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Are Ketamine Infusions a Viable Therapeutic Option for Refractory Neonatal Seizures?
Journal Pre-proof Are Ketamine infusions a viable therapeutic option for refractory neonatal seizures? R.J. Huntsman, L. Strueby, W. Bingham PII:
S0887-8994(19)30821-5
DOI:
https://doi.org/10.1016/j.pediatrneurol.2019.09.003
Reference:
PNU 9660
To appear in:
Pediatric Neurology
Received Date: 17 April 2019 Revised Date:
22 August 2019
Accepted Date: 4 September 2019
Please cite this article as: Huntsman R, Strueby L, Bingham W, Are Ketamine infusions a viable therapeutic option for refractory neonatal seizures?, Pediatric Neurology (2019), doi: https:// doi.org/10.1016/j.pediatrneurol.2019.09.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Are Ketamine infusions a viable therapeutic option for refractory neonatal seizures? Huntsman RJa, Strueby Lb, Bingham Wb. a
Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, Canada Division of Neonatology, Department of Pediatrics, University of Saskatchewan, Canada
b
Correspondence to: Dr. Richard J. Huntsman MD,FRCP(C), Division of Pediatric Neurology Royal University Hospital 103 Hospital Drive Saskatoon, Saskatchewan Canada S7N-0W8 Phone: 1(306) 844-1236 Fax: 1(306) 844-1356 Email: [email protected] Keywords: Ketamine, Seizures, Neonate, Hypoxic ischemic encephalopathy Declaration of Interest: None All authors took part in the care of the patient described in the illustrative case, took part in the writing of the draft manuscript and editing of final version for submission.
Abstract: Ketamine is a NMDA receptor antagonist that works by binding to the phencyclidine binding site; thereby blocking influx of cations through the NMDA receptor channel. Its use to treat refractory status epilepticus in adults and older children is well documented. Maturational changes in neonatal NMDA and GABA receptor expression and function make NMDA receptor antagonists, like ketamine, attractive potential therapeutic agents for treatment of refractory seizures in the newborn. However, descriptions of its use in this age group are limited to two case reports. Concerns regarding potential ketamine mediated neurotoxicity in the immature brain require further investigation.
Introduction: First developed by Parke-Davis in 1962, Ketamine is the only N-methyl-D-aspartate (NMDA) antagonist licensed for use in humans as an injectable drug. [1] Ketamine HCL (with the chemical name of 2-O-chlorphenyl-2 methylamino-cyclohexanone HCL) is an arylcyclohexylamine derivative that is structurally related to phencyclamine and the dissociative drug phencyclidine. [2] In 1965 ketamine was found to have anticonvulsant activity in animal seizure models. [3] Shortly afterwards ketamine’s anticonvulsant effects were confirmed in humans [4] and it has continued to be utilized to treat refractory status epilepticus in adult and pediatric patients. Benefits of ketamine include the lack of cardiovascular side effects that can be compounded in the setting of status epilepticus by other anticonvulsants. [5,6]. To date, there are only two prior case reports of ketamine as a therapy for refractory seizures in a neonate. [7,8] In this manuscript we describe the case of a neonate with refractory seizures secondary to
hypoxic-ischemic encephalopathy and hemorrhagic stroke that were successfully halted with ketamine infusion.
