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AIAN REVIEW
Year : 2022  |  Volume : 25  |  Issue : 4  |  Page : 587-600
 

Fever, seizures and encephalopathy: From bush fires to firestorms


1 Department of Pediatric Neurology, Consultant Pediatric Neurology, Rainbow Children's Hospital, Marathahalli, Bengaluru, Karnataka, India
2 Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India
3 Department of Pediatric Neurology, Consultant Pediatric Neurology, Rainbow Children's Hospital, Hyderabad, Telangana, India
4 Division of Pediatric Neurology and Clinical Neurological Sciences, Department of Pediatrics, Children's Hospital, London Health Sciences Centre, London, ON, Canada

Date of Submission04-Jan-2022
Date of Acceptance23-Jan-2022
Date of Web Publication9-Sep-2022

Correspondence Address:
Asuri N Prasad
Children's Hospital, London Health Sciences Centre, ELL-411, 800 Commissioners Road East N6A 5W9, London, ON
Canada
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aian.aian_12_22

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   Abstract 


Fever-associated seizures and febrile encephalopathy are common neurological problems in children. Infections of the nervous system are responsible for the majority of cases. However, there is a spectrum of infection-associated and inflammatory conditions associated with the triad of fever, seizures, and encephalopathy. Apart from complex febrile seizures and febrile status epilepticus, fever infection-related epilepsy syndrome of childhood (FIRES), infantile hemiconvulsion hemiplegia epilepsy syndrome (IHHE), acute encephalopathy with delayed diffusion restriction (AESD), acute necrotizing encephalopathy of childhood (ANE), and reversible splenial lesion syndrome (RESLES) are age-related clinical phenotypes of fever-related epilepsy and encephalopathy. Awareness of these entities is important for appropriate diagnosis and the prompt use of immunomodulatory/immunosuppressive therapies. In this review, we discuss the pathophysiology, clinical phenotypes, and management approaches of these fever-related seizure and encephalopathy states.


Keywords: Acute encephalopathy with delayed diffusion restriction (AESD), acute encephalopathy with repetitive refractory partial seizures (AERRPS), acute necrotizing encephalopathy of childhood (ANE), devastating epileptic encephalopathy in school-aged children (DESC), encephalopathy, epilepsy, febrile seizures, febrile status epilepticus, fever, fever infection-related epilepsy syndrome of childhood (FIRES), infantile hemiconvulsion hemiplegia epilepsy syndrome (IHHE), reversible splenial lesion syndrome (RESLES)


How to cite this article:
Kaur P, Sharma S, Konanki R, Prasad AN. Fever, seizures and encephalopathy: From bush fires to firestorms. Ann Indian Acad Neurol 2022;25:587-600

How to cite this URL:
Kaur P, Sharma S, Konanki R, Prasad AN. Fever, seizures and encephalopathy: From bush fires to firestorms. Ann Indian Acad Neurol [serial online] 2022 [cited 2022 Dec 2];25:587-600. Available from: https://www.annalsofian.org/text.asp?2022/25/4/587/345251





   Introduction Top


Seizures associated with fever are common in children. Febrile seizures are probably the most commonly encountered acute neurological condition in children, with benign outcomes in the majority.[1] The spectrum of fever-related seizures ranges from simple and complex febrile seizures to febrile status epilepticus, genetic epilepsy with febrile seizure plus, and Dravet syndrome. In addition to these predominantly genetically determined entities, other fever-associated epilepsy and encephalopathy disorders include fever-infection-related epilepsy syndrome (FIRES), devastating epileptic encephalopathy in school-aged children (DESC), new-onset refractory status epilepticus (NORSE), acute encephalopathy with repetitive refractory partial seizures (AERRPS), idiopathic hemiplegia hemiconvulsion syndrome (IHHE), and acute encephalopathy with delayed diffusion restriction (AESD). Disorders that are characterized by fever and encephalopathy but infrequent seizures include acute necrotizing encephalopathy (ANE), mild encephalopathy with reversible splenial lesions (MERS), and acute demyelinating encephalomyelitis (ADEM). The complex interplay of fever, brain immaturity, and infection-triggered immune and inflammatory mechanisms seems to create a setting for this group of disorders [Figure 1]. In this review, we discuss the clinical features, possible underlying pathophysiological mechanisms, and treatment options for childhood neurological disorders associated with fever, seizures, and encephalopathy [Table 1].
Figure 1: Venn diagram depicting the overlap between epilepsy, fever, inflammation, autoimmunity, infections, genetics, and related clinical conditions. Abbreviations: CDH2: Cathedrin-2, DS: Dravet syndrome, GABARα: gamma-aminobutyric acid receptor, GEFS: genetic epilepsy with febrile seizure, HCN1A: hyperpolarization-activated cyclic-nucleotide gated channel, HMGB1: high-mobility group box 1, IEMS: Inborn errors of metabolism, IHHE: infantile hemiconvulsion hemiplegia epilepsy syndrome, LPS: lipopolysaccharide, PCDH19-protocathedrin 19, POLG: polymerase gamma, SCN: voltage-gated sodium channel, TNFα: tumor necrosis factorα

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Table 1: Summary of fever-triggered epilepsy syndromes

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   Fever and the Nervous System's Susceptibility to Seizures Top


Fever increases neuronal excitability, especially in the hippocampus. At higher body temperatures, alteration of membrane properties of pyramidal cells and interneurons in the hippocampus occurs.[2] Many physiological events, including resting neuronal membrane excitability, synaptic transmission, and endo- and exocytosis, are affected by hyperthermia.[3] L-type calcium channels have been found to be hyperpolarization-activated and become intrinsically active at temperatures >37°C.[4] It has also been postulated that hyperthermia induces glutamatergic excitatory inputs through N-methyl-D-aspartate receptor (NMDAR) and transient receptor potential vallinoid-4 (TRPV-4), resulting in a net neuro-excitatory state.[5],[6],[7]

Fever, either by itself or by virtue of the associated infection, incites an inflammatory response in the brain. IL-1β, a potent pyrogen, has been extensively studied for its putative role in the pathogenesis of febrile seizures. It induces hyperthermia, NMDA-induced intracellular calcium influx,[8] and glutamate-mediated hyperexcitability[9] and thus potentiates seizure generation.[9],[10] IL-1-receptor and NMDAR are co-localized on hippocampal dendrites, with possible enhanced crosstalk.[8],[10] Additionally, the IL-1β allele 511*2, which confers enhanced IL-1β production, has been found in higher frequency in children with FS and in adults with temporal lobe epilepsy.[11] In a recent Korean study, significantly elevated post-ictal levels of IL-1β, IL-6, and HMGB1 (high-mobility group box 1) were found in children with FS. In the same study, gene variants at IL-1β*31 and IL-1β *511 promoter regions correlated with higher post-ictal IL-1β levels, suggesting that few genetic variants predispose to increases inflammatory cytokines after febrile seizures.[12] Tumor necrosis factor-α (TNF-α) also amplifies glutamate-mediated AMPA response and increases GABAA receptor endocytosis, contributing to hyperexcitability. 9 Hyperthermia-induced hyperventilation and subsequent respiratory alkalosis has also been postulated to contribute to seizure generation, but this has not been proven [Figure 2].[13]
Figure 2: Possible pathophysiological mechanisms underlying fever-associated increased seizure sensitivity

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These responses are further modified by individual genetic factors. Pathogenic variations in several temperature-sensitive ion-channel mutations have been described in children with fever-triggered seizures. Classically, SCN1A mutations are known to cause temperature-sensitive epilepsy.[14] GABAA-R γ-subunit mutations result in reduced expression and rapid endocytosis of GABAA receptors; these subcellular events are significantly enhanced at elevated temperatures.[3],[15],[16] Under experimental conditions, GABAA receptor-mediated gamma oscillations have been found to underlie the temperature-induced population spikes.[17] Decreased pre-synaptic release and post-synaptic GABA-R function have been documented in CA1 hippocampal neurons.[18],[19] Interplay of genetic, inflammatory, and direct hyperthermia-associated factors contributed to the generation of prolonged febrile seizures in animal models.[9]

