- Email: [email protected]
Febrile Response and Seizures
C H A P T E R
29 Febrile Response and Seizures Annamaria Vezzani1, Tamas Bartfai2 1
Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy; 2 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
O U T L I N E Fever and Seizures
403
Causative Factors Mediating Seizures Caused by Fever 404 Genetic Susceptibility 404 Increased Brain Temperature Affects Permeability of the Ion Channels 405 The Role of the Innate Immune System 405 Clinical Studies Experimental Studies
405 405
FEVER AND SEIZURES Fever can cause seizuresda condition termed febrile seizures (FS)din infants and young children usually between 3 months and 5 years of age therefore in a restricted age-dependent manner. FS is the most common type of childhood seizure disorder occurring in about 2%e5% of children in the United States and Western Europe, more frequently in some Asian countries.1 However, fever also leads to ictal events in 14% of adults with established epilepsy,2 thus FS is not an exclusively pediatric phenomenon. FSs are associated with a fever of 38 C or higher and occur with no evidence of central nervous system infection, metabolic abnormality, or
Stress: Physiology, Biochemistry, and Pathology https://doi.org/10.1016/B978-0-12-813146-6.00029-1
Alkalosis and FS Potassium Chloride Cotransporter
406 406
FSs and Epilepsy: Human and Animal Studies
406
FSs and Cognitive Dysfunction
408
Implications for Therapy
408
References
408
a defined cause.3 This does not exclude that children with FS may have preexisting neurological deficits, which is a confounding factor when studying the outcomes of FS.
403
KEY POINTS • Fever is a concerted stress response that is associated with temporarily elevated brain temperature and core body temperature but does not involve a change in the temperature set point of the homoeothermic animal. • Fever is one of the oldest biomarkers and involves neuronal activity changes in the anterior hypothalamus, hippocampus, and cerebral cortex.
Copyright © 2019 Elsevier Inc. All rights reserved.
404
29. FEBRILE RESPONSE AND SEIZURES
• Interleukin-1 (IL-1), tumor necrosis factor, and prostaglandin E have all been shown to act as endogenous pyrogens. IL-1b, the most potent endogenous pyrogen, is balanced by the IL-1 receptor antagonist (IL-1Ra). • The human recombinant form of IL-1Ra (i.e., anakinra) is an approved antiinflammatory drug endowed with anticonvulsive effects. • High fever is common in children where it may cause febrile seizures in 2%e5% of cases. Although most febrile seizures are benign, prolonged febrile seizures increase the risk of developing epilepsy. • Anakinra may control unprovoked seizures, initially triggered by fever, in children and adolescents who are not responsive to traditional antiepileptic drugs. • The search for genetic and molecular predictors of the long-term consequences of febrile seizures represents an area of active clinical and experimental studies.
FS can be divided into three main types based on their semiology and duration: (1) simple FSs are single seizures of short duration occurring during a febrile illness, and they are generally generalized and benign; (2) complex FSs are longer in duration (15e30 min), may have focal onset, and can recur within 24 h; (3) FSs lasting for more than 30 min are termed as febrile status epilepticus (FSE). The second and the third type of FS can be associated with neurological sequelae with subsequent afebrile or unprovoked seizures and may predispose to the development of cognitive deficits4,5 and to temporal lobe epilepsy, a severe drug-resistant form of acquired epilepsy.6 In prospective epidemiological studies, the risk of developing epilepsy after prolonged FS is in the range of 3%e7% by 25 years after the first FS (reviewed in the study by Baulac et al.7). Prospective and retrospective clinical studies in children with FS and the use of experimental models mimicking this condition enabled to
unveil some causative factors by which fever can cause seizures and permitted us to examine the molecular mechanisms by which prolonged FS may result in epilepsy (Fig. 29.1) and cognitive dysfunctions.
CAUSATIVE FACTORS MEDIATING SEIZURES CAUSED BY FEVER Genetic Susceptibility FSs are suspected to involve a genetic component; in this context, susceptibility genes have been described in familial forms of FS.7 There are molecular defects linking FS and epilepsy, such as the generalized epilepsy with FSþ, a clinical condition which describes families in which FS coexist with epilepsy.8 The genes implicated in FS include the voltage-gated Naþ channels (SCN1B, SCN1A), various gamma-aminobutyric acid (GABA-A) ligand-gated/receptor-coupled ion channel subunits, and hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels.9,10 Mutations in these genes encoding ion channel subunits are associated with channelopathies that elicit neuronal network hyperexcitability and seizures in response to fever. Severe myoclonic epilepsy in infancy (or Dravet’s syndrome) is an epileptic encephalopathy, which begins in infants with FS and is predominantly linked to SCN1A mutations in a proportion of patients,11 although additional genes are being reported to cause a similar clinical phenotype.12 Another notable example is the missense mutation in HCN2 channel that has been identified in two patients with FS. This mutant channel has elevated sensitivity to temperature, that is, the activation kinetics of mutant HCN2 were faster in hyperthermic conditions compared with the wild-type gene, increasing the availability of Ih current, thus promoting neuronal firing. This suggests that mutant HCN2 exposed to increased temperature induces neuronal hyperexcitability-promoting FS.10 However, gene mutations do not include the large majority of patients experiencing FS therefore implying that other mechanisms may also play a causative
CAUSATIVE FACTORS MEDIATING SEIZURES CAUSED BY FEVER
role. This mechanism will be discussed in the following paragraphs.
Increased Brain Temperature Affects Permeability of the Ion Channels An increase in brain temperature is known to alter the function of specific ion channels influencing both excitatory and inhibitory neurons.13 For example, the function of transient-receptor potential vanilloid channels (TRPV1 and TRPV4) is modulated by temperature, and these channels have been implicated in the precipitation of FS evoked by hyperthermia in animal models.14 A critical contribution of L-type Ca2þ channelsdCav1.2 subunitdto the temperaturedependent intrinsic firing of hippocampal pyramidal neurons was also reported. This subunit was significantly involved in the incidence and duration of FS in immature rodents.15
The Role of the Innate Immune System Clinical Studies The neuroimmune response to FS has been studied with particular attention to the potential involvement of ictogenic cytokines such as interleukin (IL)-1b and tumor necrosis factor (TNF)a.16 The first evidence for the involvement of IL-1b in FS was provided by a clinical study in children with FSs. This study showed an enhaced response of white blood cells to lipopolysaccharide (LPS), a membrane component of gram-negative bacteria that activates toll-like receptors (TLR4), compared with children with fever but no seizures and healthy controls.17 Similar findings were reported in WBC exposed to Poly I:C, a dsRNA which activates TLR3, therefore representing a viral mimicry.18 Moreover, functional polymorphisms in IL-1b and IL-1 receptor antagonist (Ra) gene promoters have been associated with increased susceptibility to FS in both Asian and Caucasian populations.19e22 Changes in cytokines concentrations in both cerebrospinal fluid (CSF) and blood were also measured in FS children although with variable results (reviewed in the study by Vezzani and Granata23). Studies in humans are however
405
difficult to interpret due to clinical variables and drug treatments; therefore the immune system involvement in FS was more robustly studied using animal models of fever. Experimental Studies Fever response can be induced by systemic LPS injection in immature rats between postnatal day (PN) 7e14 (reflecting early infancy in humans) when animals are kept at 30 C, corresponding to nesting temperature.16 In this condition, LPS evoked a monophasic increase in core body temperature and brain temperature mimicking a fever response lasting 60e120 min. This acute febrile response was associated with both short-term and chronic (lasting until animal’s adulthood) decreases in seizure threshold, which were assessed by exposing animals to low subconvulsive doses of various convulsive drugs.24 These animals however did not develop spontaneous seizures. Acute precipitation of seizures after LPS could be induced by low doses of kainic acid which were ineffective in causing seizures in naive rats. This acute effect occurred only in a proportion of animals and was dependent on both IL-1b and TNF-a increases in the hippocampus of the LPS-exposed animals. TNF-a has a pivotal role in determining the long-term increased seizure susceptibility after neonatal LPS exposure. Thus the long-term reduction in seizure threshold was prevented by anti-TNF, but not antieIL-1, antibodies delivered intracerebroventricularly (icv) and by systemic minocycline, a drug blocking microglia activation. Notably, FS in LPS-exposed rats led to an imbalance in the IL-1b-to-IL-1Ra ratio in the hippocampus, thus favoring an increase of the proinflammatory over the anti-inflammatory cytokine. A causal role of IL-1b in the genesis of FS in the LPS model was demonstrated by an increased incidence of FS after icv injection of IL-1b, while IL-1Ra had the opposite effect.25 The pivotal role of both IL-1b and IL-1Ra in acute FS was further supported by studies in a different model where FSs were induced in immature mice by hyperthermia provoked by a stream of warm air.26 IL-1 receptor type 1
406
29. FEBRILE RESPONSE AND SEIZURES
knockout mice, which are unable to respond to IL-1b, required an increased temperature for experiencing seizures, whereas a lower temperature was sufficient to evoke seizures in IL-1be injected mice.26
Alkalosis and FS Animal models of hyperthermia-induced seizures revealed another mechanism involved in seizure precipitation, which was subsequent to hyperventilation-induced alkalosis, a phenomenon also reported in some children with FS.27,28 Brain alkalosis may promote neuronal excitability29 and could contribute to FS when hyperventilation occurs.