Illustrative Case Following an uncomplicated pregnancy, the male neonate was born at 39+1 weeks gestation via a forceps and vacuum assisted vaginal delivery with meconium stained amniotic fluid. Immediately after birth he required intubation and ventilation for respiratory failure. Apgar scores were 2, 5 and 7 at 1, 5 and 10 minutes respectively with a venous cord pH of 6.88 and an initial lactate of 15 mmol/l. Total body cooling was initiated (targeting a body temperature of 33.5°C) and he was placed on amplitude integrated electroencephalogram monitoring that was suspicious for recurrent right cerebral hemisphere seizures. The patient was loaded with phenobarbital totalling 40 mg/kg over 3 doses with no improvement on amplitude integrated electroencephalogram recording. Conventional polygraphic electroencephalogram (EEG) video telemetry using standard neonatal EEG array and eye movement, respiratory, oxygen saturation and single lead electrocardiogram monitoring was initiated. The interictal recording displayed a generalized tracé discontinue pattern with frequent sharp waves in the right temporal and central head regions (electrodes T4/C4). Very frequent electrographic seizures were seen arising from electrodes T4/C4 lasting 2-3 minutes and recurring on average every 5 minutes. (Fig. 1) Many of these seizures were associated clinically with repetitive tongue movements and oxygen desaturation. Phenytoin 20 mg/kg had no effect on seizure frequency, therefore at 28 hours of age a midazolam infusion was initiated at 0.05 mg/kg/hr and increased to 0.2 mg/kg/hr over the next 24 hours. Despite maintenance phenobarbital and phenytoin
(both at 5 mg/kg/day) and midazolam infusion the patient had recurrent electrographic seizures arising from the right temporal head region (electrode T4) lasting 1-2 minutes in duration and occurring every 10 minutes. Many continued to be associated clinically with rhythmic tongue movements, clonic activity of the left hand and oxygen desaturation. Occasional brief electrographic only seizures were observed from the left central head region (electrode C3). Background EEG activity showed generalized suppression of all frequencies interictally. The patient developed significant hypotension necessitating inotropic support with epinephrine and dobutamine. In light of the systemic side effects, topiramate was initiated (5 mg/kg x 4 doses over 24 hours followed by maintenance 10 mg/kg/day) as an alternative to further increases in the midazolam infusion. Phenytoin was discontinued as it was deemed ineffective and phenobarbital levels were therapeutic at 192 umol/l. On completion of total body cooling a brain Magnetic Resonance Imaging was performed that demonstrated a large subacute infarction containing a large acute-subacute haemorrhage in the right temporal lobe with a smaller area of haemorrhage in the left parietal region. Magnetic Resonance venography and angiography showed no evidence of venous sinus thrombosis or arterial filling defect. As steady state topiramate would not be achieved for 24hrs, a discussion regarding ketamine initiation was had with the family. Ketamine was started at 0.5 mg/kg/hr and increased 12 hours later to 1 mg/kg/hr, which resulted in a decrease in seizure frequency to every 1 hour while the EEG background activity took on a generalized burst suppression pattern (Fig 2). Reduction of the midazolam infusion improved the systemic blood pressure but
increased seizure frequency to every 20 minutes; therefore, the ketamine infusion was increased to 1.5 mg/kg/hr resulting in a complete cessation of seizures. Over the next two days the patient remained on ketamine 1.5 mg/kg/hr, topiramate 10 mg/kg/day and phenobarbital 5 mg/kg/day, while the midazolam was weaned and successfully discontinued permitting discontinuation of the epinephrine and dobutamine. No further seizure activity was observed and the degree of burst suppression on background EEG improved. Occasional sharp waves were seen independently over the right temporal head region (electrode T4). The ketamine was subsequently weaned via decreasing the dosage by 0.5 mg/kg/hr q12 hours until discontinuation. The patient had no further clinical or electrographic seizures and was successfully extubated. By 10 days of age the patient demonstrated a normal neurological examination apart from mild generalized hypotonia. Repeat EEG at 17 days of age showed normal background activity with frequent sharp waves seen in both temporal head regions (electrodes T3/T4) with no seizures recorded. The patient was subsequently discharged home on maintenance topiramate (8.3 mg/kg/day) and phenobarbital (4.3 mg/kg/day). Trough phenobarbital level prior to discharge was 129.2 umol/l. The patient remained seizure free at 3 months of age with a normal neurological examination apart from mild truncal hypotonia on pull to sit manoeuvre. His EEG at that time showed normal background activity and sharp waves arising from the right parietal head region (electrode P4). At 10 months of age as remained seizure free with a normal EEG his topiramate was discontinued. By 17 months of age his neurological examination showed mild spasticity in the left lower extremity but was otherwise normal. He continued to be seizure free and his EEG remained normal and he was successfully weaned off his phenobarbital.