Prolonged seizures appear to independently induce a cyclical cascade of inflammation and seizures. Seizures/status epilepticus results in activation on astroglia and microglia, release of cytokines (IL-1β, TNF-α, HMGB1), and activation of various downstream pathways such as NFkB induction, nuclear induction of cytokine proteins, and calcium-influx mediated activation of the kinase pathways. This further begets more seizure activity and increased permeability of the blood–brain barrier, leading to the recruitment of systemic inflammatory cells into the brain.[20]

In addition to the inflammatory cascade, long-term neurophysiological and possibly neuroanatomical changes occur in neuronal circuitry. Experimentally, increased inhibitory post-synaptic potentials (IPSP) have been observed 1 week after febrile status in rat pups, with paradoxically increased excitability.[21] This is due to activation of the “molecular inhibition excitation converter,” the HCN (Ih) channels that are activated by hyperpolarization and result in a persistent hyper-excitable state in the hippocampus.[22],[23] Another mechanism is the persistent potentiation of “depolarization-induced suppression of inhibition” (DSI). DSI is mediated by pre-synaptic cannabinoid type 1 (CBD1) receptor, activated by depolarization-induced retrograde endocannabinoid release in CA1 neurons. CBD1 receptors have been found to be upregulated following prolonged febrile seizures, hence the persistent potentiation.[24]

Although no gross neuronal loss has been observed in animal studies, increased sprouting of mossy fibers in granule cell and molecular layers and decreased number of cells that differentiate to excitatory amino acid transporter-3 (EAAT-3; function- synaptic reuptake of glutamate) containing cells have been observed after exposure to prolonged febrile status early in life.[25],[26] The underlying pathogenesis of FIRES, and possibly IHHC, follows a similar pattern. The acute, explosive epilepsy in FIRES occurs following a time lag of a few days after an inciting febrile illness. It has been postulated that during this lag period, an imbalance between pro- and anti-inflammatory mechanisms occurs, tipping the scales toward seizures. Autoimmune and metabolic etiologies have been found in a small subset of cases; however, in the majority, extensive autoimmune and infective and genetic workup fails to disclose any causative associations. Moreover, the lack of a defined time interval between the onset of acute status epilepticus and evolution to chronic epilepsy has been cited as an argument against the pure acquired nature of FIRES; however, unknown or unidentified genetic factors may have a role to play.[27] Genetic mutations in sodium channels (SCN1A, SCN2A) and recently, Dynamin (DNM) DNM1 gene, which codes for a membrane remodeling GTPase involved in membrane fission and is specifically expressed in the nervous system, have been implicated in a few cases.[28] DNM1L mutation has been described in association with a mitochondrial epilepsy syndrome with fever sensitivity and refractory status epilepticus in developmentally normal children and children with minor developmental delay.[29],[30] A recent study identified significantly higher Th1-associated cytokines (TNF-α, CXCL9, CXCL10, CXCL11), IL6, CCL2, CCL19, CXCL1, and chemokines in FIRES/FIRES-related disorders and FSE (CXCL9, CXCL10, CXCL19, and CCL19) when compared to chronic epilepsy [Figure 3].[31]
Figure 3: Postulated status epilepticus related inflammatory mechanisms and long-term effects underlying generation of ongoing acute and chronic seizures

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   The Febrile Seizures Spectrum Top


Complex febrile seizures (CFSs)

CFSs are defined as seizures occurring in children aged 6–60 months with fever ≥38°C, lasting ≥15 min, more than one episode in 24 h or a febrile event having focal features in the ictal/post-ictal semiology,[32],[33] CFS constitute approximately 20%–30% of all febrile seizures.[1],[34] Recurrent or prolonged focal seizures evolving to generalized seizures lasting >30 min without regaining consciousness are termed as febrile status epilepticus (FSE). Infants <18 months at the time of 1st febrile seizure are at risk of CFS, whereas a lower degree of rise of body temperature and longer duration of recognized fever before FS and structural temporal lobe abnormalities (hippocampal malrotation or HIMAL) are associated with a greater risk of FSE.[35] In the FEBSTAT study, the risk of second FS of any type after a first FSE/SFS was not significantly different; however, the presence of baseline MRI abnormality and occurrence of FSE as the first FS was related to increased risk of recurrent FSE compared to the first episode of SFS.[36] The risk of developing epilepsy following febrile seizures has been reported to be 2%–7%;[1],[34] however, the data for independent risk associated with SFS and CFS remains unclear. Complex FS and FSE have been previously postulated to increase the risk of hippocampal sclerosis and subsequent mesial temporal lobe epilepsy. In children with FSE, impaired hippocampal growth at 1-year follow-up was seen, both in children with acute hippocampal injury (T2 hyperintense hippocampi, with evolution to hippocampal sclerosis at 1 year) and those with normal imaging in the acute period.[37] Further long-term follow-up studies on long-term effects on hippocampal development are awaited.

Febrile seizure plus

Children with febrile seizure plus (FS+) experience febrile seizures beyond 6 years of age and/or associated afebrile seizures.[2] Cases with a family history of FS/FS + are designated GEFS-plus. Intra-familial phenotypic expression is heterogenous; 1/3rd experience only febrile seizures that may persist being 6 years age, 1/3rd have remote generalized afebrile seizures during childhood with remission in adolescence, and the remaining 1/3rd present with a variety of generalized epilepsies.[38]

Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy, SMEI) is characterized by fever-triggered, focal, hemiclonic/myoclonic seizures in infants below 6 months of age, evolving to a refractory epilepsy with polymorphic seizure semiologies and development arrest, with underlying SCN1A mutations that are believed to be causal.

Genetics

Linkage analyses have identified six loci for febrile seizures: FEB1 (Chr8q18–q21), FEB2 (Chr19p13.3), FEB3 (Chr2q23–q24; 3A-SCN1A, 3B-SCN9A), FEB4 (Chr5q14–q15; GPR98), FEB5 (Chr6q22–q24), FEB6 (Chr18p11.2), FEB7 (Chr21q22), FEB8 (Chr5q31; GABARG2), FEB9 (Chr3p24.2-p23), FEB10 (Chr3q26), and FEB11 (Chr8q13; CPA6).[39],[40] SCN1A, SCN1B, SCN2A (neuronal voltage gated sodium channels), and GABARA1 (α1 subunit of GABAA receptor) are the common mutations underlying GEFS+.[41] De-novo SCN1A mutations underlie approximately 85% cases of SMEI; other putative genes include SCN2A, SCN1B, SCN8A, GABARA1, GABARG2, and GABARB3.[42] Recently, fever-sensitive seizures have been described with STXBP1,[43] PCDH19,[44],[45] SCN9A,[46] FGF13,[47] and HCN2.[3]

NORSE and FIRES

1. 2a New-onset refractory status epilepticus (NORSE) is a clinical presentation in a patient without active epilepsy or preexisting neurological disorder, with new-onset refractory status epilepticus, without clear acute or active structural, toxic or metabolic cause.[48]

1. 2b Fever-infection-related refractory epilepsy syndrome (FIRES) is a subacute category of NORSE that requires fever 24 h to 2 weeks prior to the onset of status epilepticus, with or without fever at the onset of status epilepticus [Table 1].[48] The presence of fulminant onset of bilateral focal/generalized seizures or SE, poorly responsive to treatment for days or weeks, preceded by fever/infection occurring in school-aged children in the absence of previous neurological illness, infectious or metabolic etiology, abnormal behavior or movement disorder, positive neuronal antibody testing and progression to a state of chronic epilepsy immediately following the acute phase, frequently with moderate-severe neuropsychological impairment, are required for the diagnosis of FIRES. Elevated CSF protein or the presence of oligoclonal bands and response to immunotherapy can be present occasionally. Isolation of infectious agents from body or CSF in the absence of laboratory or imaging markers of encephalitis, presence of CSF pleocytosis without isolation of infectious agent (maybe SE rated), presence of symmetrical gray matter hyperintensities on T2 weighted MRI (can be immune-mediated/SE-related), and elevated lactate peak on MRS do not rule out FIRES.[27]

Acute encephalitis with refractory, repetitive, partial seizures (AERRPS)[49] and devastating epileptic encephalopathy in school-aged children (DESC)[50] have the same course and outcomes as FIRES; these are probably the same entities with different nomenclature.

