Keywords
ketamine - status epilepticus - refractory - alternating hemiplegia of childhood
Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder and
characterized by infantile onset hemiplegia involving either side of the body and
other paroxysmal spells, including epilepsy. Status epilepticus (SE) is reported in
patients with AHC with the common occurrence of refractory SE due to failure of cessation
of seizures after administration of first and second line benzodiazepine and nonbenzodiazepine
antiepileptics. Use of ketamine, an emerging third-line agent for SE, in AHC patients
has not been reported.
Case Description
A 6-year-old girl with molecularly confirmed AHC (E815K) admitted with episodes of
picking at bed sheets and lip-smacking. She had frequent epileptic seizures and SE
since early infancy. At the presentation, She was more somnolent during day time with
the inability to sleep at nights and excessive irritability. She was afebrile with
no evidence of recent infection. The patient had several episodes of the right arm
and leg flexion, lip-smacking, followed by bilateral leg rhythmic clonic jerking after
coming to the hospital. Routine laboratory, imaging, and infectious workup were unremarkable.
She had several episodes of focal seizures without returning to her normal self in
between and required rectal diazepam, intravenous (IV) lorazepam, fosphenytoin, levetiracetam,
followed by IV midazolam and dexmedetomidine infusion for management of super refractory
SE. Later, she required pentobarbital coma due to continuing electroclinical or electrographic-only
seizures. She had a total 25 days stay in the critical care unit due to several complications
associated with super refractory SE: hypotension requiring ionotropic support, intermittent
bradycardia, prolonged intubation, and pleural effusion. She had prolonged wean of
anesthetics with methadone, lorazepam, and clonidine. She slowly returned to her baseline
except for a mild decline in her cognitive skill and worsening behavioral outbursts.
After 7 months of the previous presentation, this patient again returned with episodes
of bilateral convulsion involving all four extremities in the setting of vomiting
and rhinorrhea. She was on valproate, oxcarbazepine, topiramate, clonazepam, and levetiracetam,
with no recent medication noncompliance. Rectal diazepam at home, followed by several
doses of IV lorazepam by the fast responders did not stop these seizures. She was
intubated for airway protection, and several nonbenzodiazepine IV antiseizure medications
were administered that failed to control SE. Midazolam infusion (1.5 mg/kg/h) controlled
seizures for 36 hours with the eventual return of multiple episodes of electroclinical
focal seizures. IV ketamine bolus dose (2 mg/kg) is given followed by continuous infusion
(0.5–2.5 mg/kg/h; [Fig. 1]). The patient remained seizure free with successful weaning of anesthetic infusions
over the next 48 hours and discharged from the hospital within 1 week.
Fig. 1 (A) EEG revealed ictal rhythm of bilateral 2.5 Hz high amplitude sharply contoured delta
activity intermixed with fast frequency discharges. EMG artifacts were due to clinical
seizures. (B) Recurrent electrographic-only seizure with rhythmic high amplitude delta with admixed
fast frequency discharges with a right hemispheric predominance. (C) A focal seizure started from the left hemisphere during midazolam infusion. (D) Diffuse delta slowing with mild suppression with ketamine infusion. EEG, electroencephaography;
EMG, electromyography.
A 3-year-old boy with AHC diagnosis (D801N) admitted due to recurrent episodes paroxysmal
epileptic (convulsive) and nonepileptic episodes over 24 hours. He was diagnosed with
AHC due to recurrent episodes of eye deviation at the age of 3 months and developed
paretic episodes involving either side of the body since age 7 months. He also developed
episodes of convulsive seizures since age 9 months and had multiple episodes of SE
since that time. His daily home regimen of antiepileptics was a combination of levetiracetam
and topiramate, and the family denied any missed doses or any other possible triggering
factors except insomnia and irritability for two prior nights. At that time of presentation,
he was noted to have a paucity of movement of the right side of the body with electroclinical
evidence of frequent bilateral convulsive seizures ([Fig. 2]). The patient was treated with intranasal midazolam and IV lorazepam, fosphenytoin,
levetiracetam, lacosamide, followed by midazolam infusion (1.2 mg/kg/h), and several
propofol boluses due to frequent recurrent seizures. After 30 hours of recurrent seizures,
ketamine bolus (1 mg/kg) was given, and maintenance infusion (0.5–2 mg/kg/h) was started.