Potassium Chloride Cotransporter During embryonic life and early postnatal development, the intracellular chloride concentration in GABAergic neurons is relatively high due to the low expression level of KCC2 (the Kþ-Cl cotransporter), which normally extrudes Cl ions from the cells and because of the relatively high expression of NKCC1 (Naþ, Kþ, Cl cotransporter), which mediates Cl influx. This is in tune with the known developmental phenomenon that GABA mediates depolarizing rather than hyperpolarizing responses in immature neurons. This phenomenon is reversed after the first postnatal week by the rapid upregulation of KCC2.30,31 Notably, a variant of the KCC2-encoding gene was identified in a family with FS,32 which leads to a reduced Cl extrusion possibly resulting in increased neuronal network excitability. Moreover, a recent study using a model of complex FS reported an aberrant ectopic migration of neonatal-generated granule cells that persisted into adulthood and was mediated by NKCC1 and depolarizing GABA. Inhibition of NKCC1 by bumetanide after FS rescued the ectopic granule cells as well as development of epilepsy in the animals.33 This study provides a cellular and molecular mechanism for the ensuing epilepsy that has long been suspected to occur in young children after prolonged FS.
FSS AND EPILEPSY: HUMAN AND ANIMAL STUDIES Temporal lobe epilepsy and hippocampal sclerosis (HS) commonly arise after FSE in children. However, the causal relationship has not been unequivocally demonstrated as yet. The FEBSTAT (Consequences of Prolonged Febrile Seizures in Childhood) study was designed to prospectively examine the association between FSE, development of HS, and temporal lobe epilepsy.34,35 Although this study is still under way, several interesting observations have already emerged. These include (1) the high rate of human herpesvirus 6B infection in the FEBSTAT cohort compared with children with acute febrile illness but no seizures36; notably, the same virus is overexpressed in temporal lobe epilepsy brain specimens37; (2) a series of risk factors for developing epilepsy have been identified38 (reviewed in the study by Harden39); (3) potential early mechanistic biomarkers of epileptogenesis have been described including electroencephalographic (EEG) signatures, CSF cytokines, and serum cytokines. In particular, the serum IL-1b-to-IL-1Ra ratio is higher in FSE versus children with fever but no seizures,40 denoting an inefficient control by IL1Ra of the IL-1b signaling, which may contribute to decreased seizure threshold.41 MRI T2 signal of hippocampal injury35 and possibly preexisting hippocampal abnormalities42,43 have been analyzed by FEBSTAT as potential biomarkers for neurological sequelae. Febrile infection-related epilepsy syndrome (FIRES) is one of the most severe and presumably immune-mediated epileptic encephalopathies affecting healthy children. Refractory status epilepticus or a cluster of seizures typically start a few days after the onset of an acute febrile illness. Sequelae of FIRES are drugresistant epilepsy (seizures do not respond to traditional antiepileptic drugs) and neuropsychological impairments occurring without latency.44 In favor of the hypothesis of an immune-mediated pathological mechanism triggering unremitting seizures after fever, there is a recent proof-of-concept study showing the
FSS AND EPILEPSY: HUMAN AND ANIMAL STUDIES
therapeutic effect of anakinra in controlling seizures in a child affected by FIRES.45 Therapeutic effects of anakinra were also reported in four children affected by specific polysaccharide antibody deficiency with recurrent febrile infections and drug-resistant epilepsy.46 The mechanistic relationship between FSE and epilepsy is being extensively studied in animal models (reviewed in the study by Sanon47; Fig. 29.1). These studies demonstrated the FSE induced in animals which are otherwise normal at the time of induced fever can cause epilepsy suggesting that the epileptogenic process can be initiated by FSE itself. In particular, the duration of FSE induced by hyperthermia is a crucial factor influencing the incidence of epilepsy and the severity of the ensuing spontaneous seizures.48 Although no overt cell loss in forebrain areas was found in FSE models, the induction of FSE in animals with a preexisting injured brain increased dramatically the incidence of later epilepsy.49 A crucial question is how does epilepsy arise after FSE? Neuroinflammation has emerged as a major mechanism of epileptogenesis in various clinical conditions.50 In the context of FS, fever involves the release of inflammatory mediators including IL-1b, TNF-a, high-mobility group Box (HMGB1) and prostaglandin E2 that are
407
implicated in lowering seizure threshold and have been shown to promote the generation of acute and chronic seizures in animals.41,51,52 The potential mechanisms by which inflammatory mediators promote seizures include the rapid onset posttranslational changes in voltage-gated and ligand-gated/receptorcoupled ion channels (e.g., GABA-A, a-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid, and N-methyl-D-aspartate receptors), resulting in enhanced neuronal excitability.53,54 For example, the activation of IL-1b-IL-1R1 axis or the TLR4 signaling activated by the endogenous protein HMGB1 released by neurons during FSE55,56 leads to increased neuronal Ca2þ influx via the NMDA receptors. This event causes neuronal hyperexcitability57,58 and promotes seizures.59,60 The TLR4 activation by LPS in PN14 rats provoked both fever and decreased seizure threshold, which was coincident with increased excitability in the rat hippocampus. These neuronal effects lasted until rat’s adulthood and were associated with transcriptional changes in both NMDA and GABA receptor subunits, as well as increased NKCC1 transporter expression in the hippocampus and cortex.61,62 Similarly, long-term molecular modifications were measured in immature animals exposed FIGURE 29.1 Risk factors (blue frame) and triggers (pink frames) of cellular/molecular mechanisms (green box) potentially involved in the acute and chronic precipitation of seizures induced by fever. The green box reports a list of brain tissue molecular changes described in animal models of prolonged febrile seizures or febrile status epilepticus that were associated with febrile seizure precipitation (acute effects). The same molecular changes (green box) may also contribute to persistent neuronal network hyperexcitability (chronic effects) resulting in decreased seizure threshold thereby promoting epilepsy development.