Neuroimaging

In the acute stage, MRI is normal in 60% of cases; abnormal features encountered most frequently are T2 weighted/FLAIR hyperintensity in temporal lobes (~25%), basal ganglia, insular region, and leptomeningeal enhancement.[51],[52] Generalized cerebral atrophy, mesial temporal sclerosis, and WM signal abnormalities are the most common abnormalities in the chronic stage.[51] In addition, extensive WM signal abnormalities, probably secondary to focal demyelination, are associated with poor outcomes.[52]

EEG

Interictal findings include diffuse slowing, focal or bilateral temporal, frontal or frontotemporal discharges,[53],[54] and recurrent background extreme-delta brushes.[55] The ictal pattern consists of focal fast activity of >10 Hz of moderate amplitude with evolution to rhythmic spike and spike-wave complexes and with inter-hemispheric shifting of the ictal activity [Figure 4].[56]
Figure 4: EEG patterns in FIRES. (a) Generalized burst of epileptiform discharges. (b) Two generalized bursts of discharges, followed by left temporal-occipital spike wave discharges evolving sequentially to low amplitude fast rhythm (1) followed by spike-slow wave discharges (2). Right sided leads show fast activity immediately post the generalized burst with evolves into slower spikes, and continues after the left sided ictal activity resolves. (c) Generalized slow spike wave discharges

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Genetics

While no specific causative genetic mutations have been associated with FIRES to date, Alpers disease (POLG mutations), PCDH19, and SCN1A-related fever-triggered epilepsies remain close differentials. Recently, DMN1L gene mutations, coding for a dynamin-1-like protein that participates in the synaptic vesicle cycle of neurotransmitter release, have been reported with FIRES and fever-triggered epilepsy.[27]

Infantile hemiplegia hemiconvulsion with epilepsy syndrome (IHHE)

Infantile hemiplegia hemiconvulsion with epilepsy is a rare clinic-radiological syndrome, occurring in previously healthy children below 2 years of age. It presents acutely with febrile, focal, prolonged status epilepticus (lasting up to 24 h) with postictal hemiplegia and hemispheric cytotoxic edema on MRI [Table 1].[57] After a seizure-free interval of a few months to <3 years (mean: 1–2 years), spontaneous recurrent, often refractory, focal seizures ensue, with variable residual hemiparesis and hemiatrophy on neuroimaging.[58]

Infantile-onset hemiconvulsion hemiplegia epilepsy syndrome can be diagnosed in a child <2 years with new-onset refractory, unilateral, focal status epilepticus with ipsilateral hemiparesis lasting >24 h after SE, high-grade fever at the onset of SE, and unilateral abnormal imaging in the acute stage after exclusion of infectious encephalitides.[48]

Neuroimaging

Diffuse hemispheric cytotoxic edema with T2 and DWI hyperintense signal and corresponding hypointense signal on ADC maps, with subcortical predominance, is seen.[58],[59],[60] At times, mass effect over the opposite hemisphere is also observed. Over the next 8–15 days, edema decreases with pseudo-normalization of ADC values and persistent high T2 signal. Cerebral atrophy involving the pathogenic hemisphere sets in by 1 month [Figure 5].[58]
Figure 5: Infantile hemiplegia hemiconvulsion epilepsy syndrome (IHHE) (a) Noncontrast CT showing diffuse edema with loss of cortico-medullary junction differentiation of the right hemisphere, (b) FLAIR image showing right hemispheric cortical edema and caudate hyper-intensity with minimal midline shift anteriorly, (c) Right-hemispheric cortical diffusion restriction suggestive of cytotoxic edema, and (d) right-hemispheric cortical atrophy at follow-up

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EEG

In the acute phase, the ictal EEG consists of bilateral or unilateral rhythmic (2–3 Hz), slow waves with intermixed spikes, sharps, and intermittent fast activity with an asymmetric expression over the affected hemisphere (with higher amplitude delta, and not infrequently, attenuation on the affected side). Frequent evolution of ictal rhythms can be observed. Post-ictally, high-amplitude slow waves can be seen over the affected hemisphere. In the chronic stage, focal EEG discharges may be observed.[57],[58],[61]

Etiology/Genetics

Classically, HHE is considered to be idiopathic; the term “symptomatic IHHE” has been used in the literature when the clinical mimicker is seen as a complication during the course of a preexisting disorder, such as Sturge–Weber syndrome, structural abnormalities such as agenesis of the corpus callosum, polymicrogyria–pachygyria–lissencephaly spectrum, associated with precipitating factors such as viral infections (HHV-6, HHV-7),[60] coagulation disorders without thrombosis (protein S deficiency, factor V mutation, MTHFR mutation) and SCN1A mutations.[58] The role of CACNA1A mutations has been postulated considering observation of hemispheric cytotoxic edema in patients with hemiplegic migraine and fatal, malignant hemispheric edema following trivial trauma in children. The role of genetic polymorphisms in inflammatory mediator genes is hypothesized.[58] Alternating hemiplegia of childhood (AHC) must be considered in cases with recurrent hemiparesis, with normal inter-ictal neurological examination initially, which is followed by a gradual decline over multiple attacks; AHC is associated with seizures in almost 50% of cases. Neuroimaging is normal at the onset but in older patients, cerebral and cerebellar atrophy may set in.[62]

Acute encephalopathy with biphasic seizures and delayed reduced diffusion (AESD)

This condition was initially described in Japanese/East Asian children. AESD is a severe fever-triggered epilepsy syndrome in children aged 10 months–4 years[63],[64],[65],[66],[67] with a distinct clinico-radiological profile. At the onset, prolonged febrile status (>30 min) and altered sensorium are noted. This is followed by a seizure-free period during which sensorium improves transiently, commonly to a persistent subnormal level and occasionally to the normal level with a normal neurological examination. Secondary seizures begin between days 3 and 9, commonly as clustered focal seizures with/without generalization, with associated worsening of sensorium. Long-term outcomes include moderate to severe intellectual disability, focal neurological deficits, and epilepsy. A milder phenotype with short initial febrile seizure followed by biphasic seizures at days 4–6, normal sensorium in between biphasic seizures, and normal neurological outcome. Associated characteristic neuroimaging is well described.[63]

Acute encephalopathy with febrile status epilepticus, acute encephalopathy with biphasic clinical course, and acute infantile encephalopathy predominantly affecting frontal lobes (AIEF) are terminologies that have been reported in the literature, which probably fall along the spectrum of AESD, with similar imaging findings, limited to frontal lobes in AIEF, with some variation in the clinical course and outcomes.

Neuroimaging

The pattern and evolution of neuroimaging findings are the hallmarks of AESD. Initial MRI on day 2 is normal. Subsequently, with the appearance of secondary seizures, MRI on days 3–9 shows bilaterally symmetrical, frontal or frontoparietal (with peri-rolandic sparing) subcortical white matter hyperintensity, most evident on DWI images with corresponding decreased ADC values [Figure 6]. Central sparing is associated with relatively milder presentations.[68] On T2 and FLAIR, linear U-fiber hyperintensity, more prominent than cortical hyperintense signal, is observed. After day 9, the subcortical DWI hyperintense signal normalizes with a corresponding increase in ADC values; cortical DWI hyperintensity becomes the most prominent feature between days 9 and 25. Imaging done beyond 2 weeks shows T2/FLAIR hyperintensity of subcortical white matter and cerebral atrophy.[63]
Figure 6: Acute encephalopathy with delayed diffusion restriction (AESD): DWI images showing diffuse white matter diffusion restriction affecting both hemispheres and posterior limb of the internal capsule (a) and central white matter and peri-rolandic sparing in “central sparing pattern” of AESD (b)

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EEG

EEG features are often nonspecific, and features of nonconvulsive status epilepticus, electrographic seizures, lateralized periodic discharges, and lateralized slow waves have all been reported.[65]

Etiology

In contrast to the above entities, AESD is more commonly associated with infectious prodromes, of which influenza A and B and HHV-6 and 7 are the most common; others are varicella, mumps, respiratory syncytial virus, rotavirus, and streptococcus and H influenza.