Discussion: In the setting of prolonged status epilepticus there is excessive release of the excitatory neurotransmitter Glutamate and upregulation in the expression of the post-synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors. This results in amplified glutamate induced neuronal hyperexcitability and excitotoxicity causing increased resistance to anticonvulsant therapy. [9] At the same time the number of postsynaptic γ-aminobutyric acid (GABA) receptors decreases, reducing the efficacy of GABA-ergic anticonvulsant medications such as benzodiazepines, barbiturates, valproic acid and propofol. [1,9] At the blood brain barrier the activity of drug efflux transporters such as P-glycoprotein increases. This reduces concentrations of anticonvulsants such as phenobarbital and phenytoin in the central nervous system making them less effective. [9]
The NMDA receptor is a nonspecific transmembrane cation channel found throughout the central nervous system. It is made of five subunits that form a voltage and ligand gated channel within the cell membrane that when activated allow the intracellular influx of cations. On the post synaptic neuronal membrane, activation of the NMDA receptor and the resultant influx of Ca2+ and Na+ causes a large and prolonged excitatory post-synaptic potential of the post synaptic neuron. [10,11] On the extracellular portion of the NMDA receptor there are binding sites for l-glutamate and glycine. Within the channel there are binding sites for Mg2+ and polyamines (specifically phencyclidine) that when bound with ligand block the influx of ligands through the channel. NMDA receptors are voltage and ligand gated; therefore, activation of the
NMDA receptors requires both membrane depolarization and binding of both l-glutamate and glycine at their extracellular binding sites. [10] Membrane depolarization, usually provided by activation of adjacent AMPA receptors, results in the displacement of Mg2+ from within the NMDA receptor channel allowing cations to enter the cell. [10,11]. Binding of the phencyclidine binding site within the NMDA receptor channel by polyamines such as phencyclidine and ketamine causes a blockade of cation influx through the channel and inactivation of the NMDA receptor. This binding at the phencyclidine binding site can only occur when the channel is opened through activation of the NMDA receptor. [11] It is through this mechanism that ketamine exerts its NMDA receptor antagonistic activity. [1]
In the newborn, seizures are the most frequent manifestation of neurological disease and are usually symptomatic secondary to an underlying cerebral insult. Hypoxic-ischemic encephalopathy and hypoglycaemia are two of the most common causes of neonatal seizures in most case series. [12] Several developmental features of the neonatal brain not only predispose towards seizures but also make seizures more resistant to standard anticonvulsants that act on the GABAergic system. [13] In the neonatal brain there is a relative excess of excitatory activity relative to inhibitory GABAergic activity. Concentrations of extracellular glutamate are higher in the neonatal brain due to increased release into and decreased reuptake of glutamate within the synaptic cleft. [13,14] In the setting of a cerebral insult such as perinatal hypoxic ischemic encephalopathy, the concentrations of extracellular glutamate increase even further. [13] The relative expression of neurotransmitter receptors in the neonatal brain also predisposes to seizure activity with NMDA and AMPA receptors being the
predominant receptor types expressed. [14,15] The NMDA receptors themselves also display several maturational changes in the neonate enhancing their excitatory function. These include reduced voltage gating mediated by Mg2+, a greater sensitivity to glycine enhancement and prolonged excitatory post-synaptic potential duration following activation of the receptor. [14,15] In contrast, concentrations of GABA are decreased in the neonatal brain compared to those of adults and older children. Moreover, activation of GABA receptors can have a paradoxical excitatory effect on the post synaptic neuron due to a developmental mismatch between the NKCC1 and KCC2 Cl-cotransporters. This mismatch results in a higher intracellular concentration of Cl- at resting state, Activation of the GABA receptors then results in an efflux of Cl- from the neurons and resultant depolarization. [14,15] This in part explains why GABAergic medications can have limited efficacy in treating neonatal seizures. [13,14]