408
29. FEBRILE RESPONSE AND SEIZURES
to poly I:C-induced fever.63 The activation of cannabinoid (CB1) receptors was involved in LPS, but not in poly I:C, induced FS and the consequent transcriptional gene activation.64 These results indicate that coordinated changes in FSE-induced expression of various genes may contribute to epileptogenesis in animal models. In support, FSE provokes a reduction of HCN channel expression and Ih current in pyramidal neurons, an increase in endocannabinoid receptors on GABAergic terminals promoting inhibition of GABA release65 and the induction of specific transcription factors, such as the neuron-restrictive silencer factor (NRSF), implicated in the regulation of the expression of neuronal channels and synaptic proteins.66 FSE can also affect the hippocampal astrocytic network by reducing Connexin-43 protein and consequently impairing the gap junctional coupling of astrocytes, which is instrumental for removing extracellular Kþ and for water homeostasis.67 These transcriptional and molecular changes were also described in other rodent models of epilepsy where they contribute to the generation of spontaneous seizures.68
FSS AND COGNITIVE DYSFUNCTION Cognitive dysfunction may arise in a subset of animals exposed to prolonged FS,4 a condition which involves disturbances in the function of hippocampal place cells that encode information about spatial orientation.69 FSE provoked regionspecific dendritic loss in the hippocampus and aberrant generation of excitatory synapses in dentate gyrus granule cells.66,70 Blocking the transcriptional factor NRSF after FSE prevented granule cell dysfunction and restored spatial memories.66 Notably, cognitive impairment may occur before the animal develops epilepsy therefore is not a mere consequence of spontaneous seizures. A recent study showed that FSE induces structural reorganizations in the hippocampus and modifies learning abilities in an age-dependent manner.71 Animals experiencing FS at PN11,
but not at PN14, developed ectopic granule cells, increased mossy fiber terminals, and the drug bumetanide reversed these effects and improved memory.71 The FEBSTAT study was designed to address the question whether FSE can cause cognitive deficits in children, and a follow-up of FEBSTAT is in progress to track potential long-term cognitive dysfunctions.72
IMPLICATIONS FOR THERAPY Experimental models highlight the importance of avoiding long duration of FS for preventing epileptogenesis in a noncompromised brain. However, it is clinically difficult to intervene rapidly enough to interrupt FSE. The identification of children who will develop epilepsy and cognitive dysfunctions would permit intervention to block the progression of the disease. Hence the FEBSTAT study is investigating the predictive value of MRI, EEG, and blood cytokines measures. In animal models of FSE early but persistent changes in MRI T2 signal in the hippocampus correlated with hippocampal dysfunction manifested as spatial memory deficits but not with epilepsy development.4,48 On the other hand, T2 signal modifications in the amygdala predicted epilepsy development in the same model.55 EEG interictal spikes after FSE showed a predictive value for epilepsy development only in animals with a preexisting focal cortical lesion.49 In summary, a combination of biomarkers together with a better understanding of the genetic predisposition, causative factors, and molecular mechanisms involved in the precipitation of prolonged FS or FSE and their long-term pathologic sequelae is instrumental for developing effective preventive treatment strategies that are still lacking.
References 1. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia. 1994;35(Suppl. 2): S1eS6.
REFERENCES
2. Frucht MM, Quigg M, Schwaner C, Fountain NB. Distribution of seizure precipitants among epilepsy syndromes. Epilepsia. 2000;41(12):1534e1539. 3. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia. 1996;37(2):126e133. 4. Dube´ CM, Zhou J-L, Hamamura M, et al. Cognitive dysfunction after experimental febrile seizures. Exp Neurol. 2009;215(1):167e177. 5. Chang YC, Guo NW, Wang ST, Huang CC, Tsai JJ. Working memory of school-aged children with a history of febrile convulsions: a population study. Neurology. 2001;57(1):37e42. 6. Patterson KP, Baram TZ, Shinnar S. Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics. 2014;11(2):242e250. 7. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes, and epilepsy. Lancet Neurol. 2004;3:421e430. 8. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain. 1997;120(Pt 3): 479e490. 9. Dibbens LM, Reid CA, Hodgson B, et al. Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann Neurol. 2010;67(4):542e546. 10. Nakamura Y, Shi X, Numata T, et al. Novel HCN2 mutation contributes to febrile seizures by shifting the channel’s kinetics in a temperature-dependent manner. PLoS One. 2013;8(12):e80376. 11. Nabbout R, Gennaro E, Dalla Bernardina B, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003;60(12):1961e1967. 12. Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia. 2017;58(11):1807e1816. 13. Kim JA, Connors BW. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus. Front Cell Neurosci. 2012; 6:27. 14. Hunt RF, Hortopan GA, Gillespie A, Baraban SC. A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDAtype glutamate receptors. Exp Neurol. 2012;237(1): 199e206. 15. Radzicki D, Yau H-J, Pollema-Mays SL, et al. Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures. J Neurosci. 2013;33(24):9920e9931. 16. Heida JG, Moshe SL, Pittman QJ. The role of interleukin-1beta in febrile seizures. Brain Dev. 2009;31: 388e393. 17. Helminen M, Vesikari T. Increased interleukin-1 (IL-1) production from LPS-stimulated peripheral blood monocytes in children with febrile convulsions. Acta Paediatr Scand. 1990;79:810e816. 18. Matsuo M, Sasaki K, Ichimaru T, Nakazato S, Hamasaki Y. Increased IL-1beta production from
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
409 dsRNA-stimulated leukocytes in febrile seizures. Pediatr Neurol. 2006;35:102e106. Kanemoto K, Kawasaki J, Yuasa S, et al. Increased frequency of interleukin-1beta-511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Epilepsia. 2003;44: 796e799. Virta M, Hurme M, Helminen M. Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures. Pediatr Neurol. 2002;26:192e195. Kira R, Torisu H, Takemoto M, et al. Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases. Neurosci Lett. 2005;384:239e244. Chou I-C, Lin W-D, Wang C-H, Tsai C-H, Li T-C, Tsai FJ. Interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor alpha gene polymorphisms in patients with febrile seizures. J Clin Lab Anal. 2010;24(3):154e159. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005;46: 1724e1743. Heida JG, Boisse L, Pittman QJ. Lipopolysaccharideinduced febrile convulsions in the rat: short-term sequelae. Epilepsia. 2004;45:1317e1329. Heida JG, Pittman QJ. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia. 2005;46:1906e1913. Dube´ C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol. 2005;57: 152e155. Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermiainduced respiratory alkalosis. Nat Med. 2006;12(7): 817e823. Schuchmann S, Hauck S, Henning S, et al. Respiratory alkalosis in children with febrile seizures. Epilepsia. 2011;52(11):1949e1955. Aram JA, Lodge D. Epileptiform activity induced by alkalosis in rat neocortical slices: block by antagonists of N-methyl-D-aspartate. Neurosci Lett. 1987;83(3): 345e350. Ben-Ari Y, Cherubini E, Corradetti R, Gaiarsa JL. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol. 1989;416:303e325. Rivera C, Voipio J, Payne JA, et al. The Kþ/Cl- cotransporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397(6716): 251e255. Puskarjov M, Seja P, Heron SE, et al. A variant of KCC2 from patients with febrile seizures impairs neuronal Clextrusion and dendritic spine formation. EMBO Rep. 2014;15(6):723e729. Koyama R, Tao K, Sasaki T, et al. GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat Med. 2012;18(8):1271e1278.