Prognostic factors

Attempts have been made to elucidate markers that predict progression to biphasic seizures after febrile status and prognosis after AESD. Poor outcomes have been associated with the presence of involuntary movements and persistent coma prior to the onset of secondary seizures, extensive lesions with low ADC values involving anterior, posterior cerebrum, and basal ganglia, elevated alanine transferase levels,[64] aspartate aminotransferase (AST) within 24 h, elevated creatinine levels within 2 h, and presence of electrographic seizures.[65] Additionally, longer time to arousal or return to consciousness after FSE, elevated AST, ALT, lactate dehydrogenase, hyperglycemia, and hyperammonemia have been found to be related to a higher risk of developing secondary seizures after FSE; a scoring system for the same has also been developed.[69]

Acute necrotizing encephalopathy of childhood (ANE)

ANE is primarily a childhood disorder but has also been described in adults. Similar to AESD, viral prodrome is almost always preceded and is present at the time of onset of neurological symptoms. Classically, three stages have been described: prodromal, acute encephalopathy, and recovery. The prodrome usually manifests as a viral upper respiratory tract or gastrointestinal infection. This is followed by the onset of encephalopathy (~100%), seizures (50%–100%),[70],[71],[72] and focal deficits [Table 3]. Features of disseminated intravascular coagulation, shock, and multiple organ injury, and laboratory abnormalities such as elevated liver enzymes, hypoglycemia, and lactic acidosis can be present in variable combinations, suggestive of a systemic inflammatory response. The recovery phase is characterized by neurologic sequelae; normal outcomes are present in <10% and the mortality rate is estimated to be high at ~30%.[73]
Table 3: Treatment options

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Diagnostic criteria have been described for the diagnosis of ANE.[73] Sporadic ANE is diagnosed in the presence of acute encephalopathy following a febrile illness, presence of typical neuroimaging features, elevated CSF protein in the absence of pleocytosis, elevated aminotransferase with normal ammonia levels, and exclusion of clinical and radiological differentials.[73],[94],[95] In addition to sporadic ANE, if the patient has a family history of neurological illness (may be para-infectious), recurrent fever-triggered encephalopathy episodes, or additional MRI changes in any one area (medial temporal lobe, amygdala, claustrum, hippocampi, mammillary bodies, and spinal cord), familial/genetic ANE (ANE1) should be considered.[73],[96],[97]

Neuroimaging

While the clinical features of ANE are nonspecific, the neuroimaging findings are almost diagnostic. The “tricolor pattern,” “concentric/laminar structure,” or the “target-like appearance” of the thalamus is the most striking and consistent feature, most readily apparent on ADC images- innermost necrosis and hemorrhage, middle layer of cytotoxic edema, and outermost layer of vasogenic edema [Figure 7]. The brainstem, cerebellum, and cerebral white matter are commonly involved; spinal cord involvement can be seen occasionally. Involvement is usually bilateral; unilateral lesions are not uncommon.[73],[98] Familial ANE has a predilection for the thalamus and pons rather than a more diffuse involvement.[72]
Figure 7: Acute Necrotizing Encephalopathy of childhood (ANEC): (a) Non-contrast CT showing bilaterally symmetrical thalamic hypodensity; (b) Bilateral symmetrical thalamic involvement with edema, T2 hyperintensity (arrowhead), central heterogeneous areas (arrow); (c) Central heterogeneous areas show cytotoxic edema with diffusion restriction and surrounding area of facilitated diffusion on ADC images, note the innermost area with hyperintensity consistent with necrosis giving classical Target-like appearance of thalamus; (d) DWI sequences with central areas of diffusion restriction; (e) foci of haemorrhage on SWI images (arrowheads); (f) Sagittal T2 images shows hyper-intensity in dorsal pons & cerebellar white matter

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Etiology/triggering factors

Influenza A/B, H1N1, metapneumovirus, HHV6, HHV7, parainfluenza, varicella, enterovirus, rotavirus, rubella, coxsackievirus, measles, parvo B,[99] dengue,[100] E. coli,[98] and most recently, SARS-CoV[101] have been isolated; of these, influenza and HHV6 are the most common.[71],[73],[102]

Genetics

As ANE is rare, the true prevalence of familial/genetic ANE, known as ANE1, is not known. Approximately 31% of ANE1 have dominantly inherited RANBP2 (Chr2) mutation,[103] with ~40%–50% penetration.[104],[105] Carnitine palmitoyl transferase-2 (CPT2) gene is another gene implicated in ANE.[106] Digenic inheritance of both genes with fatal outcomes in a single family has also been reported.[107]

Reversible splenial lesion syndrome (RESLES)

In the spectrum of prodromal febrile encephalopathy/seizure clinico-radiological syndromes, RESLES falls toward the milder end. Clinically, it is characterized by a prodromal viral illness followed by the onset of neurological symptoms 1–2 days[63],[108] (up to 10 days)[109] after fever onset. Encephalopathy lasting >12 h (54%), seizures (33%), sleepwalking, and delirious behavior are frequent neurological features.[63] Pleocytosis with normal/mildly elevated protein or normal CSF study and hyponatremia are the most common laboratory abnormalities.[63],[108],[109],[110] Irrespective of treatment, normal outcome has been reported in all cases.

This entity was previously known as mild encephalopathy/encephalitis with a reversible splenial lesion (MERS) and has been revised recently revised to RESLES to incorporate all entities with transient reversible lesion with diffusion restriction. Another term, reversible splenium lesion with febrile illness (RESLEF), has been proposed to additionally include entities without encephalopathy but similar neuroimaging findings.

Neuroimaging

The MRI shows diffusion restriction limited to the splenium (MERS1), involving the entire corpus callosum with/without extension to contiguous deep white matter (MERS2) [Figure 8]. Extra-splenial lesions involving subcortical white matter have been reported.[108] The lesions disappear on repeat imaging done 2–5 weeks after symptom onset.[108],[109],[110]
Figure 8: Reversible splenial lesion syndrome (RESLES): Axial (a) and sagittal (b) T2 images show focal, well-defined hyper-intensity in splenium; the same area shows diffusion restriction on DWI image (c). Abbreviations: AED: antiepileptics, AESD: acute encephalopathy with biphasic seizures and delayed reduced diffusion, ANE: acute necrotizing encephalopathy of childhood, DBS: deep brain stimulation, ECT: electroconvulsive therapy, FIRES: fever infection-related epilepsy syndrome, IHHE: infantile hemiconvulsion hemiplegia epilepsy syndrome, IvIG: intravenous immunoglobulin, KD: ketogenic diet

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   Investigations Top


An individually tailored approach consisting of detailed clinical evaluation and investigations as per the likely clinical possibilities is recommended [Table 2]. For any child presenting with fever and seizure that is not a febrile seizure, ruling out meningitis is a must. CSF microscopy, protein, sugars, and cultures along with blood and if required, urine cultures testing for common pathogens are the first-line investigations. Considering the clinical features and epidemiologically prevalent infections, testing for dengue, chikungunya, enterovirus, H1N1, varicella, scrub typhus, tuberculosis, E. coli, malaria, mycoplasma, and chlamydia needs to be considered. In immunocompromised patients, additional investigations may be required to rule out opportunistic infections as well.
Table 2: Investigations and workup

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Neuroimaging is indicated for all patients. Plain and contrast CT can help to diagnose acute hydrocephalus, basal exudates, bleeding, major sinus thrombosis, and infarcts. In cases where the workup for an infectious etiology is normal, MRI findings can play a discriminatory role and are helpful in deciding the next steps. The imaging findings may be normal or disclose nonspecific, or specific radiological findings such as ANE, AESD, or RESLES. Metabolic testing, including serum ammonia, lactate, TMS, and GCMS, may be included on a selective basis. A toxicology screen may be indicated if history is suggestive, and if negative, autoimmune testing as detailed in [Table 2] should be considered. Thus, every attempt to diagnose conditions where targeted therapeutic interventions are available must remain a priority. At times, it may be necessary to do invasive investigations such as brain biopsy/muscle biopsy to diagnose conditions such as CNS vasculitis. Genetic testing (whole-exome sequencing with rapid turnaround time) should be sent if workup has been unrevealing, especially in all cases with ANE phenotype. With the upcoming role of inflammation and targeted therapies, there may be a potential role of serum and CSF cytokine profiles to tailor therapies in the future.


