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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 39-41

Febrile infection-related epilepsy syndrome treated successfully with enteral lorazepam as a substitute for intravenous midazolam as weaning drug


Department of Pediatrics and Pediatric Neurology, Santokba Durlabhji Memorial Hospital, Jaipur, Rajasthan, India

Date of Submission04-Aug-2020
Date of Decision12-Sep-2020
Date of Acceptance16-Sep-2020
Date of Web Publication08-Jan-2021

Correspondence Address:
Dr. Vivek Jain
Department of Pediatrics and Pediatric Neurology, Santokba Durlabhji Hospital and Medical Research Institute, Bhawani Singh Marg, Jaipur, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPCC.JPCC_123_20

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  Abstract 


Febrile infection-related epilepsy syndrome (FIRES) is an acute-onset epilepsy syndrome usually refractory to conventional antiepileptics and immunomodulation. Here, we report an adolescent male child whose seizures were refractory to multiple anticonvulsants, high-dose phenobarbitone, and ketogenic diet. He subsequently responded to coma induction with midazolam, though with seizure recurrences following multiple attempts at weaning of midazolam over the next 2½ months. Due to continuing prolonged intensive care stay, we substituted intravenous midazolam for equivalent dose of enteral lorazepam with good seizure control.

Keywords: Enteral lorazepam, febrile infection-related epilepsy syndrome, successful, treatment


How to cite this article:
Kumar A, Sharma R, Kharwas P, Chaturvedi A, Jain V. Febrile infection-related epilepsy syndrome treated successfully with enteral lorazepam as a substitute for intravenous midazolam as weaning drug. J Pediatr Crit Care 2021;8:39-41

How to cite this URL:
Kumar A, Sharma R, Kharwas P, Chaturvedi A, Jain V. Febrile infection-related epilepsy syndrome treated successfully with enteral lorazepam as a substitute for intravenous midazolam as weaning drug. J Pediatr Crit Care [serial online] 2021 [cited 2021 Jan 26];8:39-41. Available from: http://www.jpcc.org.in/text.asp?2021/8/1/39/306480




  Introduction Top


Febrile infection-related epilepsy syndrome (FIRES) is an acute-onset severe epilepsy syndrome typically affecting school-age children, preceded by a febrile illness followed by multifocal seizures and refractory status epilepticus (SE).[1],[2],[3] More recently, it has been reclassified as a subcategory of new-onset refractory SE with fever starting between 2 weeks and 24 h before the onset of refractory SE.[4]

There is though still no definitive therapy for FIRES, with most conventional antiepileptics and immune modulation being usually ineffective.[5] Ketogenic diet, high-dose phenobarbitone, and coma induction with midazolam or thiopentone though have been found to be efficacious in some of the patients.[6],[7],[8]

Here, we report a patient who had failed to respond to multiple anticonvulsants including high-dose phenobarbitone and ketogenic diet. His seizures though were exquisitely responsive to midazolam infusion. The continuing prolonged intensive care stay and ventilation necessitated a change from intravenous midazolam infusion to equivalent amount of enteral lorazepam, without subsequent seizure recurrence.


  Case Report Top


A previously well and healthy 14-year-old boy had presented with frequent predominantly left and also independent right orobrachial seizures with secondary generalization, following an acute febrile illness.

His infection workup including cerebrospinal fluid (CSF) cell count, protein, sugar, cultures, herpes simplex virus polymerase chain reaction, and mycoplasma antibodies was negative. Extensive serum and CSF autoimmune antibody workup (N-methyl-D-aspartate, gamma-aminobutyric acid [GABA] B receptor, contactin-associated protein 2, LG1, AMPA1, and AMPA2 antibodies) was also noncontributory. His 3 Tesla magnetic resonance imaging done twice (day 2 and 6 weeks after admission) was also normal. The continuous video electroencephalogram (EEG) monitoring before coma induction had shown frequent independent right more than left anterior temporal onset electroclinical and electrographic seizures.

In the first 24 h of admission, he was given fosphenytoin (total 30 mg/kg), sodium valproate (40 mg/kg), and levetiracetam (60 mg/kg cumulative dose) without much effect [Figure 1]. High-dose phenobarbitone (100 mg/kg total dose over the next 48 h) was also tried. In spite of reaching a supratherapeutic serum concentration of 66 μg/ml (normal: 15–40 μg/ml), seizures were refractory to treatment. Hence, 96 h after admission, he was put on coma induction with midazolam infusion with continuous video EEG monitoring.
Figure 1: Anticonvulsant durations

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The initial EEGs before coma induction showed predominantly right frontotemporal onset small-amplitude fast rhythm between 12 and 14 Hz which would evolve into run of spike and spike-wave complexes. Similar independent ictal events originating from the left frontal region were also seen infrequently. Initial recordings had shown up to 20 ictal events in 12-h epochs before starting midazolam infusion. The electrographic seizures resolved over the next 24 h (day 5 of admission), after escalating to a midazolam dose of 32 mg/h (12 μg/kg/min) equivalent to 780 mg/day, though drug-induced burst suppression was never aimed.

