephalitis. Clin Neurophysiol. review. Expert Rev Neurother. autoimmune reaction to the parasitic 2016;127(10):3217 3224 2015;15(12):1391–1419 worm Onchocerca volvulus. Sci Transl – 153. Dalmau J, Lancaster E, Martinez- 139. Suleiman J, Brilot F, Lang B, Vincent Med. 2017;9(377):eaaf6953 Hernandez E, Rosenfeld MR, Balice- A, Dale RC. Autoimmune epilepsy in 146. Quek AM, Britton JW, McKeon A, et al. Gordon R. Clinical experience and children: case series and proposed Autoimmune epilepsy: clinical laboratory investigations in patients guidelines for identification. Epilepsia. characteristics and response with anti-NMDAR encephalitis. Lancet 2013;54(6):1036–1045 to immunotherapy. Arch Neurol. Neurol. 2011;10(1):63–74 2012;69(5):582–593 140. Armangue T, Moris G, Cantarín- 154. Kurian M, Fluss J, Korff C. Anti-NMDA Extremera V, et al; Spanish 147. Schmitt SE, Pargeon K, Frechette ES, receptor encephalitis: the importance Prospective Multicentric Study of Hirsch LJ, Dalmau J, Friedman D. of early diagnosis and aggressive Autoimmunity in Herpes Simplex Extreme delta brush: a unique EEG immunotherapy in tumor negative Encephalitis. Autoimmune post- pattern in adults with anti-NMDA pediatric patients. Eur J Paediatr herpes simplex encephalitis of receptor encephalitis. Neurology. Neurol. 2012;16(6):764–765 adults and teenagers. Neurology. 2012;79(11):1094 1100 – 155. Kashyape P, Taylor E, Ng J, 2015;85(20):1736–1743 148. Sinclair AJ, Wienholt L, Tantsis E, Krishnakumar D, Kirkham F, Whitney 141. Solis N, Salazar L, Hasbun R. Anti-NMDA Brilot F, Dale RC. Clinical association of A. Successful treatment of two Receptor antibody encephalitis with intrathecal and mirrored oligoclonal paediatric cases of anti-NMDA receptor concomitant detection of Varicella bands in paediatric neurology. Dev encephalitis with cyclophosphamide: zoster virus. J Clin Virol. 2016;83:26–28 Med Child Neurol. 2013;55(1):71–75 the need for early aggressive 142. Schein F, Gagneux-Brunon A, Antoine 149. Dale RC, Brilot F, Fagan E, Earl J. immunotherapy in tumour negative JC, et al. Anti-N-methyl-D-aspartate Cerebrospinal fluid neopterin in paediatric patients. Eur J Paediatr receptor encephalitis after Herpes paediatric neurology: a marker Neurol. 2012;16(1):74–78 simplex virus-associated encephalitis: of active central nervous system 156. Ramanathan S, Mohammad SS, an emerging disease with diagnosis inflammation. Dev Med Child Neurol. Brilot F, Dale RC. Autoimmune and therapeutic challenges [published 2009;51(4):317–323 encephalitis: recent updates and online ahead of print November 150. Gershen LD, Zanotti-Fregonara P, emerging challenges. J Clin Neurosci. 8, 2016]. Infection. doi:​10.​1007/​ Dustin IH, et al. Neuroinflammation 2014;21(5):722–730 s15010-​016-​0959-​y in temporal lobe epilepsy measured 157. Pranzatelli MR, Tate ED. Trends and 143. Pillai SC, Mohammad SS, Hacohen Y, using positron emission tomographic tenets in relapsing and progressive et al. Postencephalitic epilepsy and imaging of translocator protein. JAMA opsoclonus-myoclonus syndrome. drug-resistant epilepsy after infectious Neurol. 2015;72(8):882–888 Brain Dev. 2016;38(5):439–448

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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 The Immune System in Pediatric Seizures and Epilepsies Christian M. Korff and Russell C. Dale Pediatrics originally published online August 9, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/08/08/peds.2 016-3534 References This article cites 154 articles, 18 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/08/08/peds.2 016-3534#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Neurology http://www.aappublications.org/cgi/collection/neurology_sub Neurologic Disorders http://www.aappublications.org/cgi/collection/neurologic_disorders_ sub Allergy/Immunology http://www.aappublications.org/cgi/collection/allergy:immunology_s ub Immunologic Disorders http://www.aappublications.org/cgi/collection/immunologic_disorder s_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on October 1, 2021 The Immune System in Pediatric Seizures and Epilepsies Christian M. Korff and Russell C. Dale Pediatrics originally published online August 9, 2017;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/early/2017/08/08/peds.2016-3534

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