He had a recurrent seizure after 6 hours when additional ketamine bolus (2 mg/kg)
was given with increment of the infusion rate to 3 mg/kg/h. The patient remained seizure
free afterward, and no additional antiepileptic was needed to introduce before successful
weaning of anesthetics after 36 hours of seizure-free period.
Fig. 2 (A) Fast frequency ictal rhythm was started from the midline electrodes.(B) Bilateral spread of ictal rhythm was noted with high amplitude sharply contoured
delta with admixed fast frequency discharges.
Discussion
Internalization of gamma aminobutyric acid (GABA) receptors from the postsynaptic
surface and overexpression of glutamate receptors during SE may make GABA mediated
third-line seizure agents relatively ineffective in late stages of SE.[1] Additionally, abnormal network physiology has been suggested in AHC with the GABAergic
interneuron activity might be preferentially affected in ATP1A3 pathogenic variants and produces an excitatory state due to glutamate–GABA imbalance.[2] Moreover, glutamate concentration may also increase due to impaired glutamate transporters
(EAAT-1), colocalized with Na+–K+–ATPase. Around half of the patients with AHC have epilepsy, and the majority of these
patients have drug-resistant epilepsy, including both focal and generalized epilepsy.[3] Approximately one-fourth of AHC patients have SE. They can have recurrent SE and
refractory and super refractory SE. In a cohort of 24 patients, 6 had convulsive (focal
to secondary bilateral) SE and all were refractory with one had a superrefractory
event.[4] These patients required more than three medications, including benzodiazepine and
nonbenzodiazepine antiepileptics, to terminate the SE in a mean duration of 7.5 hours.[4] Ketamine was not used in this cohort. Neurodevelopmental regression after SE episodes
has been reported in AHC.
Ketamine, a N-methyl-D-aspartate (NMDA) receptor antagonist, has been proved to be
effective terminating SE in animal models and human case studies. This is the first
description of the effectiveness of ketamine as an effective third-line agent for
super refractory SE associated with AHC. Less than 50 cases of using ketamine have
been reported in the management of pediatric SE of all etiologies, and the use of
both oral and IV routes was described.[5] The overall success rate was estimated to be around three-fourths of the pediatric
patients, with 100% response noted in a case series involving patients with Lennox–Gastaut
syndrome, pseudo Lennox–Gastaut syndrome, myoclonic-astatic epilepsy, and progressive
myoclonic epilepsy.[6] In this particular case series, all children had seizure cessation within 48 hours
of ketamine administration with no mortality. Rosati et al reported six of nine children
with refractory status epilepticus (RSE) who responded positively to ketamine therapy.[7] Side-effect profile of ketamine is attractive, and predominantly irritability and
increased salivation were reported as adverse effects. Ketamine by preventing glutamate
excitotoxicity may reduce Ca2+ influx and subsequent cell death. Ketamine increases blood pressure, heart rate,
and cardiac output, and can counteract negative hemodynamic consequences from other
anesthetics commonly used in the management of SE.
In these two patients, ketamine was used after they failed combination of IV anesthetics
and continuous electroencephalography (EEG) was utilized for monitoring throughout
the stay. Ketamine infusion rate was controlled to maintain seizure freedom but not
to reach a definitive burst suppression pattern. Coinfusions were weaned within 24 hours
of ketamine infusion and didn't require prolonged dual therapy. Ketamine was the last
antiepileptic agent to be included in both the patients and no other antiepileptic
agent was administered via gastrostomy tube to wean anesthetics. One of the patients
required less vasopressor support after initiation of ketamine. Both patients were
discharged home without requirement of inpatient rehabilitation or significant change
in the cognition and behavior during short–posthospital discharge follow-up.
Though the natural resolution of seizure, irrespective of ketamine, is possible in
these cases; the close temporal resolution of seizure after ketamine may indicate
potential effectiveness. It is unknown if dual therapy of midazolam and ketamine had
a synergistic effect in these patients. Moreover, as neuroregression is possible after
SE in AHC, earlier termination of SE by using ketamine can be an effective option
in this population. Although there is a growing interest in the use of ketamine infusion
for SE, further prospective controlled studies are needed to determine the optimum
dose, appropriate timing (early versus after the failure of conventional third-line
agents), and use as third-line monotherapy versus early polytherapy with other IV
anesthetics. Moreover, further studies are necessary to determine if ketamine can
induce neuronal cell death or alter neurogenesis.[8]