The maturational changes seen in NMDA and GABA receptors in the neonatal brain would make a NMDA receptor antagonist such as ketamine an attractive therapeutic option for neonates with refractory seizures. To date, there are two reports of ketamine being used to abort refractory status epilepticus in neonates. Taroco et al. reported using ketamine successfully to abort status epilepticus in a preterm infant born at 34 weeks gestation with Pierre-Robin sequence, polymicrogyria and lissencephaly. After failing several anticonvulsants including phenobarbital, midazolam and levetiracetam the patient received two boluses of ketamine followed by a ketamine infusion that was gradually increased to 24 mcg/kg/min (1.44 mg/kg/hr). The patient remained seizure free while the ketamine infusion was maintained from days 82-103 of life approximating a corrected gestational age of 40-63 days. Following
withdrawal of ketamine the patients’ seizures recurred despite re-initiating the ketamine infusion with a maximum dose of 60 mcg/kg/hr (3.6 mg/kg/hr) and the patient subsequently died. [7] Freibauer and Jones reported using ketamine in a 2 day-old male infant with Encephalopathy of Infancy with Migrating Focal Seizures secondary to a KCNQ2 mutation. After having failed treatment with phenobarbital, phenytoin and midazolam, a ketamine infusion (dosage not specified) was successful in controlling both clinical and electrographic seizures. Due to the poor prognosis, care was withdrawn soon after and the patient subsequently died. [8] Our case demonstrates excellent clinical efficacy in stopping seizures after several appropriate anticonvulsants at appropriate doses failed. There are however some concerns about long term neurodevelopmental sequelae of ketamine exposure in the developing brain. Along with several other commonly used anaesthetics including midazolam and isoflurane, ketamine exposure can induce neuronal degeneration and apoptosis in several brain regions in immature rodents and non-human primates. [16,17,18] With exposure to ketamine this is thought to be secondary to upregulation of NR1 NMDA receptors on neural cell membranes. Because ketamine has rapid clearance from blood and brain its withdrawal then allows for glutamate induced activation of these excessive NMDA receptors. This results in accumulation of excessive intracellular Ca2+ which activates apoptotic cascades and neuronal death. [16] In in vivo animal models the ketamine induced neuronal death was seen predominantly in the frontal cortices but only when they were exposed to repeated high doses of ketamine suggesting that brief treatments with low doses may not be enough to induce upregulation of NMDA receptors. In 24 human infants undergoing cardiopulmonary bypass randomized to receive either a single pre-surgical dose of ketamine at 2 mg/kg or normal saline placebo,
ketamine did not show any neuro-protective or neuro-toxic qualities with postsurgical near infrared cerebral spectroscopy and developmental follow up using the Bayley Score of Infant Development 2-3 weeks post surgery. [19] Mitochondrial dysfunction seems to play a pivotal role in the neuronal apoptosis seen with ketamine exposure. Several in vitro studies have shown that the addition of carnitine blocks the neurotoxic effects of ketamine. [16] This suggests that if ketamine is chosen as an anticonvulsant in a newborn carnitine supplementation may allay some of the concerns regarding potential neuro-toxic effects of the ketamine. However, this has yet to be proven in human models and the appropriate dose of carnitine supplementation has yet to be determined.
Conclusion: Ketamine’s antagonistic activity on the NMDA receptor renders it an attractive potential anticonvulsant for use in neonates with refractory seizures. The fact that our patient responded well to ketamine therapy and demonstrated no evidence of neurotoxicity at tenmonth follow up further supports its use in this clinical situation. Concerns regarding potential neuro-toxic effects and the possible role of carnitine supplementation in preventing ketamineinduced neuro-toxicity in the immature brain warrant further investigation.
