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 Table of Contents  
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 95-98

A less aggressive approach to the management of super refractory status epilepticus

Department of Pediatrics, G Kuppuswamy Naidu Memorial Hospital, Coimbatore, Tamil Nadu, India

Date of Submission26-Sep-2020
Date of Decision21-Dec-2020
Date of Acceptance31-Dec-2020
Date of Web Publication10-Mar-2021

Correspondence Address:
Dr. Madhumathi Gunasekaran
Department of Pediatrics, G Kuppuswamy Naidu Memorial Hospital, Coimbatore - 641 037, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_153_20

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Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic encephalopathy of unknown etiology. It commonly affects previously healthy children. FIRES is a subcategory of new-onset refractory status epilepticus (NORSE), term used specifically for adult population, and FIRES is used for pediatric population. Uniformly, both FIRES and NORES have poor outcomes with chronic drug-resistant epilepsy, severe neurological sequelae, and mortality in one-fifth of patients. We report a case of FIRES in a 9-year-old previously healthy child in whom a less aggressive approach was used to manage anesthetic resistant super refractory status epilepticus, which has reduced the potentially fatal complications of prolonged use of intravenous anesthetics and also the need for tracheostomy.

Keywords: Anticonvulsants, coma, febrile infection-related epilepsy syndrome, intravenous anesthetics, new-onset refractory status epilepticus

How to cite this article:
Gunasekaran M, Reddi G, Palaniappan A, Singaravadivelu V, Chinnappan Ramalingam RT. A less aggressive approach to the management of super refractory status epilepticus. J Pediatr Crit Care 2021;8:95-8

How to cite this URL:
Gunasekaran M, Reddi G, Palaniappan A, Singaravadivelu V, Chinnappan Ramalingam RT. A less aggressive approach to the management of super refractory status epilepticus. J Pediatr Crit Care [serial online] 2021 [cited 2022 Dec 6];8:95-8. Available from: http://www.jpcc.org.in/text.asp?2021/8/2/95/311052

  Introduction Top

The definition of new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) comes from proceedings of NORSE and FIRES symposium held in 2017 with no strong scientific evidence.[1],[2] FIRES requires a prior febrile illness with fever starting between 2 weeks and 24 h before onset of refractory status epilepticus (SE), with or without fever at onset of SE.[1] We report a 9-year-old girl who presented with super refractory seizures where less aggressive approach aimed at avoiding anesthetics induced coma was followed after IV sedation failed. Intravenous (IV) anesthetic use has been associated with mortality and other complications such as metabolic acidosis, bowel ileus, and ischemia, nosocomial infections, deep vein thrombosis, and anesthetic withdrawal seizures.[3],[4],[5]

  Case Report Top

Our patient 9-year-old previously healthy girl child presented to the pediatric emergency department with history of 4 days of fever and altered sensorium. On examination, she was pain responsive, able to localize pain, pupils-bilateral equally reacting to light, airway was clear, breathing and circulation were stable. She was admitted to PICU and started on 3% saline infusion and antimicrobials including ceftriaxone, vancomycin, doxycycline, and acyclovir.

Initial bloods showed leukopenia (4800/mm3) with thrombocytopenia (1,24,000/mm3). Blood glucose, serum electrolytes, ammonia, liver function test, renal function test done were normal. Real-time reverse transcription polymerase chain reaction for COVID-19 was negative. Immunoglobulin M for scrub typhus, dengue serology, and card test for malaria were negative.

Initial magnetic resonance imaging (MRI) brain done on day 2 of admission was normal. Electroencephalography (EEG) showed widespread delta/theta waves with no epileptiform discharges. Cerebrospinal fluid (CSF) was acellular with mild protein elevation (54 mg/dL).

She continued to have fever and developed generalized tonic–clonic seizures (GTCS) on day 2 of admission resistant to lorazepam, fosphenytoin bolus (30 mg/kg), and levetiracetam (60 mg/kg) bolus. She was intubated and initiated on mechanical ventilation along with midazolam and fentanyl infusion. IV immunoglobulin 2 g/kg over 5 days was given. As CSF meningoencephalitis panel was negative IV methylprednisolone 30mg/kg/day for 5 days was given. CSF autoimmune panel and serum antinuclear antibody were negative. Serum anti-thyroid peroxidase (TPO) antibody was elevated (220.8U/mL) and T3, T4, and TSH were low normal. Blood for neuromyelitis optica and myelin oligodendrocyte glycoprotein antibodies were negative. Ultrasonography abdomen to rule out ovarian tumor was normal.

