Response of focal refractory status epilepticus to lacosamide in an infant

  1. Asra Akbar 1,
  2. Aaron A Harthan 2,
  3. Sean Creeden 3 and
  4. Girish G Deshpande 4
  1. 1 Pediatric Neurology, University of Illinois College of Medicine at Peoria (UICOMP), Peoria, Illinois, USA
  2. 2 Pharmacy, OSF HealthCare System, Peoria, Illinois, USA
  3. 3 Radiology, University of Illinois College of Medicine at Peoria (UICOMP), Peoria, Illinois, USA
  4. 4 Pediatric Critical Care, University of Illinois College of Medicine at Peoria (UICOMP), Peoria, Illinois, USA
  1. Correspondence to Dr Asra Akbar; aakbar1@uic.edu

Publication history

Accepted:15 Apr 2022
First published:29 Apr 2022
Online issue publication:29 Apr 2022

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Status epilepticus (SE) is a life-threatening medical emergency which is frequently encountered in the critical care setting and can be refractory to treatment. Refractory status epilepticus (RSE) is defined as SE that has failed to respond to adequately used first-line and second-line antiepileptic medications. Super refractory status epilepticus is defined as SE that persists for 24 hours or more after the use of an anaesthetic agent or recurs after its withdrawal.

If SE persists beyond a period of 7 days it is referred to as prolonged, refractory status epilepticus (PRSE). There are limited data guiding treatment of RSE in the paediatric population.

Lacosamide (LCM) is licensed as an adjunctive treatment for partial-onset seizures. Evidence for the efficacy of LCM in paediatric SE is scarce. This case report may suggest a synergistic effect of LCM on slow-activation sodium channels in conjunction with medications such as phenytoin that causes fast inactivation of sodium channels. The dual fast and slow inactivation of sodium channels may enhance the effectiveness in treatment of RSE. This is the first case report of PRSE in an infant, successfully treated with LCM. A brief review of literature is also a part of this report.

Background

Epilepsy is one of the most commonly reported neurological conditions, with an estimated annual incidence of 50/100 000 population and a prevalence of 700/100 000 population.1 The annual incidence of status epilepticus (SE) is estimated to be 17–23 episodes per 100 000 children.2 Between 10% and 40% of patients with SE will develop refractory status epilepticus (RSE). RSE can be life-threatening with a mortality rate of 16%–43.5%.3 Non-convulsive SE is a commonly under-recognised condition in critically ill patients.4

There are no clear guidelines for the management of RSE. Only few medications have been studied in prospective controlled trials so there are limited data to guide therapy.5

The antiepileptic drug (AED) lacosamide (LCM) has been approved in the USA and Europe as both monotherapy and adjunctive therapy in adults since 2008 to treat refractory focal seizures. It was approved as adjunctive therapy for children older than 4 years of age in 2017.6 LCM has a unique mechanism of action in that it selectively enhances the slow inactivation component of the neuronal voltage-gated sodium channels.7 The concomitant use of LCM in conjunction with more routine sodium channel antiepileptics may provide a synergistic effect in terminating SE. This case describes the use of LCM in an infant with RSE after management with multiple pharmacological therapies had failed. This case also allows for an opportunity to review the literature regarding LCM for management of RSE in infants and children.

Case presentation

Our patient is a baby who was admitted to paediatric intensive care unit (PICU) for management of RSE. A routine outpatient electroencephalogram (EEG) showed multiple subclinical left hemisphere seizures prompting the admission. The patient was monitored on continuous video EEG and was noted to have seizures which were refractory to first-line and second-line AEDs as well as an anaesthetic agent, midazolam.

The patient’s medical history was significant for a term birth at 39 weeks of gestation complicated by left subdural haematoma secondary to traumatic attempted forceps delivery which was followed by an emergency caesarean section. At birth, the patient had a left parietal bone fracture, left larger than right subdural haematomas and subgaleal haemorrhage (figure 1). The infant underwent urgent decompressive craniotomy and haematoma evacuation and was status post left cranioplasty on day 8 of life. On day 10 of life while in the neonatal intensive care unit an EEG was obtained which showed generalised suppression, more so over the left hemisphere and generalised low voltage, suppressed background as well as occasional sharp waves over the right centrotemporal and midline regions. No electroclinical or electrographic seizures were seen at that time. The patient was discharged from the neonatal intensive care unit on levetiracetam (40 mg/kg/day divided into two times per day) and phenobartibal (5 mg/kg/day divided into two times per day) for seizure control.

Figure 1

Coronal and axial non-contrast CT of the head.

