MANUSCRIPT CITATION

Nangle AM, He Z, Bhalla S, Bullock J, Carlson A, Dutt M, Hamrick S, Jones P, Piazza A, Vale A, Sewell EK. Reducing the percentage of surviving infants with acute symptomatic seizures discharged on anti-seizure medication. J Perinatol 2024. PMID 39043995

REVIEWED BY

Danielle Barber, MD PhD

Assistant Professor

Department of Pediatrics- Section of Neurology

University of Colorado/ Children’s Hospital of Colorado

Danielle.2.barber@cuanschutz.edu

Jill Chang, MD

Assistant Professor

Department of Pediatrics- Section of Neonatology

University of Colorado/ Children’s Hospital of Colorado

Jill.chang@cuanschutz.edu

 

 

TYPE OF INVESTIGATION

Quality improvement

 

QUESTION

In infants with acute symptomatic seizures who had been treated with anti-seizure medication (ASM), did inclusion of an ASM wean protocol in a neonatal seizure pathway decrease the percentage of infants discharged on ASM.

 

METHODS

Design: Retrospective cohort study

Allocation:

Infants with acute symptomatic seizures were evaluated from 2 epochs during the study time period from January 1, 2018 to November 30, 2023.

• Epoch 1 pre- implementation of the ASM weaning protocol
• Epoch 2 post-implementation of the ASM weaning protocol

Blinding: Blinding unclear

Follow-up period: Hospital discharge to 1 year of age

Setting: Three hospitals were included in this study: two level III Neonatal intensive care units (NICUs) and one level IV NICU.

• Level III NICUs: delivery centers at which neurology was available for phone but not in-person neurology consultations.
• Level IV NICU: referral hospital, with no in-born deliveries, at which in-person neurology consultations were available.
• Continuous EEG monitoring was available at all hospitals.

Patients:

• Inclusion criteria:
  • Infants with acute symptomatic seizures, confirmed on EEG, who had been treated with anti-seizure medication (ASM) and who were discharged from one of the three study hospitals.
  • Acute symptomatic seizures were defined as seizures provoked by hypoxic ischemic encephalopathy, stroke, hemorrhage, meningitis, or transient metabolic disturbances such as sodium or glucose abnormalities
• Exclusion criteria:
  • Death before discharge
  • Infants with seizures that did not meet the study definition of acute symptomatic seizures

Intervention: Formal evidence-based ASM weaning protocol was added to the Neonatal Seizure Pathway in October 2020.

Outcomes:

• Primary outcome: Discharge on ASM, which was also analyzed based on hospital type at discharge (delivery vs referral center).
• Secondary outcomes: If ASM wean was initiated prior to discharge, number of ASMs at discharge per patient, and percent of infants with seizure post-discharge up to one year of age.

Analysis and Sample Size:

• A sample size of 116 infants, divided into 2 epochs, was used in this study. Epoch 1: n= 52 infants and Epoch 2: n= 64 infants.
• All statistical analyses were performed using R software. Welch two-sample t-test was used for continuous data and Pearson’s chi squared test and Fisher’s exact test were used for categorical data to compare Epoch 1 and Epoch 2. P value <05 was considered statistically significant.

Patient follow-up:

• Of the 193 infants with electrographic seizures with final encounters in the NICU system, 38 (20%) were excluded due to death prior to discharge and 39 (20%) excluded for not meeting study definition of acute symptomatic seizures
• Of the remaining 116 infants included in the study, 96 (83%) had a follow-up visit.

MAIN RESULTS

Demographic characteristics were similar between epoch groups including gestational age, birthweight, sex, discharge hospital time (delivery vs referral), age at seizure diagnosis, and underlying brain injury.

Primary outcome: There was a decrease in percent of infants discharged on ASMs across all hospitals, delivery and referral, in epoch 1 versus epoch 2: 69% versus 34% (p<0.002).

Secondary outcomes:

• There was a significant increase in the percent of infants who had an ASM wean initiated prior to discharge from 44% in epoch 1 to 77% in epoch 2 (p=0.014).
• There was a significant decrease in number of ASMs at discharge per patient from 0.9 in epoch 1 to 0.7 in epoch 2 (p<0.001).
• There was no significant difference in percentage of infants who had seizures after discharge by 1 year of age between epochs: 32% in epoch 1 and 18% in epoch2 (p = 0.125).