410
29. FEBRILE RESPONSE AND SEIZURES
34. Hesdorffer DC, Shinnar S, Lewis DV, et al. Design and phenomenology of the FEBSTAT study. Epilepsia. 2012; 53(9):1471e1480. 35. Lewis DV, Shinnar S, Hesdorffer DC, et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol. 2014;75:178e185. 36. Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012;53(9):1481e1488. 37. Donati D, Akhyani N, Fogdell-Hahn A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology. 2003;61(10): 1405e1411. 38. Hesdorffer DC, Shinnar S, Lax DN, et al. Risk factors for subsequent febrile seizures in the FEBSTAT study. Epilepsia. 2016;57(7):1042e1047. 39. Harden C. Findings from the FEBSTAT study: can observations after a provoked seizure occurrence have broad implications for epileptogenesis? Epilepsy Curr. 2013; 13(3):143e145. 40. Gallentine WB, Shinnar S, Hesdorffer DC, et al. Plasma cytokines associated with febrile status epilepticus in children: a potential biomarker for acute hippocampal injury. Epilepsia. 2017;58(6):1102e1111. 41. Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun. 2011;25:1281e1289. 42. Chan S, Bello JA, Shinnar S, et al. Hippocampal malrotation is associated with prolonged febrile seizures: results of the FEBSTAT study. AJR Am J Roentgenol. 2015; 205(5):1068e1074. 43. McClelland AC, Gomes WA, Shinnar S, et al. Quantitative evaluation of medial temporal lobe morphology in children with febrile status epilepticus: results of the FEBSTAT study. AJNR Am J Neuroradiol. 2016;37(12): 2356e2362. 44. van Baalen A, Vezzani A, Ha¨usler M, Kluger G. Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis. Neuropediatrics. 2017;48(1):5e18, 1. 45. Kenney-Jung DL, Vezzani A, Kahoud RJ, et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol. 2016;80:939e945. 46. Jyonouchi H. Intractable epilepsy (IE) and responses to anakinra, a human recombinant IL-1 receptor antagonist (IL-1Ra): case reports. J Clin Cell Immunol. 2016;7: 456e460. 47. Sanon N, Shaker T, Carmant L. Poststatus epilepticus models: hyperthermia. In: Pitkanen A, Buckmaster P, Galanopoulou AS, Moshe´ SL, eds. Models of Seizures and Epilepsy. Elsevier Inc; 2017:651e660. 48. Dube´ CM, Ravizza T, Hamamura M, et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci. 2010; 30:7484e7494.
49. Scantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropoulou C, Carmant L. Febrile seizures in the predisposed brain: a new model of temporal lobe epilepsy. Ann Neurol. 2005;58:41e49. 50. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7: 31e40. 51. Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia. 2017;58(Suppl. 3):27e38. 52. Iori V, Iyer AM, Ravizza T, et al. Blockade of the IL-1R1/ TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis. 2017;99:12e23. 53. Roseti C, van Vliet EA, Cifelli P, et al. GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis. 2015;82:311e320. 54. Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70e82. 55. Choy M, Dube CM, Patterson K, et al. A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J Neurosci. 2014;34:8672e8684. 56. Patterson KP, Brennan GP, Curran B, et al. Coordinate inflammatory responses after experimental febrile status epilepticus: implication for epileptogenesis. eNeuro. 2015;2. e0034e15. 57. Viviani B, Bartesaghi S, Gardoni F, et al. Interleukin1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23:8692e8700. 58. Balosso S, Liu J, Bianchi ME, Vezzani A. Disulfidecontaining High Mobility Group Box-1 promotes Nmethyl-d-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal. 2014;21: 1726e1740. 59. Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010;16:413e419. 60. Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain. 2008;131: 3256e3265. 61. Reid AY, Riazi K, Campbell Teskey G, Pittman QJ. Increased excitability and molecular changes in adult rats after a febrile seizure. Epilepsia. 2013;54:e45ee48. 62. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocr. 2012;33:116e125. 63. Galic MA, Riazi K, Henderson AK, Tsutsui S, Pittman QJ. Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. Neurobiol Dis. 2009;36:343e351. 64. Duncan M, Galic MA, Wang A, et al. Cannabinoid 1 receptors are critical for the innate immune response to
REFERENCES
65.
66.
67.
68.
TLR4 stimulation. Am J Physiol Regul Integr Comp Physiol. 2013;305(3):R224eR231. Chen K, Ratzliff A, Hilgenberg L, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron. 2003;39(4):599e611. Patterson KP, Barry JM, Curran MM, et al. Enduring memory impairments provoked by developmental febrile seizures are mediated by functional and structural effects of neuronal restrictive silencing factor. J Neurosci. 2017;37(14):3799e3812. Khan D, Dupper A, Deshpande T, Graan PNED, Steinha¨user C, Bedner P. Experimental febrile seizures impair interastrocytic gap junction coupling in juvenile mice. J Neurosci Res. 2016;94(9):804e813. Kova´cs R, Heinemann U, Steinha¨user C. Mechanisms underlying blood-brain barrier dysfunction in brain
69.
70.
71.
72.
411 pathology and epileptogenesis: role of astroglia. Epilepsia. 2012;53(Suppl 6):53e59. Reid AY, Pittman QJ, Teskey GC. A prolonged experimental febrile seizure results in motor map reorganization in adulthood. Neurobiol Dis. 2012;45(2): 692e700. Raijmakers M, Clynen E, Smisdom N, et al. Experimental febrile seizures increase dendritic complexity of newborn dentate granule cells. Epilepsia. 2016;57(5):717e726. Tao K, Ichikawa J, Matsuki N, Ikegaya Y, Koyama R. Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice. Neuroscience. 2016;318:34e44. Weiss EF, Masur D, Shinnar S, et al. Cognitive functioning one month and one year following febrile status epilepticus. Epilepsy Behav EB. 2016;64(Pt A):283e288.
29 Febrile Response and Seizures Annamaria Vezzani1, Tamas Bartfai2 1
Department of Neuroscience, Mario Negri Institute for Pharmacological Research IRCCS, Milano, Italy; 2 Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
O U T L I N E Fever and Seizures
403
Causative Factors Mediating Seizures Caused by Fever 404 Genetic Susceptibility 404 Increased Brain Temperature Affects Permeability of the Ion Channels 405 The Role of the Innate Immune System 405 Clinical Studies Experimental Studies
405 405
FEVER AND SEIZURES Fever can cause seizuresda condition termed febrile seizures (FS)din infants and young children usually between 3 months and 5 years of age therefore in a restricted age-dependent manner. FS is the most common type of childhood seizure disorder occurring in about 2%e5% of children in the United States and Western Europe, more frequently in some Asian countries.1 However, fever also leads to ictal events in 14% of adults with established epilepsy,2 thus FS is not an exclusively pediatric phenomenon. FSs are associated with a fever of 38 C or higher and occur with no evidence of central nervous system infection, metabolic abnormality, or
Stress: Physiology, Biochemistry, and Pathology https://doi.org/10.1016/B978-0-12-813146-6.00029-1
Alkalosis and FS Potassium Chloride Cotransporter
406 406
FSs and Epilepsy: Human and Animal Studies
406
FSs and Cognitive Dysfunction
408
Implications for Therapy
408
References
408
a defined cause.3 This does not exclude that children with FS may have preexisting neurological deficits, which is a confounding factor when studying the outcomes of FS.