References:
1) Fang Y, Wang X. Ketamine for the treatment of refractory status epilepticus. Seizure.2015;30:14-20. 2) Dorandeu F, Dhote F, Barbier L, Baccus B, Testylier G. Treatment of status epilepticus with ketamine, Are we there yet? CNS Neuroscience and therapeutics. 2013;19:411-27 3) McCarthy D, Chen G, Kaump DH, Ensor C. General anesthetic and other pharmacological properties of 2-(O-chlorphenyl)-2 methylamino-cyclohex-anone HCL (Cl-58L). J New Drugs. 1965;5:21-33. 4) Corssen G, Miyasaka M, Domino EF. Changing concepts during surgery: dissociative anesthesia with Cl-581. A progress report. Anesth Anlg. 1968;47:746-59. 5) Zeiler FA, Teitelbaum J, Gillman LM, West M. NMDA antagonists for refractory seizures. Neurocrit Care. 2014;20:502-13. 6) Verrotti A, Ambrosi M, Pavone P, Striano P. Pediatric status epilepticus: improved management with new drug therapies? Expert Opin Pharmaco. 2017;18:789-98. 7) Tarocco A, Ballardini E, Garani G. Use of ketamine in a newborn with refractory status epilepticus: A case report. Pediatr Neurol. 2014;51;154-6. 8) Freibauer A, Jones K. KCNQ2 mutation in an infant with encephalopathy of infancy with migrating focal seizures. Epileptic Disord. 2018;16:541-4. 9) Loscher W. Mechanisms of drug resistance in status epilepticus. Epilepsia. 2007;48 (suppl. 8):74-7. 10) Siegel A, Sapru HN. Neurotransmitters. In: Essential Neuroscience Third Edition. Siegel A, Sapru HN. Eds. Wolters Kluwer. 2018. 11) Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev. 1999;51:7-61. 12) Seshia SS, Huntsman RJ, Lowry NJ, Seshia M, Yager JY, Sankaran K. Neonatal Seizures; diagnosis and management. Chin J Contemp Pediatr. 2011;13:81-96. 13) Abend SN, Jensen FE, Inder TE, Volpe JJ. Neonatal seizures. In: Volpe’s Neurology of the Newborn Sixth Edition. Volpe JJ. Ed. Elsevier. 2018. 14) Sanchez RM, Jensen FE. Maturational aspects of epilepsy mechanisms and consequences for the immature brain. Epilepsia. 2001;42:577-85.
15) Rakhade SN, Jensen FE. Epileptogenesis in the immature brain: emerging mechanisms. Nat Rev Neurol. 2009;5:380-404 16) Wang C, Fang L, Patterson TA, Paule MG, Slikker W Jr. Preclinical assessment of ketamine. CNS Neurosci Ther. 2013;9:448-53. 17) Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876-82. 18) Bambrink AM, Evers AS, Avidan MS, Farber NB, Smith DJ, Zhang X, et al. Isofluraneinduced neuroapoptosis in the neonatal rhesus macaque brain. Aesthesiology. 2010;112:834-41. 19) Bhutta A, Schmitz ML, Swearingen C, James L, Wardebegnoche WL, Lindquist DM, et al. Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: A pilot randomized, double blind placebo controlled trial. Pediatr Crit Care Me. 2012;13:328-37.
Legend: Figure 1: Neonatal polygraphic EEG showing seizure arising from right temporal head region at electrode T4. The patient is on phenobarbital monotherapy and therapeutic hypothermia at the time of this recording. Figure 2: Neonatal polygraphic EEG showing burst suppression pattern. The patient is on phenobarbital and topiramate as well midazolam infusion at 0.15 mg/kg/hr and ketamine infusion at 1.5 mg/kg/hr.
S0887-8994(19)30821-5
DOI:
https://doi.org/10.1016/j.pediatrneurol.2019.09.003
Reference:
PNU 9660
To appear in:
Pediatric Neurology
Received Date: 17 April 2019 Revised Date:
22 August 2019
Accepted Date: 4 September 2019
Please cite this article as: Huntsman R, Strueby L, Bingham W, Are Ketamine infusions a viable therapeutic option for refractory neonatal seizures?, Pediatric Neurology (2019), doi: https:// doi.org/10.1016/j.pediatrneurol.2019.09.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Are Ketamine infusions a viable therapeutic option for refractory neonatal seizures? Huntsman RJa, Strueby Lb, Bingham Wb. a
Division of Pediatric Neurology, Department of Pediatrics, University of Saskatchewan, Canada Division of Neonatology, Department of Pediatrics, University of Saskatchewan, Canada
b
Correspondence to: Dr. Richard J. Huntsman MD,FRCP(C), Division of Pediatric Neurology Royal University Hospital 103 Hospital Drive Saskatoon, Saskatchewan Canada S7N-0W8 Phone: 1(306) 844-1236 Fax: 1(306) 844-1356 Email: [email protected] Keywords: Ketamine, Seizures, Neonate, Hypoxic ischemic encephalopathy Declaration of Interest: None All authors took part in the care of the patient described in the illustrative case, took part in the writing of the draft manuscript and editing of final version for submission.