   Management Top


There is a lack of robust evidence-backed protocols as these entities are rare. Of these, management of FIRES is the most challenging as by definition, it is refractory SE; in other entities, the acute status decreases over time in the natural course of the disease. Management is based on two lines, namely status control and immunomodulation, as inflammatory/cytokine-mediated mechanisms are thought to play a major role in pathogenesis [Table 3], [Figure 9].
Figure 9: Summary of management in entities with refractory status

Click here to view


Refractory/Super-refractory status epilepticus

Management protocols are available for the treatment of status epilepticus; it is often individualized for refractory and super-refractory status (RSE/SRSE). Following the failure of first-line anti-epileptic drugs (AEDs), pharmacological or therapeutic coma is used as second-line therapy. Drugs used include midazolam, pentobarbital, phenobarbitone, and inhaled anesthetics (thiopentone, propofol, and desflurane). Targeting burst suppression rather than electrographic seizure control was found to be associated with a trend toward better seizure control and GCS at 6 months follow-up; however, higher drug doses and a higher rate of hemodynamic instabilities without longer PICU stay/hospitalization were also present.[111] Duration of inter-burst intervals was not found to be significant in predicting RSE control.[112] Midazolam was found to carry a better side effect profile and shorter intensive care unit care stay as compared to thiopentone in an adult study; similar comparisons in the pediatric cohort have not been attempted. These findings may be applicable to pediatric cases as well.[113] High-dose phenobarbitone infusion (1–3 mg/kg/h) has been shown to be effective in SRSE.[114] High rates of seizure recurrence after tapering pharmacological coma have been reported. Additional therapies include early initiation of ketogenic diet (KD), therapeutic hypothermia, cannabidiol, and magnesium sulfate, of which KD appears to be the most effective. In a recent metanalysis, KD was the only therapy related with positive outcomes when used in the acute stage.[115]

Immunomodulatory therapies

The use of corticosteroids, intravenous immunoglobulin, and plasma exchange[49] has not been associated with favorable outcomes. Of these, the use of high-dose pulsed intravenous corticosteroids as a first-line agent is almost universal. Intravenous immunoglobin alone or paired with pulsed steroids does not appear to provide additional benefit over pulsed steroids alone in FIRES.[116] However, all three probably do not have any significant effect on seizure control in FIRES and related epilepsy phenotypes. High-dose intravenous corticosteroids (methylprednisolone or dexamethasone) are probably the most effective in ANEC and probably the only treatment, if at all used, in RESLES. Of the other immunomodulatory therapies, anakinra and tocilizumab appear to be promising for FIRES and ANE, respectively [Table 3].

Ketogenic diet

The ketogenic diet (KD), a low-carbohydrate, high-fat diet, deserves a special mention among the myriad of available treatment options. This is the only modality to have shown statistically significant benefit in FIRES patients, especially when used in the acute phase.[115] It is postulated to have antiepileptic, immunomodulatory, and neuroprotective effects through multiple mechanisms of action.[75] Time to cessation of SE after KD initiation varied from 1–10 days[117] to 4–6 days,[74] maximum up to 19 days[118] in three different studies. Oral and parenteral formulations are available in the market; indigenous ingredients can be used to tailor-make the diet where these are either not available or affordability is an issue. Planning should probably commence at the time of initiation of pharmacological coma, and early initiation should be considered for optimal outcomes once it is clear that early immunomodulatory therapies (steroids/immunoglobulins) are probably not working.


   Conclusions Top


Fever-triggered epilepsy and encephalopathy syndromes present a wide spectrum of clinical and radiological phenotypes. The knowledge of underlying pathophysiological mechanisms is still evolving. An interplay of brain immaturity, genetic predisposition, and inflammation seems likely. Awareness of these entities is important for the prompt institution of immunosuppressive and immunomodulatory treatments. As these are individually rare entities, long-term, prospective, multicentric studies are required to improve the understanding on treatment strategies and long outcomes.

Search strategy and selection

References for this review were identified by searching PubMed for articles published in English between June 1, 1993 and May 31, 2020 and by further examining the reference lists from relevant articles. Combinations of the following terms were used: “febrile seizures,” “febrile status epilepticus,” “encephalopathy,” “inflammation,” “fever infection-related epilepsy syndrome of childhood,” “new-onset refractory status epilepticus,” “acute encephalopathy with delayed diffusion restriction,” “infantile hemiconvulsion hemiplegia epilepsy syndrome,” “reversible splenial lesion syndrome,” and “genetics.” The final reference list was generated based on the relevance to the scope of this review.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Gupta A. Febrile seizures. Continuum (Minneap Minn) 2016;22:51-9.  Back to cited text no. 1
    
2.
Kim JA, Connors BW. High temperatures alter physiological properties of pyramidal cells and inhibitory interneurons in hippocampus. Front Cell Neurosci 2012;6:27.  Back to cited text no. 2
    
3.
Deng H, Zheng W, Song Z. The genetics and molecular biology of fever-associated seizures or epilepsy. Expert Rev Mol Med 2018;20:e3.  Back to cited text no. 3
    
4.
Radzicki D, Yau H-J, Pollema-Mays SL, Mlsna L, Cho K, Koh S, 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;33:9920-31.  Back to cited text no. 4
    
5.
Morimoto T, Nagao H, Yoshimatsu M, Yoshida K, Matsuda H. Pathogenic role of glutamate in hyperthermia-induced seizures. Epilepsia 1993;34:447-52.  Back to cited text no. 5
    
6.
Hunt RF, Hortopan GA, Gillespie A, Baraban SC. A novel zebrafish model of hyperthermia-induced seizures reveals a role for TRPV4 channels and NMDA-type glutamate receptors. Exp Neurol 2012;237:199-206.  Back to cited text no. 6
    
7.
Morimoto T, Kida K, Nagao H, Yoshida K, Fukuda M, Takashima S. The pathogenic role of the NMDA receptor in hyperthermia-induced seizures in developing rats. Dev Brain Res 1995;84:204-7.  Back to cited text no. 7
    
8.
Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-1β enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 2003;23:8692-700.  Back to cited text no. 8
    
9.
Vezzani A, Granata T. Brain inflammation in epilepsy: Experimental and clinical evidence. Epilepsia 2005;46:1724-43.  Back to cited text no. 9
    
10.
Dubé C, Vezzani A, Behrens M, Bartfai T, Baram TZ. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann Neurol 2005;57:152-5.  Back to cited text no. 10
    
11.
Virta M, Hurme M, Helminen M. Increased frequency of interleukin-1beta (-511) allele 2 in febrile seizures. Pediatr Neurol 2002;26:192-5.  Back to cited text no. 11
    
12.
Choi J, Choi SA, Kim SY, Kim H, Lim BC, Hwang H, et al. Association analysis of interleukin-1β, interleukin-6, and HMGB1 variants with postictal serum cytokine levels in children with febrile seizure and generalized epilepsy with febrile seizure plus. J Clin Neurol Seoul Korea 2019;15:555-63.  Back to cited text no. 12
    
13.
Schuchmann S, Vanhatalo S, Kaila K. Neurobiological and physiological mechanisms of fever-related epileptiform syndromes. Brain Dev 2009;31:378-82.  Back to cited text no. 13
    
14.
Ohno Y, Ishihara S, Mashimo T, Sofue N, Shimizu S, Imaoku T, et al. Scn1a missense mutation causes limbic hyperexcitability and vulnerability to experimental febrile seizures. Neurobiol Dis 2011;41:261-9.  Back to cited text no. 14
    
15.
Kang J-Q, Shen W, Macdonald RL. Why does fever trigger febrile seizures? GABAA receptor gamma2 subunit mutations associated with idiopathic generalized epilepsies have temperature-dependent trafficking deficiencies. J Neurosci 2006;26:2590-7.  Back to cited text no. 15
    
16.
Kang J-Q, Shen W, Macdonald RL. The GABRG2 mutation, Q351X, associated with generalized epilepsy with febrile seizures plus, has both loss of function and dominant-negative suppression. J Neurosci 2009;29:2845-56.  Back to cited text no. 16
    
17.
Wu J, Javedan SP, Ellsworth K, Smith K, Fisher RS. Gamma oscillation underlies hyperthermia-induced epileptiform-like spikes in immature rat hippocampal slices. BMC Neurosci 2001;2:18.  Back to cited text no. 17
    
18.
Qu L, Leung LS. Mechanisms of hyperthermia-induced depression of GABAergic synaptic transmission in the immature rat hippocampus. J Neurochem 2008;106:2158-69.  Back to cited text no. 18
    
19.
Qu L, Liu X, Wu C, Leung LS. Hyperthermia decreases GABAergic synaptic transmission in hippocampal neurons of immature rats. Neurobiol Dis 2007;27:320-7.  Back to cited text no. 19
    