Repeat MRI done on day 6 of admission showed symmetrical T2-weighted/fluid-attenuated inversion recovery hyperintensity in bilateral medial temporal lobes and right external capsule, hyperintensity noted in the diffusion-weighted imaging without significant hypointensity in Apparent diffusion coefficient (ADC) [Figure 1]. She continued to have generalized seizures hence burst suppression was induced with thiopentone (max 5 mg/kg/h), ketamine (max 40 mcg/kg/min), and propofol infusions (max 2mg/kg/h) on day 8 and maintained for 48 h [Figure 2]. Plasmapheresis was tried with no success hence second-line immunotherapy with weekly Rituximab was given in the dose of 375mg/m2 for 2 weeks. Repeat anti-TPO was negative. Propofol was stopped and when thiopentone was tapered she developed repetitive seizures both generalized and focal involving the right leg and foot. Phenobarbitone coma with burst suppression was also tried but still subclinical seizures persisted. Phenobarbitone started with 5 mg/kg/day and increased to 10 mg/kg/day over 4 days. It was decided by the team of pediatric neurologists and pediatric intensivist to taper and stop IV anesthetics and manage only generalized seizures that last >5 min with phenobarbitone bolus accepting brief focal seizures. Multiple antiepileptic drug regimen with high-dose phenobarbitone and with titration of dosage and frequencies of other nonsedating anticonvulsants: Brivaracetam (3 mg/kg/d), topiramate (4–7 mg/kg/d), lacosamide (10 mg/kg/d), fosphenytoin (8 mg/kg/d), valproate (30 mg/kg/d), clobazam (5–15 mg BD), and perampanel (4 mg OD) were done. Clobazam 15 mg BD brought seizure control. On day 14, repeat EEG showed multifocal spike and wave with right >left hemisphere involvement [Figure 3]. She was extubated after 12 days of mechanical ventilation. Generalized seizures became rare and were managed with lorazepam followed by increase in phenobarbitone dose. Her sensorium remained poor with intermittent stridor and pooling of secretions during the treatment which was managed with frequent suctioning. She was started on physical rehabilitation, then she started responding to her parent's voice by facial expressions and obeyed commands. Serum phenobarbitone levels were frequently monitored with the median and highest level being 68.4 μg/ml and 82.9 μg/ml, respectively.
Figure 1: Magnetic resonance imaging brain showing symmetrical hyperintensity in bilateral medial temporal lobes and right external capsule

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Figure 2: Electroencephalography shows burst suppression with interictal attenuation lasting for 3–4 sec

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Figure 3: Electroencephalography showing right-sided frontotemporal spike and waves and slow waves in delta range

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During the long course of her pediatric intensive care unit (PICU) stay, she suffered methicillin-resistant Staphylococcus aureus bloodstream infection (grown from peripheral prick of blood and not from dialysis catheter) which was treated with vancomycin and daptomycin. ECHO and whole-body MRI did not reveal any focus. Nosocomial pneumonia and catheter-associated urinary tract infection were treated with meropenem, a probable invasive fungal infection with caspofungin.

The frequency of Generalized tonic-clonic seizures (GTCS) and focal seizures got better and she was shifted to ward after 1 month of PICU stay with following anticonvulsants: Phenobarbitone (10 mg/kg/d), topiramate (4 mg/kg/d), perampanel (4 mg OD), and clobazam 15 mg BD. Her sensorium got better gradually and she was discharged after 45 days with phenobarbitone (10 mg/kg/d), topiramate (4 mg/kg/d), and clobazam 15 mg BD. At discharge, she was conscious, oriented to person, place, and time and walks unassisted, speaks simple sentences however she had inappropriate smiling at times.