Ketamine infusion (maximum infusion rate of 3 mg/kg/h) and multiple other anticonvulsants [Figure 1] and ketogenic diet (adequate ketosis achieved at 3:1 ratio) were tried consecutively to attempt weaning of midazolam infusion, without success. Immunomodulation with high dose intravenous methylprednisolone (30 mg/kg/d for 5 days) with concomitant intravenous immunoglobulin (2 g/kg) given within the 1st week of the hospital, the stay was also not beneficial.

Over the next 75 days, multiple attempts at weaning off midazolam infusion (10 times) were unsuccessful. He though remained seizure free on a midazolam infusion dose of 8 mg/h (3 μg/kg/min) equivalent to 194 mg/day.

On day 78 of admission following a protracted intensive care stay, we decided to wean off intravenous midazolam infusion for equivalent dose of enteral (nasogastric) lorazepam. We extrapolated the enteral lorazepam dose from the conversion used for substituting oral lorazepam for intravenous midazolam when weaning pediatric intensive care patients off sedation.[9]

The required calculated dose of enteral lorazepam [Figure 2] of 64 mg, equivalent to 194 mg/day of midazolam infusion, was gradually introduced over the next 4 days in tablet form. Concomitantly, midazolam infusion was weaned off (25% dose reduction every 24 h) during this period. The two anticonvulsants which were ongoing for the previous 4 weeks, oral phenobarbitone (blood levels now kept only in therapeutic range) and lamotrigine (10 mg/kg/day), were continued in the same doses.
Figure 2: Oral lorazepam equivalent calculation formula

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There was no electrographic or electroclinical seizure recurrence in 48 h of continuous video EEG monitoring, after stopping intravenous midazolam. The child could be rapidly extubated and was discharged home within a week of weaning off coma induction. He was ambulant, coherent, oriented, and off nasogastric feeding with no neurological deficits, before discharge. As he was perceiving mild sedation, lorazepam dose was reduced to 40 mg/day in 4 divided doses (1 mg/kg/day; body weight 40 Kg). This dose was equivalent to two-third of the initial calculated required dose. At 1 month after hospital discharge, he has remained seizure free with normal higher mental functions and no neurological deficits. A formal neuropsychological assessment is planned at 3-month follow-up.


  Discussion Top


Seizures in FIRES patients are mostly resistant to routine anticonvulsants.[5] Only high-dose phenobarbitone and ketogenic diet have shown to have some good results.[6],[7] In our patient, both these strategies though had failed in the first 2 weeks of the illness. As has been observed in previous studies, immune modulation was also not helpful.

Anticonvulsants, except intravenous midazolam infusion, given in maximum permissible doses [Figure 1] were unsuccessful in controlling his seizures. This hence had resulted in multiple failed attempts at weaning of intravenous midazolam infusion.

Our patient had a good seizure control on a small dose (3 μg/kg/min) of intravenous midazolam infusion. This though continued to prolong his hospital stay. Lorazepam is more potent and has a longer duration of action as compared to midazolam, though with a similar mechanism of action.[9] We hence shifted the child from intravenous midazolam to enteral lorazepam, as has been often used in pediatric intensive care units to wean off ventilated patients from sedation [Figure 2].[9] The child has remained seizure free for a month since discharge from hospital. This supports the effectiveness of our strategy of changing intravenous midazolam to enteral lorazepam.

Our FIRES patient is the first case report of substitution of intravenous benzodiazepine (midazolam) for an equivalent enteral formulation of a similar GABA mimetic medication (lorazepam) for refractory seizures. This strategy could benefit FIRES patients who respond to midazolam coma induction but fail its weaning attempts, as in our patient. This observation though needs to be validated with larger case series in the future. To the best of our knowledge, this is the first case report of FIRES from India successfully treated with enteral lorazepam.

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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest



 
  References Top

1.
Kramer U, Chi CS, Lin KL, 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. 1
    
2.
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. 2
    
3.
Suleiman J, Brilot F, Lang B, Vincent A, Dale RC. Autoimmune epilepsy in children: Case series and proposed guidelines for identification. Epilepsia 2013;54:1036-45.  Back to cited text no. 3
    
4.
Gaspard N, Hirsch LJ, Sculier C, Loddenkemper T, van Baalen A, Lancrenon J, et al. New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES): State of the art and perspectives. Epilepsia 2018;59:745-52.  Back to cited text no. 4
    
5.
Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: A critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802-18.  Back to cited text no. 5
    
6.
Byun JI, Chu K, Sunwoo JS, Moon J, Kim TJ, Lim JA, et al. Mega-dose phenobarbital therapy for refractory status epilepticus. Epileptic disord 2015;17:444-52.  Back to cited text no. 6
    
7.
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. 7
    
8.
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. 8
    
9.
Warrington SE, Collier HK, Himebauch AS, Wolfe HA. Evaluation of IV to enteral benzodiazepine conversion calculations in a pediatric intensive care setting. Pediatr Crit Care Med 2018;19:e569-75.  Back to cited text no. 9
    


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