403
KEY POINTS • Fever is a concerted stress response that is associated with temporarily elevated brain temperature and core body temperature but does not involve a change in the temperature set point of the homoeothermic animal. • Fever is one of the oldest biomarkers and involves neuronal activity changes in the anterior hypothalamus, hippocampus, and cerebral cortex.
Copyright © 2019 Elsevier Inc. All rights reserved.
404
29. FEBRILE RESPONSE AND SEIZURES
• Interleukin-1 (IL-1), tumor necrosis factor, and prostaglandin E have all been shown to act as endogenous pyrogens. IL-1b, the most potent endogenous pyrogen, is balanced by the IL-1 receptor antagonist (IL-1Ra). • The human recombinant form of IL-1Ra (i.e., anakinra) is an approved antiinflammatory drug endowed with anticonvulsive effects. • High fever is common in children where it may cause febrile seizures in 2%e5% of cases. Although most febrile seizures are benign, prolonged febrile seizures increase the risk of developing epilepsy. • Anakinra may control unprovoked seizures, initially triggered by fever, in children and adolescents who are not responsive to traditional antiepileptic drugs. • The search for genetic and molecular predictors of the long-term consequences of febrile seizures represents an area of active clinical and experimental studies.
FS can be divided into three main types based on their semiology and duration: (1) simple FSs are single seizures of short duration occurring during a febrile illness, and they are generally generalized and benign; (2) complex FSs are longer in duration (15e30 min), may have focal onset, and can recur within 24 h; (3) FSs lasting for more than 30 min are termed as febrile status epilepticus (FSE). The second and the third type of FS can be associated with neurological sequelae with subsequent afebrile or unprovoked seizures and may predispose to the development of cognitive deficits4,5 and to temporal lobe epilepsy, a severe drug-resistant form of acquired epilepsy.6 In prospective epidemiological studies, the risk of developing epilepsy after prolonged FS is in the range of 3%e7% by 25 years after the first FS (reviewed in the study by Baulac et al.7). Prospective and retrospective clinical studies in children with FS and the use of experimental models mimicking this condition enabled to
unveil some causative factors by which fever can cause seizures and permitted us to examine the molecular mechanisms by which prolonged FS may result in epilepsy (Fig. 29.1) and cognitive dysfunctions.
CAUSATIVE FACTORS MEDIATING SEIZURES CAUSED BY FEVER Genetic Susceptibility FSs are suspected to involve a genetic component; in this context, susceptibility genes have been described in familial forms of FS.7 There are molecular defects linking FS and epilepsy, such as the generalized epilepsy with FSþ, a clinical condition which describes families in which FS coexist with epilepsy.8 The genes implicated in FS include the voltage-gated Naþ channels (SCN1B, SCN1A), various gamma-aminobutyric acid (GABA-A) ligand-gated/receptor-coupled ion channel subunits, and hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels.9,10 Mutations in these genes encoding ion channel subunits are associated with channelopathies that elicit neuronal network hyperexcitability and seizures in response to fever. Severe myoclonic epilepsy in infancy (or Dravet’s syndrome) is an epileptic encephalopathy, which begins in infants with FS and is predominantly linked to SCN1A mutations in a proportion of patients,11 although additional genes are being reported to cause a similar clinical phenotype.12 Another notable example is the missense mutation in HCN2 channel that has been identified in two patients with FS. This mutant channel has elevated sensitivity to temperature, that is, the activation kinetics of mutant HCN2 were faster in hyperthermic conditions compared with the wild-type gene, increasing the availability of Ih current, thus promoting neuronal firing. This suggests that mutant HCN2 exposed to increased temperature induces neuronal hyperexcitability-promoting FS.10 However, gene mutations do not include the large majority of patients experiencing FS therefore implying that other mechanisms may also play a causative
CAUSATIVE FACTORS MEDIATING SEIZURES CAUSED BY FEVER
role. This mechanism will be discussed in the following paragraphs.
Increased Brain Temperature Affects Permeability of the Ion Channels An increase in brain temperature is known to alter the function of specific ion channels influencing both excitatory and inhibitory neurons.13 For example, the function of transient-receptor potential vanilloid channels (TRPV1 and TRPV4) is modulated by temperature, and these channels have been implicated in the precipitation of FS evoked by hyperthermia in animal models.14 A critical contribution of L-type Ca2þ channelsdCav1.2 subunitdto the temperaturedependent intrinsic firing of hippocampal pyramidal neurons was also reported. This subunit was significantly involved in the incidence and duration of FS in immature rodents.15
The Role of the Innate Immune System Clinical Studies The neuroimmune response to FS has been studied with particular attention to the potential involvement of ictogenic cytokines such as interleukin (IL)-1b and tumor necrosis factor (TNF)a.16 The first evidence for the involvement of IL-1b in FS was provided by a clinical study in children with FSs. This study showed an enhaced response of white blood cells to lipopolysaccharide (LPS), a membrane component of gram-negative bacteria that activates toll-like receptors (TLR4), compared with children with fever but no seizures and healthy controls.17 Similar findings were reported in WBC exposed to Poly I:C, a dsRNA which activates TLR3, therefore representing a viral mimicry.18 Moreover, functional polymorphisms in IL-1b and IL-1 receptor antagonist (Ra) gene promoters have been associated with increased susceptibility to FS in both Asian and Caucasian populations.19e22 Changes in cytokines concentrations in both cerebrospinal fluid (CSF) and blood were also measured in FS children although with variable results (reviewed in the study by Vezzani and Granata23). Studies in humans are however
405
difficult to interpret due to clinical variables and drug treatments; therefore the immune system involvement in FS was more robustly studied using animal models of fever. Experimental Studies Fever response can be induced by systemic LPS injection in immature rats between postnatal day (PN) 7e14 (reflecting early infancy in humans) when animals are kept at 30 C, corresponding to nesting temperature.16 In this condition, LPS evoked a monophasic increase in core body temperature and brain temperature mimicking a fever response lasting 60e120 min. This acute febrile response was associated with both short-term and chronic (lasting until animal’s adulthood) decreases in seizure threshold, which were assessed by exposing animals to low subconvulsive doses of various convulsive drugs.24 These animals however did not develop spontaneous seizures. Acute precipitation of seizures after LPS could be induced by low doses of kainic acid which were ineffective in causing seizures in naive rats. This acute effect occurred only in a proportion of animals and was dependent on both IL-1b and TNF-a increases in the hippocampus of the LPS-exposed animals. TNF-a has a pivotal role in determining the long-term increased seizure susceptibility after neonatal LPS exposure. Thus the long-term reduction in seizure threshold was prevented by anti-TNF, but not antieIL-1, antibodies delivered intracerebroventricularly (icv) and by systemic minocycline, a drug blocking microglia activation. Notably, FS in LPS-exposed rats led to an imbalance in the IL-1b-to-IL-1Ra ratio in the hippocampus, thus favoring an increase of the proinflammatory over the anti-inflammatory cytokine. A causal role of IL-1b in the genesis of FS in the LPS model was demonstrated by an increased incidence of FS after icv injection of IL-1b, while IL-1Ra had the opposite effect.25 The pivotal role of both IL-1b and IL-1Ra in acute FS was further supported by studies in a different model where FSs were induced in immature mice by hyperthermia provoked by a stream of warm air.26 IL-1 receptor type 1
406
29. FEBRILE RESPONSE AND SEIZURES
knockout mice, which are unable to respond to IL-1b, required an increased temperature for experiencing seizures, whereas a lower temperature was sufficient to evoke seizures in IL-1be injected mice.26
Alkalosis and FS Animal models of hyperthermia-induced seizures revealed another mechanism involved in seizure precipitation, which was subsequent to hyperventilation-induced alkalosis, a phenomenon also reported in some children with FS.27,28 Brain alkalosis may promote neuronal excitability29 and could contribute to FS when hyperventilation occurs.