  Discussion Top

In our case, we have used less sedating anticonvulsants with high-dose phenobarbitone as base after failure of IV anesthetic agents and accepting brief seizures. Maximum phenobarbitone level reached was 82.9 μg/ml to achieve seizure control. Phenobarbitone at supratherapeutic dose with blood levels as high as 290 μg/mL has been reported with good efficacy and minimal side effects.[6],[7],[8] Avoiding burst suppression coma induction for every seizure improves parent's perception and facilitates interaction with child and improve the hope for positive outcome.[5] Focal seizures can be tolerated with no major long-term effects on brain as compared to generalized seizure; hence, we have accepted focal seizures that last for <5 min and treated generalized seizure only with lorazepam followed by titration of other nonsedating anticonvulsants. Even though we managed to remove dialysis catheter, urinary catheter, and extubate as early as possible she suffered nosocomial infections possibly due to immunosuppression associated with steroids, rituximab as well as thiopentone infusion. There is possible role of immunotherapy in FIRES with no evidence of autoimmunity.[8],[9] Hence, we have started on immunotherapy even though her autoimmune encephalitis panel was negative. Irrespective of treatment provided outcome of SE is dependent on etiology. As repeated MRI in this child did not show any major abnormality except possible seizure-induced reversible changes, we have chosen less aggressive therapy which has probably resulted in better outcomes considering the diagnosis of FIRES.[10],[11]

This case describes a less aggressive approach in a child with super refractory SE, which has reduced the potentially fatal complications of prolonged use of intravenous anesthetics and also the need for tracheostomy.

Declaration of patient consent

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


We would like to thank our nurses who are involved in care of the patient and the postgraduates involved in clinical management.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Gaspard N, Hirsch LJ, Sculier C, Loddenkemper T, van Baalen A, Lancrenon J, et al. New-onset refractory statusepilepticus (NORSE) and febrile infection – Related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia 2018;59:745-52.  Back to cited text no. 1
Serino D, Santarone ME, Caputo D, Fusco L. Febrile infection-related epilepsy syndrome (FIRES): Prevalence, impact and management strategies. Neuropsychiatr Dis Treat 2019;15:1897-903.  Back to cited text no. 2
Ferguson M, Bianchi MT, Sutter R, Rosenthal ES, Cash SS, Kaplan PW, et al. Calculating the risk benefit equation for aggressive treatment of non-convulsive status epilepticus. Neurocrit Care 2013;18:216-27.  Back to cited text no. 3
Sutter R, Marsch S, Fuhr P, Kaplan PW, Ruegg S. Anesthetic drugs in status epilepticus: Risk or rescue? A 6 year cohort study. Neurology 2014;82:656-64.  Back to cited text no. 4
Eaton JE, Meriweather MT, Abou-Khalil BW, Sonmezturk HH. Avoiding anaesthetics after multiple failed drug-induced comas: An unorthodox approach to management of new-onset refractory status epilepticus (NORSE). Epileptic Disord 2019;21:483-91.  Back to cited text no. 5
Uchida T, Takayanagi M, Kitamura T, Nishio T, Numata Y, Endo W, et al. High dose pheno-barbital with intermittent short- acting barbiturates for acute encephalitis with refractory, repititive partial seizures. Pediatr Int 2016;58:750-3.  Back to cited text no. 6
Lee WK, Liu KT, Young BW. Very-high-dose phenobarbital for childhood refractory status epilepticus. Pediatr Neurol 2006;34:63-5.  Back to cited text no. 7
Rai S, Drislane FW. Treatment of refractory and super-refractory status epilepticus. Neurotherapeutics 2018;15:697-712.  Back to cited text no. 8
Trinka E, Hofler J, Leitinger M, Brigo F. Pharmacotherapy for status epilepticus. Drugs 2015;75:1499-521.  Back to cited text no. 9
Cianfoni A, Caulo M, Cerase A, Della Marca G, Falcone C, Di Lella GM, et al. Seizure induced brain lesions: A wide spectrum of variably reversible MRI abnormalities. Eur J Radiol 2013;82:1964-72.  Back to cited text no. 10
Cartagena AM, Young GB, Lee DH, Mirsattari SM. Reversible and irreversible cranial MRI findings associated with status epilepticus. Epilepsy Behav 2014;33:24-30.  Back to cited text no. 11


  [Figure 1], [Figure 2], [Figure 3]


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