20.
Shimada T, Takemiya T, Sugiura H, Yamagata K. Role of inflammatory mediators in the pathogenesis of epilepsy. Mediators Inflamm 2014;2014:901902.  Back to cited text no. 20
    
21.
Dube C, Chen K, Eghbal-Ahmadi M, Brunson K, Soltesz I, Baram TZ. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann Neurol 2000;47:336-44.  Back to cited text no. 21
    
22.
Chen K, Aradi I, Thon N, Eghbal-Ahmadi M, Baram TZ, Soltesz I. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med 2001;7:331-7.  Back to cited text no. 22
    
23.
Dyhrfjeld-Johnsen J, Morgan RJ, Földy C, Soltesz I. Upregulated H-current in hyperexcitable CA1 dendrites after febrile seizures. Front Cell Neurosci 2008;2:2.  Back to cited text no. 23
    
24.
Chen K, Ratzliff A, Hilgenberg L, Gulyás A, Freund TF, Smith M, et al. Long-term plasticity of endocannabinoid signaling induced by developmental febrile seizures. Neuron 2003;39:599-611.  Back to cited text no. 24
    
25.
Lemmens EM, Schijns OE, Beuls EA, Hoogland G. Cytogenesis in the dentate gyrus after neonatal hyperthermia-induced seizures: What becomes of surviving cells? Epilepsia 2008;49:853-60.  Back to cited text no. 25
    
26.
Koyama R, Matsuki N. Novel etiological and therapeutic strategies for neurodiseases: Mechanisms and consequences of febrile seizures: Lessons from animal models. J Pharmacol Sci 2010;113:14-22.  Back to cited text no. 26
    
27.
van Baalen A, Vezzani A, Häusler M, Kluger G. Febrile infection-related epilepsy syndrome: Clinical review and hypotheses of epileptogenesis. Neuropediatrics 2017;48:5-18.  Back to cited text no. 27
    
28.
von Spiczak S, Helbig KL, Shinde DN, Huether R, Pendziwiat M, Lourenço C, et al. DNM1 encephalopathy: A new disease of vesicle fission. Neurology 2017;89:385-94.  Back to cited text no. 28
    
29.
Schmid SJ, Wagner M, Goetz C, Makowski C, Freisinger P, Berweck S, et al. A de novo dominant negative mutation in DNM1L causes sudden onset status epilepticus with subsequent epileptic encephalopathy. Neuropediatrics 2019;50:197-201.  Back to cited text no. 29
    
30.
Ladds E, Whitney A, Dombi E, Hofer M, Anand G, Harrison V, et al. De novo DNM1L mutation associated with mitochondrial epilepsy syndrome with fever sensitivity. Neurol Genet 2018;4:e258.  Back to cited text no. 30
    
31.
Kothur K, Bandodkar S, Wienholt L, Chu S, Pope A, Gill D, et al. Etiology is the key determinant of neuroinflammation in epilepsy: Elevation of cerebrospinal fluid cytokines and chemokines in febrile infection-related epilepsy syndrome and febrile status epilepticus. Epilepsia 2019;60:1678-88.  Back to cited text no. 31
    
32.
Capovilla G, Mastrangelo M, Romeo A, Vigevano F. Recommendations for the management of “febrile seizures” Ad hoc task force of LICE guidelines commission. Epilepsia 2009;50(Suppl 1):2-6.  Back to cited text no. 32
    
33.
Chungath M, Shorvon S. The mortality and morbidity of febrile seizures. Nat Clin Pract Neurol 2008;4:610-21.  Back to cited text no. 33
    
34.
Whelan H, Harmelink M, Chou E, Sallowm D, Khan N, Patil R, et al. Complex febrile seizures-A systematic review. Dis Mon 2017;63:5-23.  Back to cited text no. 34
    
35.
Hesdorffer DC, Shinnar S, Lewis DV, Nordli DR, Pellock JM, Moshé SL, et al. Risk factors for febrile status epilepticus: A case-control study. J Pediatr 2013;163:1147-51.e1.  Back to cited text no. 35
    
36.
Hesdorffer DC, Shinnar S, Lax DN, Pellock JM, Nordli DR, Seinfeld S, et al. Risk factors for subsequent febrile seizures in the FEBSTAT study. Epilepsia 2016;57:1042-7.  Back to cited text no. 36
    
37.
Lewis DV, Shinnar S, Hesdorffer DC, Bagiella E, Bello JA, Chan S, et al. Hippocampal sclerosis after febrile status epilepticus: The FEBSTAT study. Ann Neurol 2014;75:178-85.  Back to cited text no. 37
    
38.
Camfield P, Camfield C. Febrile seizures and genetic epilepsy with febrile seizures plus (GEFS+). Epileptic Disord 2015;17:124-33.  Back to cited text no. 38
    
39.
Nakayama J, Arinami T. Molecular genetics of febrile seizures. Epilepsy Res 2006;70:190-8.  Back to cited text no. 39
    
40.
Feng B, Chen Z. Generation of febrile seizures and subsequent epileptogenesis. Neurosci Bull 2016;32:481-92.  Back to cited text no. 40
    
41.
Baulac S, Gourfinkel-An I, Nabbout R, Huberfeld G, Serratosa J, Leguern E, et al. Fever, genes, and epilepsy. Lancet Neurol 2004;3:421-30.  Back to cited text no. 41
    
42.
Matthews E, Balestrini S, Sisodiya SM, Hanna MG. Muscle and brain sodium channelopathies: Genetic causes, clinical phenotypes, and management approaches. Lancet Child Adolesc Health 2020;4:536-47.  Back to cited text no. 42
    
43.
Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet 2014;46:1327-32.  Back to cited text no. 43
    
44.
Chemaly N, Losito E, Pinard JM, Gautier A, Villeneuve N, Arbues AS, et al. Early and long-term electroclinical features of patients with epilepsy and PCDH19 mutation. Epileptic Disord 2018;20:457-67.  Back to cited text no. 44
    
45.
Trivisano M, Pietrafusa N, di Ciommo V, Cappelletti S, de Palma L, Terracciano A, et al. PCDH19-related epilepsy and Dravet syndrome: Face-off between two early-onset epilepsies with fever sensitivity. Epilepsy Res 2016;125:32-6.  Back to cited text no. 45
    
46.
Ding J, Zhang J-W, Guo Y-X, Zhang Y-X, Chen Z-H, Zhai Q-X. Novel mutations in SCN9A occurring with fever-associated seizures or epilepsy. Seizure 2019;71:214-8.  Back to cited text no. 46
    
47.
Puranam RS, He XP, Yao L, Le T, Jang W, Rehder CW, et al. Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus. J Neurosci 2015;35:8866-81.  Back to cited text no. 47
    
48.
Hirsch LJ, Gaspard N, van Baalen A, Nabbout R, Demeret S, Loddenkemper T, et al. Proposed consensus definitions for new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and related conditions. Epilepsia 2018;59:739-44.  Back to cited text no. 48
    
49.
Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, et al. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): A peculiar form of childhood encephalitis. Acta Neurol Scand 2010;121:251-6.  Back to cited text no. 49
    
50.
Mikaeloff Y, Jambaqué I, Hertz-Pannier L, Zamfirescu A, Adamsbaum C, Plouin P, et al. Devastating epileptic encephalopathy in school-aged children (DESC): A pseudo encephalitis. Epilepsy Res 2006;69:67-79.  Back to cited text no. 50
    
51.
Culleton S, Talenti G, Kaliakatsos M, Pujar S, D'Arco F. The spectrum of neuroimaging findings in febrile infection-related epilepsy syndrome (FIRES): A literature review. Epilepsia 2019;60:585-92.  Back to cited text no. 51
    
52.
Lee H-F, Chi C-S. Febrile infection-related epilepsy syndrome (FIRES): Therapeutic complications, long-term neurological and neuroimaging follow-up. Seizure 2018;56:53-9.  Back to cited text no. 52
    
53.
Kramer U, Chi C-S, Lin K-L, Specchio N, Sahin M, Olson H, et al. Febrile infection-related epilepsy syndrome (FIRES): Pathogenesis, treatment, and outcome: A multicenter study on 77 children. Epilepsia 2011;52:1956-65.  Back to cited text no. 53
    