Potassium Chloride Cotransporter During embryonic life and early postnatal development, the intracellular chloride concentration in GABAergic neurons is relatively high due to the low expression level of KCC2 (the Kþ-Cl cotransporter), which normally extrudes Cl ions from the cells and because of the relatively high expression of NKCC1 (Naþ, Kþ, Cl cotransporter), which mediates Cl influx. This is in tune with the known developmental phenomenon that GABA mediates depolarizing rather than hyperpolarizing responses in immature neurons. This phenomenon is reversed after the first postnatal week by the rapid upregulation of KCC2.30,31 Notably, a variant of the KCC2-encoding gene was identified in a family with FS,32 which leads to a reduced Cl extrusion possibly resulting in increased neuronal network excitability. Moreover, a recent study using a model of complex FS reported an aberrant ectopic migration of neonatal-generated granule cells that persisted into adulthood and was mediated by NKCC1 and depolarizing GABA. Inhibition of NKCC1 by bumetanide after FS rescued the ectopic granule cells as well as development of epilepsy in the animals.33 This study provides a cellular and molecular mechanism for the ensuing epilepsy that has long been suspected to occur in young children after prolonged FS.
FSS AND EPILEPSY: HUMAN AND ANIMAL STUDIES Temporal lobe epilepsy and hippocampal sclerosis (HS) commonly arise after FSE in children. However, the causal relationship has not been unequivocally demonstrated as yet. The FEBSTAT (Consequences of Prolonged Febrile Seizures in Childhood) study was designed to prospectively examine the association between FSE, development of HS, and temporal lobe epilepsy.34,35 Although this study is still under way, several interesting observations have already emerged. These include (1) the high rate of human herpesvirus 6B infection in the FEBSTAT cohort compared with children with acute febrile illness but no seizures36; notably, the same virus is overexpressed in temporal lobe epilepsy brain specimens37; (2) a series of risk factors for developing epilepsy have been identified38 (reviewed in the study by Harden39); (3) potential early mechanistic biomarkers of epileptogenesis have been described including electroencephalographic (EEG) signatures, CSF cytokines, and serum cytokines. In particular, the serum IL-1b-to-IL-1Ra ratio is higher in FSE versus children with fever but no seizures,40 denoting an inefficient control by IL1Ra of the IL-1b signaling, which may contribute to decreased seizure threshold.41 MRI T2 signal of hippocampal injury35 and possibly preexisting hippocampal abnormalities42,43 have been analyzed by FEBSTAT as potential biomarkers for neurological sequelae. Febrile infection-related epilepsy syndrome (FIRES) is one of the most severe and presumably immune-mediated epileptic encephalopathies affecting healthy children. Refractory status epilepticus or a cluster of seizures typically start a few days after the onset of an acute febrile illness. Sequelae of FIRES are drugresistant epilepsy (seizures do not respond to traditional antiepileptic drugs) and neuropsychological impairments occurring without latency.44 In favor of the hypothesis of an immune-mediated pathological mechanism triggering unremitting seizures after fever, there is a recent proof-of-concept study showing the
FSS AND EPILEPSY: HUMAN AND ANIMAL STUDIES
therapeutic effect of anakinra in controlling seizures in a child affected by FIRES.45 Therapeutic effects of anakinra were also reported in four children affected by specific polysaccharide antibody deficiency with recurrent febrile infections and drug-resistant epilepsy.46 The mechanistic relationship between FSE and epilepsy is being extensively studied in animal models (reviewed in the study by Sanon47; Fig. 29.1). These studies demonstrated the FSE induced in animals which are otherwise normal at the time of induced fever can cause epilepsy suggesting that the epileptogenic process can be initiated by FSE itself. In particular, the duration of FSE induced by hyperthermia is a crucial factor influencing the incidence of epilepsy and the severity of the ensuing spontaneous seizures.48 Although no overt cell loss in forebrain areas was found in FSE models, the induction of FSE in animals with a preexisting injured brain increased dramatically the incidence of later epilepsy.49 A crucial question is how does epilepsy arise after FSE? Neuroinflammation has emerged as a major mechanism of epileptogenesis in various clinical conditions.50 In the context of FS, fever involves the release of inflammatory mediators including IL-1b, TNF-a, high-mobility group Box (HMGB1) and prostaglandin E2 that are
407
implicated in lowering seizure threshold and have been shown to promote the generation of acute and chronic seizures in animals.41,51,52 The potential mechanisms by which inflammatory mediators promote seizures include the rapid onset posttranslational changes in voltage-gated and ligand-gated/receptorcoupled ion channels (e.g., GABA-A, a-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid, and N-methyl-D-aspartate receptors), resulting in enhanced neuronal excitability.53,54 For example, the activation of IL-1b-IL-1R1 axis or the TLR4 signaling activated by the endogenous protein HMGB1 released by neurons during FSE55,56 leads to increased neuronal Ca2þ influx via the NMDA receptors. This event causes neuronal hyperexcitability57,58 and promotes seizures.59,60 The TLR4 activation by LPS in PN14 rats provoked both fever and decreased seizure threshold, which was coincident with increased excitability in the rat hippocampus. These neuronal effects lasted until rat’s adulthood and were associated with transcriptional changes in both NMDA and GABA receptor subunits, as well as increased NKCC1 transporter expression in the hippocampus and cortex.61,62 Similarly, long-term molecular modifications were measured in immature animals exposed FIGURE 29.1 Risk factors (blue frame) and triggers (pink frames) of cellular/molecular mechanisms (green box) potentially involved in the acute and chronic precipitation of seizures induced by fever. The green box reports a list of brain tissue molecular changes described in animal models of prolonged febrile seizures or febrile status epilepticus that were associated with febrile seizure precipitation (acute effects). The same molecular changes (green box) may also contribute to persistent neuronal network hyperexcitability (chronic effects) resulting in decreased seizure threshold thereby promoting epilepsy development.