CONCLUSION

Inclusion of an ASM wean protocol in a neonatal seizure pathway decreased the number of infants with acute symptomatic seizures discharged on ASM regardless of type of NICU or whether in-person neurology consultation was available.

 

COMMENTARY

There is strong guidance to discontinue antiseizure medications (ASMs) prior to hospital discharge for neonates with acute symptomatic seizures. In the 2023 International League Against Epilepsy (ILAE) Task Force on Neonatal Seizures published guidelines [REF 1], one of the six main recommendations is that “following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings.” Additionally, a comparative effectiveness study found no difference in neurodevelopmental impairment or epilepsy rates at 24 months among children whose ASM was discontinued vs maintained at hospital discharge [REF 2]. While these recommendations have become stronger with time, they are not new: it has been more than a decade since the 2011 WHO Guidelines on Neonatal Seizures advised considering discontinuation of ASMs in neonates who had been seizure-free for 72 hours [REF 3].

 

Despite these strong recommendations, there remains variation in clinical practice [REF 4, 5, 6, 7]. The intuitive bias – particularly in centers without in-person neurology to evaluate the infant during the NICU hospitalization – is that the “safer” approach is to maintain the infant on ASMs until they see a neurologist in clinic. However, unnecessary ASM may contribute to long-term cognitive impairment [REF 8] and does not diminish the risk for future seizures [REF 2, 4, 6].

 

Inclusion of standardized treatment pathways for management of neonatal seizures has been shown to reduce the number of infants discharged home on ASMs. In the ILAE Task Force on Neonatal Seizures, 80% of experts surveyed “completely agreed” and the remaining 20% of experts “mostly agreed” that “a standardized treatment pathway for the management of neonatal seizures should be available in each neonatal unit.” [REF 1] Across hospitals with neonatal seizure treatment pathways, there is broad agreement on much of the treatment approach, including early discontinuation of ASMs [REF 9].

 

In Nangle et al., the authors describe the initiation of a neonatal seizure pathway in 3 hospitals where it did not previously exist and found ~50% reduction in infants discharged on ASMs in the subsequent epoch. Notably, the authors even reached 0% infants with acute symptomatic seizures discharged on ASMs in 2023 at their Delivery Hospitals. We’d like to particularly highlight that the authors of this study demonstrated feasibility and meaningful improvement in hospitals without in-person neurology consult availability. In fact, although possible confounding by disease severity and seizure burden, fewer infants were discharged on ASM in the hospitals without neurology consult compared to the NICU with neurology consultation available. Additionally, their success highlights the benefits of working in multidisciplinary teams – both across various types of clinicians and partnership between Neonatology and Neurology.

 

REFERENCES

1. Pressler RM, et al., Treatment of seizures in the neonate: Guidelines and consensus-based recommendations – Special report from the ILAE Task Force on Neonatal Seizures. Epilepsia 2023; 64:2550-2570.

2. Glass HC, et al., Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures. JAMA Neurology 2021; 78(7):817-825.

3. World Health Organization Guidelines on Neonatal Seizures, 2011.

4. Sewell EK, et al., Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study. Arch Dis Child Fetal Neonatal Ed 2023; 108:F421-F428.

5. Shellhaas RA, Soul JS, Chang T, et al. (2021) Looking at the Effect of Treatment Duration for Newborn Infants Who Have Seizures.Patient-Centered Outcomes Research Institute (PCORI).

6. Fitzgerald MP, Kessler SK, Abend NS. Early discontinuation of antiseizure medications in neonates with hypoxic-ischemic encephalopathy. Epilepsia, 58(6):1047-1053, 2017.

7. Jagadish S, et al., Epilepsy Incidence and Developmental Outcomes after Early Discontinuation of Antiseizure Medication in Neonatal Hypoxic-Ischemic Encephalopathy. Pediatric Neurology 153 (2024) 48-55.

8. Farwell JR, et al., Phenobarbital for febrile seizures – Effects on intelligence and on seizure recurrence. New England Journal of Medicine, 1990, Vol 322, No 6, 364–369.

9. Keene JC, et al., Treatment of neonatal seizures: comparison of treatment pathways from 11 Neonatal intensive care units. Pediatric Neurology