54.
van Baalen A, Häusler M, Boor R, Rohr A, Sperner J, Kurlemann G, et al. Febrile infection-related epilepsy syndrome (FIRES): A nonencephalitic encephalopathy in childhood. Epilepsia 2010;51:1323-8.  Back to cited text no. 54
    
55.
Schmitt SE, Pargeon K, Frechette ES, Hirsch LJ, Dalmau J, Friedman D. Extreme delta brush. Neurology 2012;79:1094-100.  Back to cited text no. 55
    
56.
Farias-Moeller R, Bartolini L, Staso K, Schreiber JM, Carpenter JL. Early ictal and interictal patterns in FIRES: The sparks before the blaze. Epilepsia 2017;58:1340-8.  Back to cited text no. 56
    
57.
Nabbout R. FIRES and IHHE: Delineation of the syndromes. Epilepsia 2013;54(Suppl 6):54-6.  Back to cited text no. 57
    
58.
Auvin S, Bellavoine V, Merdariu D, Delanoë C, Elmaleh-Bergés M, Gressens P, et al. Hemiconvulsion-hemiplegia-epilepsy syndrome: Current understandings. Eur J Paediatr Neurol 2012;16:413-21.  Back to cited text no. 58
    
59.
Toldo I, Calderone M, Boniver C, Dravet C, Guerrini R, Laverda AM. Hemiconvulsion-hemiplegia-epilepsy syndrome: Early magnetic resonance imaging findings and neuroradiological follow-up. Brain Dev 2007;29:109-11.  Back to cited text no. 59
    
60.
Nabbout R, Vezzani A, Dulac O, Chiron C. Acute encephalopathy with inflammation-mediated status epilepticus. Lancet Neurol 2011;10:99-108.  Back to cited text no. 60
    
61.
Albakaye M, Belaïdi H, Lahjouji F, Errguig L, Kuate C, Maiga Y, et al. Clinical aspects, neuroimaging, and electroencephalography of 35 cases of hemiconvulsion-hemiplegia syndrome. Epilepsy Behav 2018;80:184-90.  Back to cited text no. 61
    
62.
Heinzen EL, Arzimanoglou A, Brashear A, Clapcote SJ, Gurrieri F, Goldstein DB, et al. Distinct neurological disorders with ATP1A3 mutations. Lancet Neurol 2014;13:503-14.  Back to cited text no. 62
    
63.
Takanashi J. Two newly proposed infectious encephalitis/encephalopathy syndromes. Brain Dev 2009;31:521-8.  Back to cited text no. 63
    
64.
Lee S, Sanefuji M, Torio M, Kaku N, Ichimiya Y, Mizuguchi S, et al. Involuntary movements and coma as the prognostic marker for acute encephalopathy with biphasic seizures and late reduced diffusion. J Neurol Sci 2016;370:39-43.  Back to cited text no. 64
    
65.
Fukuyama T, Yamauchi S, Amagasa S, Hattori Y, Sasaki T, Nakajima H, et al. Early prognostic factors for acute encephalopathy with reduced subcortical diffusion. Brain Dev 2018;40:707-13.  Back to cited text no. 65
    
66.
Fukui KO, Kubota M, Terashima H, Ishiguro A, Kashii H. Early administration of vitamins B1 and B6 and l-carnitine prevents a second attack of acute encephalopathy with biphasic seizures and late reduced diffusion: A case control study. Brain Dev 2019;41:618-24.  Back to cited text no. 66
    
67.
Hasegawa S, Matsushige T, Inoue H, Takahara M, Kajimoto M, Momonaka H, et al. Serum and cerebrospinal fluid levels of visinin-like protein-1 in acute encephalopathy with biphasic seizures and late reduced diffusion. Brain Dev 2014;36:608-12.  Back to cited text no. 67
    
68.
Kamate M. Acute leukoencephalopathy with restricted diffusion. Indian J Crit Care Med 2018;22:519-23.  Back to cited text no. 68
[PUBMED]  [Full text]  
69.
Yokochi T, Takeuchi T, Mukai J, Akita Y, Nagai K, Obu K, et al. Prediction of acute encephalopathy with biphasic seizures and late reduced diffusion in patients with febrile status epilepticus. Brain Dev 2016;38:217-24.  Back to cited text no. 69
    
70.
Chow CK, Ma CK. Presentation and outcome of acute necrotizing encephalopathy of childhood: A 10-year single-center retrospective study from Hong Kong. J Child Neurol 2020;35:674-80.  Back to cited text no. 70
    
71.
Lim HY, Ho VP, Lim TC, Thomas T, Chan DWS. Serial outcomes in acute necrotising encephalopathy of childhood: A medium and long term study. Brain Dev 2016;38:928-36.  Back to cited text no. 71
    
72.
Levine JM, Ahsan N, Ho E, Santoro JD. Genetic acute necrotizing encephalopathy associated with RANBP2: Clinical and therapeutic implications in pediatrics. Mult Scler Relat Disord 2020;43:102194.  Back to cited text no. 72
    
73.
Wu X, Wu W, Pan W, Wu L, Liu K, Zhang H-L. Acute necrotizing encephalopathy: An underrecognized clinicoradiologic disorder. Mediators Inflamm 2015;2015:792578.  Back to cited text no. 73
    
74.
Nabbout R, Mazzuca M, Hubert P, Peudennier S, Allaire C, Flurin V, et al. Efficacy of ketogenic diet in severe refractory status epilepticus initiating fever induced refractory epileptic encephalopathy in school age children (FIRES). Epilepsia 2010;51:2033-7.  Back to cited text no. 74
    
75.
Dupuis N, Curatolo N, Benoist J-F, Auvin S. Ketogenic diet exhibits anti-inflammatory properties. Epilepsia 2015;56:e95-8.  Back to cited text no. 75
    
76.
Singh RK, Joshi SM, Potter DM, Leber SM, Carlson MD, Shellhaas RA. Cognitive outcomes in febrile infection-related epilepsy syndrome treated with the ketogenic diet. Pediatrics 2014;134:e1431-5.  Back to cited text no. 76
    
77.
Gofshteyn JS, Wilfong A, Devinsky O, Bluvstein J, Charuta J, Ciliberto MA, et al. Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol 2017;32:35-40.  Back to cited text no. 77
    
78.
Lin J-J, Lin K-L, Hsia S-H, Wang H-S; CHEESE Study Group. Therapeutic hypothermia for febrile infection-related epilepsy syndrome in two patients. Pediatr Neurol 2012;47:448-50.  Back to cited text no. 78
    
79.
Hsu M-H, Kuo H-C, Lin J-J, Chou M-Y, Lin Y-J, Hung P-L. Therapeutic hypothermia for pediatric refractory status epilepticus May Ameliorate post-status epilepticus epilepsy. Biomed J 2020;43:277-84.  Back to cited text no. 79
    
80.
Kurukumbi M, Leiphart J, Asif A, Wang J. Vagus nerve stimulation (VNS) in super refractory new onset refractory status epilepticus (NORSE). Case Rep Neurol Med 2019;2019:7852017.  Back to cited text no. 80
    
81.
Dibué-Adjei M, Brigo F, Yamamoto T, Vonck K, Trinka E. Vagus nerve stimulation in refractory and super-refractory status epilepticus-A systematic review. Brain Stimulat 2019;12:1101-10.  Back to cited text no. 81
    
82.
Tan WW, Chan DW, Lee JH, Thomas T, Menon AP, Chan YH. Use of magnesium sulfate infusion for the management of febrile illness-related epilepsy syndrome: A case series. Child Neurol Open 2015;2:2329048X14550067. doi: 10.1177/2329048X14550067.  Back to cited text no. 82
    
83.
Mirás Veiga A, Moreno DC, Menéndez AI, Siscart IM, Fernández MD, Sánchez EG, et al. Effectiveness of electroconvulsive therapy for refractory status epilepticus in febrile infection-related epilepsy syndrome. Neuropediatrics 2017;48:45-8.  Back to cited text no. 83
    
84.
Sa M, Singh R, Pujar S, D'Arco F, Desai N, Eltze C, et al. Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES-Two different outcomes. Eur J Paediatr Neurol 2019;23:749-54.  Back to cited text no. 84
    
85.
Bergamino L, Capra V, Biancheri R, Rossi A, Tacchella A, Ambrosini L, et al. Immunomodulatory therapy in recurrent acute necrotizing encephalopathy ANE1: Is it useful? Brain Dev 2012;34:384-91.  Back to cited text no. 85
    