408
29. FEBRILE RESPONSE AND SEIZURES
to poly I:C-induced fever.63 The activation of cannabinoid (CB1) receptors was involved in LPS, but not in poly I:C, induced FS and the consequent transcriptional gene activation.64 These results indicate that coordinated changes in FSE-induced expression of various genes may contribute to epileptogenesis in animal models. In support, FSE provokes a reduction of HCN channel expression and Ih current in pyramidal neurons, an increase in endocannabinoid receptors on GABAergic terminals promoting inhibition of GABA release65 and the induction of specific transcription factors, such as the neuron-restrictive silencer factor (NRSF), implicated in the regulation of the expression of neuronal channels and synaptic proteins.66 FSE can also affect the hippocampal astrocytic network by reducing Connexin-43 protein and consequently impairing the gap junctional coupling of astrocytes, which is instrumental for removing extracellular Kþ and for water homeostasis.67 These transcriptional and molecular changes were also described in other rodent models of epilepsy where they contribute to the generation of spontaneous seizures.68
FSS AND COGNITIVE DYSFUNCTION Cognitive dysfunction may arise in a subset of animals exposed to prolonged FS,4 a condition which involves disturbances in the function of hippocampal place cells that encode information about spatial orientation.69 FSE provoked regionspecific dendritic loss in the hippocampus and aberrant generation of excitatory synapses in dentate gyrus granule cells.66,70 Blocking the transcriptional factor NRSF after FSE prevented granule cell dysfunction and restored spatial memories.66 Notably, cognitive impairment may occur before the animal develops epilepsy therefore is not a mere consequence of spontaneous seizures. A recent study showed that FSE induces structural reorganizations in the hippocampus and modifies learning abilities in an age-dependent manner.71 Animals experiencing FS at PN11,
but not at PN14, developed ectopic granule cells, increased mossy fiber terminals, and the drug bumetanide reversed these effects and improved memory.71 The FEBSTAT study was designed to address the question whether FSE can cause cognitive deficits in children, and a follow-up of FEBSTAT is in progress to track potential long-term cognitive dysfunctions.72
IMPLICATIONS FOR THERAPY Experimental models highlight the importance of avoiding long duration of FS for preventing epileptogenesis in a noncompromised brain. However, it is clinically difficult to intervene rapidly enough to interrupt FSE. The identification of children who will develop epilepsy and cognitive dysfunctions would permit intervention to block the progression of the disease. Hence the FEBSTAT study is investigating the predictive value of MRI, EEG, and blood cytokines measures. In animal models of FSE early but persistent changes in MRI T2 signal in the hippocampus correlated with hippocampal dysfunction manifested as spatial memory deficits but not with epilepsy development.4,48 On the other hand, T2 signal modifications in the amygdala predicted epilepsy development in the same model.55 EEG interictal spikes after FSE showed a predictive value for epilepsy development only in animals with a preexisting focal cortical lesion.49 In summary, a combination of biomarkers together with a better understanding of the genetic predisposition, causative factors, and molecular mechanisms involved in the precipitation of prolonged FS or FSE and their long-term pathologic sequelae is instrumental for developing effective preventive treatment strategies that are still lacking.
References 1. Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia. 1994;35(Suppl. 2): S1eS6.
REFERENCES
2. Frucht MM, Quigg M, Schwaner C, Fountain NB. Distribution of seizure precipitants among epilepsy syndromes. Epilepsia. 2000;41(12):1534e1539. 3. Berg AT, Shinnar S. Complex febrile seizures. Epilepsia. 1996;37(2):126e133. 4. Dube´ CM, Zhou J-L, Hamamura M, et al. Cognitive dysfunction after experimental febrile seizures. Exp Neurol. 2009;215(1):167e177. 5. Chang YC, Guo NW, Wang ST, Huang CC, Tsai JJ. Working memory of school-aged children with a history of febrile convulsions: a population study. Neurology. 2001;57(1):37e42. 6. Patterson KP, Baram TZ, Shinnar S. Origins of temporal lobe epilepsy: febrile seizures and febrile status epilepticus. Neurotherapeutics. 2014;11(2):242e250. 7. Baulac S, Gourfinkel-An I, Nabbout R, et al. Fever, genes, and epilepsy. Lancet Neurol. 2004;3:421e430. 8. Scheffer IE, Berkovic SF. Generalized epilepsy with febrile seizures plus. A genetic disorder with heterogeneous clinical phenotypes. Brain. 1997;120(Pt 3): 479e490. 9. Dibbens LM, Reid CA, Hodgson B, et al. Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann Neurol. 2010;67(4):542e546. 10. Nakamura Y, Shi X, Numata T, et al. Novel HCN2 mutation contributes to febrile seizures by shifting the channel’s kinetics in a temperature-dependent manner. PLoS One. 2013;8(12):e80376. 11. Nabbout R, Gennaro E, Dalla Bernardina B, et al. Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy. Neurology. 2003;60(12):1961e1967. 12. Steel D, Symonds JD, Zuberi SM, Brunklaus A. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia. 2017;58(11):1807e1816. 13. Kim JA, Connors BW. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus. Front Cell Neurosci. 2012; 6:27. 14. Hunt RF, Hortopan GA, Gillespie A, Baraban SC. A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDAtype glutamate receptors. Exp Neurol. 2012;237(1): 199e206. 15. Radzicki D, Yau H-J, Pollema-Mays SL, et al. Temperature-sensitive Cav1.2 calcium channels support intrinsic firing of pyramidal neurons and provide a target for the treatment of febrile seizures. J Neurosci. 2013;33(24):9920e9931. 16. Heida JG, Moshe SL, Pittman QJ. The role of interleukin-1beta in febrile seizures. Brain Dev. 2009;31: 388e393. 17. Helminen M, Vesikari T. Increased interleukin-1 (IL-1) production from LPS-stimulated peripheral blood monocytes in children with febrile convulsions. Acta Paediatr Scand. 1990;79:810e816. 18. Matsuo M, Sasaki K, Ichimaru T, Nakazato S, Hamasaki Y. Increased IL-1beta production from
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
409 dsRNA-stimulated leukocytes in febrile seizures. Pediatr Neurol. 2006;35:102e106. Kanemoto K, Kawasaki J, Yuasa S, et al. Increased frequency of interleukin-1beta-511T allele in patients with temporal lobe epilepsy, hippocampal sclerosis, and prolonged febrile convulsion. Epilepsia. 2003;44: 796e799. Virta M, Hurme M, Helminen M. Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures. Pediatr Neurol. 2002;26:192e195. Kira R, Torisu H, Takemoto M, et al. Genetic susceptibility to simple febrile seizures: interleukin-1beta promoter polymorphisms are associated with sporadic cases. Neurosci Lett. 2005;384:239e244. Chou I-C, Lin W-D, Wang C-H, Tsai C-H, Li T-C, Tsai FJ. Interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-8, IL-10, and tumor necrosis factor alpha gene polymorphisms in patients with febrile seizures. J Clin Lab Anal. 2010;24(3):154e159. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005;46: 1724e1743. Heida JG, Boisse L, Pittman QJ. Lipopolysaccharideinduced febrile convulsions in the rat: short-term sequelae. Epilepsia. 2004;45:1317e1329. Heida JG, Pittman QJ. Causal links between brain cytokines and experimental febrile convulsions in the rat. Epilepsia. 2005;46:1906e1913. Dube´ C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol. 2005;57: 152e155. Schuchmann S, Schmitz D, Rivera C, et al. Experimental febrile seizures are precipitated by a hyperthermiainduced respiratory alkalosis. Nat Med. 2006;12(7): 817e823. Schuchmann S, Hauck S, Henning S, et al. Respiratory alkalosis in children with febrile seizures. Epilepsia. 2011;52(11):1949e1955. Aram JA, Lodge D. Epileptiform activity induced by alkalosis in rat neocortical slices: block by antagonists of N-methyl-D-aspartate. Neurosci Lett. 1987;83(3): 345e350. Ben-Ari Y, Cherubini E, Corradetti R, Gaiarsa JL. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol. 1989;416:303e325. Rivera C, Voipio J, Payne JA, et al. The Kþ/Cl- cotransporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397(6716): 251e255. Puskarjov M, Seja P, Heron SE, et al. A variant of KCC2 from patients with febrile seizures impairs neuronal Clextrusion and dendritic spine formation. EMBO Rep. 2014;15(6):723e729. Koyama R, Tao K, Sasaki T, et al. GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy. Nat Med. 2012;18(8):1271e1278.