At 8 weeks of age, a routine, follow-up EEG was obtained which showed several focal right hemisphere seizures prompting the admission for further evaluation. These subclinical seizures had been ongoing for over 7 days prior to the admission to the PICU.

On admission, the clinical exam was significant for plagiocephaly and overriding sutures with left parietal bone flap. The patient was awake and in no active distress. Vital signs were appropriate for age. The infant remained stable on room air and later required oxygen through the nasal cannula.

MRI of the brain showed progression of large area of encephalomalacia involving the entire left cerebral hemisphere and majority of the right frontal and parietal lobe with ventriculomegaly (figure 2).

Figure 2

Axial T2 and coronal fluid attenuated inversion recovery (FLAIR) and fat saturated weighted image.

Multiple focal onset electrographic seizures were recorded on video EEG arising from the right frontal region lasting for approximately 10 s with a frequency of one to two seizures every 15 min. Occasional left frontal/central electrographic seizures were noted as well. Only two of these several per minute seizures were associated with a clinical change of twitching in his left arm and shoulder lasting for 10 s (figures 3–4).

Figure 3

Focal right hemisphere spikes with evolution and seen in runs over several seconds with a field over the left hemisphere.

Figure 4

Super refractory electrographic status epilepticus with runs of rhythmic spikes over the right hemisphere with a field over the left hemisphere. Left hemisphere suppression.

During this admission, the patient’s SE was treated with benzodiazepines and a load of fosphenytoin (20 mg/kg), levetiracetam (30 mg/kg) and phenobarbital (20 mg/kg), none of which resulted in termination of the seizures. A midazolam infusion was initiated and was slowly escalated from 0.05 mg/kg/hour to 0.15 mg/kg/hour over 11 hours. The seizures remained refractory to these medications. The midazolam infusion was continued for approximately 24 hours before a loading dose of intravenous LCM 20 mg (approximately 4 mg/kg) was given. At this time, the electrographic seizures stopped for over 24 hours on continued video EEG. As the midazolam infusion was weaned off, the electrographic seizures restarted after 24 hours. Another load of LCM 20 mg was given as well as a load of fosphenytoin 20 mg/kg which again resulted in cessation of the SE. An ECG was obtained to assess the PR interval which was normal and cardiorespiratory monitoring was continued. The patient was discharged home on three antiepileptic medications.

The patient has continued to follow-up at the paediatric neurology clinic and seizures are well controlled.

Follow-up EEGs have shown focal slowing, right hemisphere spikes and background asymmetry without evidence of clinical or electrographic seizures on home AEDs.

Investigations

On day 1 of admission, the video EEG showed very frequent subclinical seizures arising from the right frontal region lasting for approximately 10 s with a frequency of 1–2 every 15 min. Occasional left frontal/central electrographic seizures were noted as well. Significant slowing and background suppression was noted on the left hemisphere (figures 2–3).

The MRI of the brain on admission showed progression of encephalomalacia and ventriculomegaly. On admission, a complete blood count, complete metabolic panel, C reactive protein, urine analysis, urine culture were collected and were within normal limits. A CSF analysis was obtained and was within normal limits. The CSF gram stain and CSF culture showed no growth and a CSF HSV PCR was also negative.

Video swallow study was conducted to ensure safety for oral feeds which was normal and unconcerning for aspiration.

Differential diagnosis

Focal non-convulsive RSE secondary to severe HIE and traumatic birth was higher on the differential. Evolution and worsening of subdural haematomas and subgaleal haemorrhage was considered. Other causes related to infections such as HSV causing RSE and other causes were considered and ruled out.

Treatment

During this admission, he continued to have SE despite loading doses of fosphenytoin, levetiracetam and phenobarbital. The RSE did not respond to a midazolam infusion. He responded to the LCM loading dose of 4 mg/kg with control of the subclinical seizures for over 24 hours. The midazolam infusion dose was titrated down with recurrence of SE. Administration of additional doses of LCM and fosphenytoin (20 mg/kg) load resulted in termination of the seizures. Subsequently, he remained seizure free until discharge with combination of LCM, phenytoin and levetiracetam.

Outcome and follow-up

The patient follows up at the paediatric neurology clinic and is well controlled on three AEDs. He has global developmental delay and receives therapies. Overall, the parents are happy with his current seizure control.