Abstract: Ketamine is a NMDA receptor antagonist that works by binding to the phencyclidine binding site; thereby blocking influx of cations through the NMDA receptor channel. Its use to treat refractory status epilepticus in adults and older children is well documented. Maturational changes in neonatal NMDA and GABA receptor expression and function make NMDA receptor antagonists, like ketamine, attractive potential therapeutic agents for treatment of refractory seizures in the newborn. However, descriptions of its use in this age group are limited to two case reports. Concerns regarding potential ketamine mediated neurotoxicity in the immature brain require further investigation.
Introduction: First developed by Parke-Davis in 1962, Ketamine is the only N-methyl-D-aspartate (NMDA) antagonist licensed for use in humans as an injectable drug. [1] Ketamine HCL (with the chemical name of 2-O-chlorphenyl-2 methylamino-cyclohexanone HCL) is an arylcyclohexylamine derivative that is structurally related to phencyclamine and the dissociative drug phencyclidine. [2] In 1965 ketamine was found to have anticonvulsant activity in animal seizure models. [3] Shortly afterwards ketamine’s anticonvulsant effects were confirmed in humans [4] and it has continued to be utilized to treat refractory status epilepticus in adult and pediatric patients. Benefits of ketamine include the lack of cardiovascular side effects that can be compounded in the setting of status epilepticus by other anticonvulsants. [5,6]. To date, there are only two prior case reports of ketamine as a therapy for refractory seizures in a neonate. [7,8] In this manuscript we describe the case of a neonate with refractory seizures secondary to
hypoxic-ischemic encephalopathy and hemorrhagic stroke that were successfully halted with ketamine infusion.
Illustrative Case Following an uncomplicated pregnancy, the male neonate was born at 39+1 weeks gestation via a forceps and vacuum assisted vaginal delivery with meconium stained amniotic fluid. Immediately after birth he required intubation and ventilation for respiratory failure. Apgar scores were 2, 5 and 7 at 1, 5 and 10 minutes respectively with a venous cord pH of 6.88 and an initial lactate of 15 mmol/l. Total body cooling was initiated (targeting a body temperature of 33.5°C) and he was placed on amplitude integrated electroencephalogram monitoring that was suspicious for recurrent right cerebral hemisphere seizures. The patient was loaded with phenobarbital totalling 40 mg/kg over 3 doses with no improvement on amplitude integrated electroencephalogram recording. Conventional polygraphic electroencephalogram (EEG) video telemetry using standard neonatal EEG array and eye movement, respiratory, oxygen saturation and single lead electrocardiogram monitoring was initiated. The interictal recording displayed a generalized tracé discontinue pattern with frequent sharp waves in the right temporal and central head regions (electrodes T4/C4). Very frequent electrographic seizures were seen arising from electrodes T4/C4 lasting 2-3 minutes and recurring on average every 5 minutes. (Fig. 1) Many of these seizures were associated clinically with repetitive tongue movements and oxygen desaturation. Phenytoin 20 mg/kg had no effect on seizure frequency, therefore at 28 hours of age a midazolam infusion was initiated at 0.05 mg/kg/hr and increased to 0.2 mg/kg/hr over the next 24 hours. Despite maintenance phenobarbital and phenytoin
(both at 5 mg/kg/day) and midazolam infusion the patient had recurrent electrographic seizures arising from the right temporal head region (electrode T4) lasting 1-2 minutes in duration and occurring every 10 minutes. Many continued to be associated clinically with rhythmic tongue movements, clonic activity of the left hand and oxygen desaturation. Occasional brief electrographic only seizures were observed from the left central head region (electrode C3). Background EEG activity showed generalized suppression of all frequencies interictally. The patient developed significant hypotension necessitating inotropic support with epinephrine and dobutamine. In light of the systemic side effects, topiramate was initiated (5 mg/kg x 4 doses over 24 hours followed by maintenance 10 mg/kg/day) as an alternative to further increases in the midazolam infusion. Phenytoin was discontinued as it was deemed ineffective and phenobarbital levels were