410
29. FEBRILE RESPONSE AND SEIZURES
34. Hesdorffer DC, Shinnar S, Lewis DV, et al. Design and phenomenology of the FEBSTAT study. Epilepsia. 2012; 53(9):1471e1480. 35. Lewis DV, Shinnar S, Hesdorffer DC, et al. Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study. Ann Neurol. 2014;75:178e185. 36. Epstein LG, Shinnar S, Hesdorffer DC, et al. Human herpesvirus 6 and 7 in febrile status epilepticus: the FEBSTAT study. Epilepsia. 2012;53(9):1481e1488. 37. Donati D, Akhyani N, Fogdell-Hahn A, et al. Detection of human herpesvirus-6 in mesial temporal lobe epilepsy surgical brain resections. Neurology. 2003;61(10): 1405e1411. 38. Hesdorffer DC, Shinnar S, Lax DN, et al. Risk factors for subsequent febrile seizures in the FEBSTAT study. Epilepsia. 2016;57(7):1042e1047. 39. Harden C. Findings from the FEBSTAT study: can observations after a provoked seizure occurrence have broad implications for epileptogenesis? Epilepsy Curr. 2013; 13(3):143e145. 40. Gallentine WB, Shinnar S, Hesdorffer DC, et al. Plasma cytokines associated with febrile status epilepticus in children: a potential biomarker for acute hippocampal injury. Epilepsia. 2017;58(6):1102e1111. 41. Vezzani A, Maroso M, Balosso S, Sanchez MA, Bartfai T. IL-1 receptor/Toll-like receptor signaling in infection, inflammation, stress and neurodegeneration couples hyperexcitability and seizures. Brain Behav Immun. 2011;25:1281e1289. 42. Chan S, Bello JA, Shinnar S, et al. Hippocampal malrotation is associated with prolonged febrile seizures: results of the FEBSTAT study. AJR Am J Roentgenol. 2015; 205(5):1068e1074. 43. McClelland AC, Gomes WA, Shinnar S, et al. Quantitative evaluation of medial temporal lobe morphology in children with febrile status epilepticus: results of the FEBSTAT study. AJNR Am J Neuroradiol. 2016;37(12): 2356e2362. 44. van Baalen A, Vezzani A, Ha¨usler M, Kluger G. Febrile infection-related epilepsy syndrome: clinical review and hypotheses of epileptogenesis. Neuropediatrics. 2017;48(1):5e18, 1. 45. Kenney-Jung DL, Vezzani A, Kahoud RJ, et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol. 2016;80:939e945. 46. Jyonouchi H. Intractable epilepsy (IE) and responses to anakinra, a human recombinant IL-1 receptor antagonist (IL-1Ra): case reports. J Clin Cell Immunol. 2016;7: 456e460. 47. Sanon N, Shaker T, Carmant L. Poststatus epilepticus models: hyperthermia. In: Pitkanen A, Buckmaster P, Galanopoulou AS, Moshe´ SL, eds. Models of Seizures and Epilepsy. Elsevier Inc; 2017:651e660. 48. Dube´ CM, Ravizza T, Hamamura M, et al. Epileptogenesis provoked by prolonged experimental febrile seizures: mechanisms and biomarkers. J Neurosci. 2010; 30:7484e7494.
49. Scantlebury MH, Gibbs SA, Foadjo B, Lema P, Psarropoulou C, Carmant L. Febrile seizures in the predisposed brain: a new model of temporal lobe epilepsy. Ann Neurol. 2005;58:41e49. 50. Vezzani A, French J, Bartfai T, Baram TZ. The role of inflammation in epilepsy. Nat Rev Neurol. 2011;7: 31e40. 51. Aronica E, Bauer S, Bozzi Y, et al. Neuroinflammatory targets and treatments for epilepsy validated in experimental models. Epilepsia. 2017;58(Suppl. 3):27e38. 52. Iori V, Iyer AM, Ravizza T, et al. Blockade of the IL-1R1/ TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis. 2017;99:12e23. 53. Roseti C, van Vliet EA, Cifelli P, et al. GABA currents are decreased by IL-1beta in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis. Neurobiol Dis. 2015;82:311e320. 54. Vezzani A, Viviani B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 2015;96:70e82. 55. Choy M, Dube CM, Patterson K, et al. A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J Neurosci. 2014;34:8672e8684. 56. Patterson KP, Brennan GP, Curran B, et al. Coordinate inflammatory responses after experimental febrile status epilepticus: implication for epileptogenesis. eNeuro. 2015;2. e0034e15. 57. Viviani B, Bartesaghi S, Gardoni F, et al. Interleukin1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci. 2003;23:8692e8700. 58. Balosso S, Liu J, Bianchi ME, Vezzani A. Disulfidecontaining High Mobility Group Box-1 promotes Nmethyl-d-aspartate receptor function and excitotoxicity by activating Toll-like receptor 4-dependent signaling in hippocampal neurons. Antioxid Redox Signal. 2014;21: 1726e1740. 59. Maroso M, Balosso S, Ravizza T, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med. 2010;16:413e419. 60. Balosso S, Maroso M, Sanchez-Alavez M, et al. A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1beta. Brain. 2008;131: 3256e3265. 61. Reid AY, Riazi K, Campbell Teskey G, Pittman QJ. Increased excitability and molecular changes in adult rats after a febrile seizure. Epilepsia. 2013;54:e45ee48. 62. Galic MA, Riazi K, Pittman QJ. Cytokines and brain excitability. Front Neuroendocr. 2012;33:116e125. 63. Galic MA, Riazi K, Henderson AK, Tsutsui S, Pittman QJ. Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. Neurobiol Dis. 2009;36:343e351. 64. Duncan M, Galic MA, Wang A, et al. Cannabinoid 1 receptors are critical for the innate immune response to
REFERENCES
65.
66.
67.
68.
TLR4 stimulation. Am J Physiol Regul Integr Comp Physiol. 2013;305(3):R224eR231. Chen K, Ratzliff A, Hilgenberg L, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron. 2003;39(4):599e611. Patterson KP, Barry JM, Curran MM, et al. Enduring memory impairments provoked by developmental febrile seizures are mediated by functional and structural effects of neuronal restrictive silencing factor. J Neurosci. 2017;37(14):3799e3812. Khan D, Dupper A, Deshpande T, Graan PNED, Steinha¨user C, Bedner P. Experimental febrile seizures impair interastrocytic gap junction coupling in juvenile mice. J Neurosci Res. 2016;94(9):804e813. Kova´cs R, Heinemann U, Steinha¨user C. Mechanisms underlying blood-brain barrier dysfunction in brain
69.
70.
71.
72.
411 pathology and epileptogenesis: role of astroglia. Epilepsia. 2012;53(Suppl 6):53e59. Reid AY, Pittman QJ, Teskey GC. A prolonged experimental febrile seizure results in motor map reorganization in adulthood. Neurobiol Dis. 2012;45(2): 692e700. Raijmakers M, Clynen E, Smisdom N, et al. Experimental febrile seizures increase dendritic complexity of newborn dentate granule cells. Epilepsia. 2016;57(5):717e726. Tao K, Ichikawa J, Matsuki N, Ikegaya Y, Koyama R. Experimental febrile seizures induce age-dependent structural plasticity and improve memory in mice. Neuroscience. 2016;318:34e44. Weiss EF, Masur D, Shinnar S, et al. Cognitive functioning one month and one year following febrile status epilepticus. Epilepsy Behav EB. 2016;64(Pt A):283e288.