Discussion

This case provides an example of the use of LCM to successfully treat an infant with prolonged refractory status epilepticus (PRSE). RSE is defined as SE that persists despite adequate treatment with first-line and second-line therapies.8 RSE is estimated to represent 10%–40% of SE cases.9 Non-convulsive SE can be defined as a prolonged state of impaired consciousness or altered sensorium associated with continuous paroxysmal activity or electrographic discharges on the EEG. It has a bimodal peak in children and the elderly with that of 25% of cases of SE.4 Non-convulsive SE is a commonly under-recognised condition in critically ill patients and the incidence can be as high as 10.5%.10

There are limited trials and studies to guide the treatment of epilepsy in paediatric patients compared with adults.11 Around 30%–40% of the patients remain refractory to an AED. Patients that fail to respond to at least two properly indicated and tolerated AEDs are referred to as drug-resistant.12

LCM is a newer antiepileptic medication and exhibits its action through selectively enhancing slow inactivation of voltage-gated sodium channels, without affecting fast inactivation. This in turn results in decreasing pathological neuronal hyperexcitability without affecting the physiological neuronal function.13 Conventional antiepileptic medications target inactivation of fast acting sodium channels thereby combination therapy with LCM and medications such as fosphenytoin may have a synergistic effect.13 14

In this patient, the response to LCM may have been a result of a synergistic effect with fosphenytoin.

Phenytoin and other traditional sodium channel blockers act on the inner vestibule of the local anaesthetic receptor and stabilise the fast-inactivated state.14 These agents are more effective when sodium channels are in a depolarised state and delay the recovery of the channel for tenths of a second.15 Alternatively, LCM exerts its activity through the stabilisation of the slow-inactivation state of sodium channels.15 This results in a diminished amplitude of action potentials. These effects inhibit activation of the channel over seconds and limits the frequency of triggered action potentials. A mouse model has described an additive effect of phenytoin and LCM, but could not ascertain if this was a synergistic effect or a potential medication interaction resulting in elevated medication levels.16

LCM binds to the collapsin response mediator protein 2 which is hypothesised to produce a neuroprotective effect.17 LCM was initially developed for focal epilepsies, however LCM has been successful in controlling generalised tonic clonic seizures and generalised genetic epilepsy.18

LCM has a favourable pharmacokinetic and safety profile, minimal protein binding, relatively fewer drug interactions and excellent bioavailability.19 LCM is a minor substrate for CYP3A4, CYP2C9 and CYP2C19. However, approximately 40% is eliminated in the urine as unchanged drug and the dosage should be adjusted in patients with renal failure.

Given the limited use of LCM to treat seizures in an infant, we conducted a literature review on the use of LCM. A search (table 1) using PubMed (National Institutes of Health, National Library of Medicine, USA) identified several reports of paediatric patients with SE and treatment response to adjunct between 2011 and 2018. There were 18 patients identified in these case reports/series. The age range was between day 2 of life and 17 years old. Of the 18 patients, four had SE lasting between 8 to 24 hours and 14 patients had SE that lasted over 24 hours in duration. One patient had partial RSE that had been ongoing for 10 weeks. All patients had been refractory to more than two AEDs except for a 16-year-old girl with AVM and focal SE who was allergic to all medications except for levetiracetam. The dose of LCM for children less than 8 years old was between 2 and 10 mg/kg. Older children between ages of 8 and 17 years old were given doses of 25–100 mg of LCM. The addition of LCM was ineffective in 4 out of the 18 patients.15 20–24

Table 1

Reported paediatric cases of status epilepticus and response to lacosamide

Year Age/Gender Duration of status epilepticus Medication given prior to LCM Dose of LCM Outcome Side effects Reference number
2012 16 years old/ Female Seizures, frontal AVM/- focal status epilepticus >24 hours LEV and LCM LCM was effective recovered   17
2011 8 years old/Male Partial onset RSE for 10 weeks LEV, phenytoin, PB, VPA and propofol infusion, pentobarbital and midazolam 25 mg two times per day LCM was effective, recovery 5 days   18
2012 16 years old/Female 29 hours VPA, LEV, CLZ, midazolam, MP, oral TPM Bolus 2–2.5 mg/kg-100 mg Recovered chorea 19
2012 17 years old/Female 28 hours Intravenous CLZ, PB, VPA, LEV and increased VNS settings 100 mg LCM was effective recovered Oculogyric crisis 19
2012 12 years old/Male 8 hours Intravenous PHT, LEV, CLZ and oral clobazam 50 mg LCM was effective recovered none 19
2016 1 month old/Female >24 hours LEV, PH, pentobarbital drip 10 mg/kg LCM was ineffective none 20
2016 18 months old/Male >24 hours LEV, PB, midazolam drip, ketamine 4 mg/kg LCM was ineffective None 20
2016 5 years old/Female >24 hours OXC, VPA, PB, pentobarbital infusion 4 mg/kg LCM was ineffective None 20
2016 7 years old/Female >24 hours VPA, propofol, LEV, FBM, pentobarbital 10 mg/kg LCM was ineffective None 20
2016 6 years old/Male >24 hours Fosphenytoin, LEV, propofol 10 mg/kg LCM was effective None 20
2016 6 months old/Female 24 hours Fosphenytoin, LEV, propofol 10 mg/kg LCM was effective None 20
2016 6 years old/Male >24 hours Fosphenytoin, LEV, midazolam 5 mg/kg LCM was effective None 20
2016 5 years old/Male >24 hours LEV, zonisamide, lamotrigine, propofol 11 mg/kg LCM was effective None 20
2016 9 months old/Male >24 hours LEV, propofol 2 mg/kg LCM was effective None 20
2016 12 years old/Female >24 hours LEV, fosphenytoin 10 mg/kg LCM was effective None 20
2016 11 months old/Male >24 hours LEV, VPA, clobazam 4 mg/kg LCM was effective None 20
2018 Day 5 of life/Female 72 hours LEV, phenytoin, phenobarbital 20 mg/kg/day LCM was effective None 21
2018 Day 2 of life/Male 24 hours LEV, topiramate, phenytoin 14 mg/kg/day LCM was effective None 21