86.
Koh JC, Murugasu A, Krishnappa J, Thomas T. Favorable outcomes with early interleukin 6 receptor blockade in severe acute necrotizing encephalopathy of childhood. Pediatr Neurol 2019;98:80-4.  Back to cited text no. 86
    
87.
Cantarín-Extremera V, Jiménez-Legido M, Duat-Rodríguez A, García-Fernández M, Ortiz-Cabrera NV, Ruiz-Falcó-Rojas ML, et al. Tocilizumab in pediatric refractory status epilepticus and acute epilepsy: Experience in two patients. J Neuroimmunol 2020;340:577142.  Back to cited text no. 87
    
88.
Chee YC, Lim CH, Halim SA, Ong BH. Extinguishing FIRES using tocilizumab. Neurol Clin Neurosci 2020;8:192-5.  Back to cited text no. 88
    
89.
Jun J-S, Lee S-T, Kim R, Chu K, Lee SK. Tocilizumab treatment for new onset refractory status epilepticus. Ann Neurol 2018;84:940-5.  Back to cited text no. 89
    
90.
Kullenberg T, Löfqvist M, Leinonen M, Goldbach-Mansky R, Olivecrona H. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 2016;55:1499-506.  Back to cited text no. 90
    
91.
Kenney-Jung DL, Vezzani A, Kahoud RJ, LaFrance-Corey RG, Ho M-L, Muskardin TW, et al. Febrile infection-related epilepsy syndrome treated with anakinra. Ann Neurol 2016;80:939-45.  Back to cited text no. 91
    
92.
Muscal E, Wells E, Shukla N, Eschbach K, Wickstrom R, Viri M, et al. Anakinra usage in febrile infection related epilepsy syndrome.:2.  Back to cited text no. 92
    
93.
Dilena R, Mauri E, Aronica E, Bernasconi P, Bana C, Cappelletti C, et al. Therapeutic effect of Anakinra in the relapsing chronic phase of febrile infection–related epilepsy syndrome. Epilepsia Open 2019;4:344-50.  Back to cited text no. 93
    
94.
Mizuguchi M. Acute necrotizing encephalopathy of childhood: A novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev 1997;19:81-92.  Back to cited text no. 94
    
95.
Mizuguchi M, Abe J, Mikkaichi K, Noma S, Yoshida K, Yamanaka T, et al. Acute necrotising encephalopathy of childhood: A new syndrome presenting with multifocal, symmetric brain lesions. J Neurol Neurosurg Psychiatry 1995;58:555-61.  Back to cited text no. 95
    
96.
Neilson DE. The interplay of infection and genetics in acute necrotizing encephalopathy. Curr Opin Pediatr 2010;22:751-7.  Back to cited text no. 96
    
97.
Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 2009;84:44-51.  Back to cited text no. 97
    
98.
Weng W-C, Peng SS-F, Lee W-T. Acute necrotizing encephalopathy of childhood with spinal cord involvement: A case report. J Child Neurol 2010;25:1539-41.  Back to cited text no. 98
    
99.
Mittal A, Kuntar S, Vaswani ND, Kaushik JS. Acute necrotizing encephalopathy of childhood associated with human parvovirus B19 infection. Indian J Pediatr 2020;87:648-9.  Back to cited text no. 99
    
100.
Abbas Q, Jafri SK, Ishaque S, Jamil MT. Acute necrotizing encephalopathy of childhood secondary to dengue infection: A case report from Pakistan. J Pediatr Neurosci 2017;12:165-7.  Back to cited text no. 100
[PUBMED]  [Full text]  
101.
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology 2020;296:E119-20.  Back to cited text no. 101
    
102.
Singh RR, Sedani S, Lim M, Wassmer E, Absoud M. RANBP2 mutation and acute necrotizing encephalopathy: 2 cases and a literature review of the expanding clinico-radiological phenotype. Eur J Paediatr Neurol 2015;19:106-13.  Back to cited text no. 102
    
103.
Neilson D. Susceptibility to Infection-Induced Acute Encephalopathy 3. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, et al., editors. GeneReviews®.  Back to cited text no. 103
    
104.
Denier C, Balu L, Husson B, Nasser G, Burglen L, Rodriguez D, et al. Familial acute necrotizing encephalopathy due to mutation in the RANBP2 gene. J Neurol Sci 2014;345:236-8.  Back to cited text no. 104
    
105.
Suri M. Genetic basis for acute necrotizing encephalopathy of childhood. Dev Med Child Neurol 2010;52:4-5.  Back to cited text no. 105
    
106.
Shinohara M, Saitoh M, Takanashi J, Yamanouchi H, Kubota M, Goto T, et al. Carnitine palmitoyl transferase II polymorphism is associated with multiple syndromes of acute encephalopathy with various infectious diseases. Brain Dev 2011;33:512-7.  Back to cited text no. 106
    
107.
Iyer G, Utage P, Bailur S, Utage A, Srirambhatla A, Hasan Q. Familial acute necrotizing encephalopathy: Evidence from next generation sequencing of digenic inheritance. J Child Neurol 2020;35:393-7.  Back to cited text no. 107
    
108.
Kashiwagi M, Tanabe T, Shimakawa S, Nakamura M, Murata S, Shabana K, et al. Clinico-radiological spectrum of reversible splenial lesions in children. Brain Dev 2014;36:330-6.  Back to cited text no. 108
    
109.
Le Bras A, Proisy M, Kuchenbuch M, Gomes C, Tréguier C, Napuri S, et al. Reversible lesions of the corpus callosum with initially restricted diffusion in a series of Caucasian children. Pediatr Radiol 2018;48:999-1007.  Back to cited text no. 109
    
110.
Zhu Y, Zheng J, Zhang L, Zeng Z, Zhu M, Li X, et al. Reversible splenial lesion syndrome associated with encephalitis/encephalopathy presenting with great clinical heterogeneity. BMC Neurol 2016;16:49.  Back to cited text no. 110
    
111.
Lin J-J, Chou C-C, Lan S-Y, Hsiao H-J, Wang Y, Chan O-W, et al. Therapeutic burst-suppression coma in pediatric febrile refractory status epilepticus. Brain Dev 2017;39:693-702.  Back to cited text no. 111
    
112.
Johnson EL, Martinez NC, Ritzl EK. EEG characteristics of successful burst suppression for refractory status epilepticus. Neurocrit Care 2016;25:407-14.  Back to cited text no. 112
    
113.
Bellante F, Legros B, Depondt C, Créteur J, Taccone FS, Gaspard N. Midazolam and thiopental for the treatment of refractory status epilepticus: A retrospective comparison of efficacy and safety. J Neurol 2016;263:799-806.  Back to cited text no. 113
    
114.
Gulati S, Sondhi V, Chakrabarty B, Jauhari P, Lodha R, Sankar J. High dose phenobarbitone coma in pediatric refractory status epilepticus; A retrospective case record analysis, a proposed protocol and review of literature. Brain Dev 2018;40:316-24.  Back to cited text no. 114
    
115.
Kessi M, Liu F, Zhan Y, Tang Y, Wu L, Yang L, et al. Efficacy of different treatment modalities for acute and chronic phases of the febrile infection-related epilepsy syndrome: A systematic review. Seizure 2020;79:61-8.  Back to cited text no. 115
    
116.
Lin J-J, Wang Y, Lan S-Y, Chan O-W, Hsia S-H, Chou M-L, et al. Combination of intravenous immunoglobulin and steroid pulse therapy improves outcomes of febrile refractory status epilepticus. Epilepsy Res 2018;142:100-5.  Back to cited text no. 116
    
117.
Peng P, Peng J, Yin F, Deng X, Chen C, He F, et al. Ketogenic diet as a treatment for super-refractory status epilepticus in febrile infection-related epilepsy syndrome. Front Neurol 2019;10:423.  Back to cited text no. 117
    
118.
Wang X, Gao X, Lu G, Lu Z, Zhou S, Wang Y, et al. The ketogenic diet for paediatric patients with super-refractory status epilepticus in febrile infection-related epilepsy syndrome. Acta Epileptol 2020;2:4.  Back to cited text no. 118
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]
 
 
    Tables

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    Abstract
     Introduction
   Fever and the Ne...
   The Febrile Seiz...
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