  • LCM, lacosamide; LVM, levetiracetam; RSE, refractory status epilepticus; SE, status epilepticus.

Yorns et al conducted a prospective study of children between ages of 5 and 15 years, with refractory partial epilepsy who had failed two or more AEDs.25 Lacosamide was given as an adjunct therapy in all of them, of which 6% of patients were seizure free, 41% of patients had a 50% reduction in seizure frequency, 4% had a reduction in seizures and 1% of patients either had no response to the seizures. LCM was found to be an effective add-on therapy for management of refractory partial epilepsy.

There is evidence in adult literature of using high dose LCM (400 mg) with good results on generalised tonic-clonic status epilepticus.26 27

While LCM may be an effective adjuvant in seizure control, it may cause problematic side effects. One study reported vomiting, diarrhoea, somnolence, irritability, dizziness, sedation, fever and gait disturbance as common side effects of LCM therapy.28 Antiepileptic combination therapy targeting sodium channels may increase the risk for cardiac arrhythmias. One study in paediatrics did not identify any reports of cardiac arrhythmia with the use of LCM.23 Some reports have suggested mild negative mood and behavioural changes including depression and suicidal ideation with LCM.29 A study by Moavero et al suggested that LCM has a specific primary cognitive enhancing effect improving information processing speed.30 Therefore, the risks and benefits of LCM will need to be evaluated in each individual patient. The response to LCM may have been a result of a synergistic effect between voltage-gated sodium channels. Phenytoin and other traditional sodium channel blockers act on the inner vestibule of the local anaesthetic receptor and stabilises the fast-inactivated state.30

Recent evidence indicates that newer medications such as LCM are a good option in paediatric patients with focal drug-resistant epilepsy and RSE as an add-on therapy given its efficacy on seizure control and safety profile. Our case report adds to the clinical data on use of LCM in paediatric patients and in patients with RSE or PRSE. The experience with use of intravenous LCM for SE in paediatric patients is limited. Large randomised controlled studies in the paediatric population are necessary to substantiate these findings (online supplemental file 1).

Supplementary data

[bcr-2022-249948supp001.pdf]

Patient’s perspective

We, the parents were so concerned about our baby having constant seizures. We are so happy that our baby got the help he needed and the constant seizures stopped in the pediatric ICU—since he has been home, the seizures are well controlled.

Learning points

  • Lacosamide (LCM) is a good treatment option in the paediatric population with focal drug-resistant epilepsy, but there are limited data on its use for management of focal status epilepticus or refractory status epilepticus (RSE).

  • Due to its favourable safety profile, the availability of an intravenous preparation and in view of the relative success we observed in our case report, we suggest early consideration of LCM in the treatment of critically ill paediatric patients.

  • There is no standardised protocol for the management of RSE and prolonged refractory status epilepticus (PRSE) in the critically ill paediatric population and our case report may add to the clinical data on the use of medications for RSE and PRSE.

  • Intravenous LCM along with traditional fast sodium channel blockers may be a potential alternative to a standard antiepileptic drug for treatment of RSE. Further studies and case reports are required to evaluate those in the paediatric age group in order to confirm this observation.

Ethics statements

Patient consent for publication

Acknowledgments

The authors would like to acknowledge Dr Huan Huynh MD with the epilepsy and epilepsy surgery team at Illinois Neurological Institute for his help with EEG slide review.

Footnotes

  • Contributors AA wrote the manuscript. GGD and AAH extensively modified the manuscript. SC provided the radiographic images and input. All authors have reviewed and made changes to the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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