therapeutic at 192 umol/l. On completion of total body cooling a brain Magnetic Resonance Imaging was performed that demonstrated a large subacute infarction containing a large acute-subacute haemorrhage in the right temporal lobe with a smaller area of haemorrhage in the left parietal region. Magnetic Resonance venography and angiography showed no evidence of venous sinus thrombosis or arterial filling defect. As steady state topiramate would not be achieved for 24hrs, a discussion regarding ketamine initiation was had with the family. Ketamine was started at 0.5 mg/kg/hr and increased 12 hours later to 1 mg/kg/hr, which resulted in a decrease in seizure frequency to every 1 hour while the EEG background activity took on a generalized burst suppression pattern (Fig 2). Reduction of the midazolam infusion improved the systemic blood pressure but
increased seizure frequency to every 20 minutes; therefore, the ketamine infusion was increased to 1.5 mg/kg/hr resulting in a complete cessation of seizures. Over the next two days the patient remained on ketamine 1.5 mg/kg/hr, topiramate 10 mg/kg/day and phenobarbital 5 mg/kg/day, while the midazolam was weaned and successfully discontinued permitting discontinuation of the epinephrine and dobutamine. No further seizure activity was observed and the degree of burst suppression on background EEG improved. Occasional sharp waves were seen independently over the right temporal head region (electrode T4). The ketamine was subsequently weaned via decreasing the dosage by 0.5 mg/kg/hr q12 hours until discontinuation. The patient had no further clinical or electrographic seizures and was successfully extubated. By 10 days of age the patient demonstrated a normal neurological examination apart from mild generalized hypotonia. Repeat EEG at 17 days of age showed normal background activity with frequent sharp waves seen in both temporal head regions (electrodes T3/T4) with no seizures recorded. The patient was subsequently discharged home on maintenance topiramate (8.3 mg/kg/day) and phenobarbital (4.3 mg/kg/day). Trough phenobarbital level prior to discharge was 129.2 umol/l. The patient remained seizure free at 3 months of age with a normal neurological examination apart from mild truncal hypotonia on pull to sit manoeuvre. His EEG at that time showed normal background activity and sharp waves arising from the right parietal head region (electrode P4). At 10 months of age as remained seizure free with a normal EEG his topiramate was discontinued. By 17 months of age his neurological examination showed mild spasticity in the left lower extremity but was otherwise normal. He continued to be seizure free and his EEG remained normal and he was successfully weaned off his phenobarbital.
Discussion: In the setting of prolonged status epilepticus there is excessive release of the excitatory neurotransmitter Glutamate and upregulation in the expression of the post-synaptic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors. This results in amplified glutamate induced neuronal hyperexcitability and excitotoxicity causing increased resistance to anticonvulsant therapy. [9] At the same time the number of postsynaptic γ-aminobutyric acid (GABA) receptors decreases, reducing the efficacy of GABA-ergic anticonvulsant medications such as benzodiazepines, barbiturates, valproic acid and propofol. [1,9] At the blood brain barrier the activity of drug efflux transporters such as P-glycoprotein increases. This reduces concentrations of anticonvulsants such as phenobarbital and phenytoin in the central nervous system making them less effective. [9]
The NMDA receptor is a nonspecific transmembrane cation channel found throughout the central nervous system. It is made of five subunits that form a voltage and ligand gated channel within the cell membrane that when activated allow the intracellular influx of cations. On the post synaptic neuronal membrane, activation of the NMDA receptor and the resultant influx of Ca2+ and Na+ causes a large and prolonged excitatory post-synaptic potential of the post synaptic neuron. [10,11] On the extracellular portion of the NMDA receptor there are binding sites for l-glutamate and glycine. Within the channel there are binding sites for Mg2+ and polyamines (specifically phencyclidine) that when bound with ligand block the influx of ligands through the channel. NMDA receptors are voltage and ligand gated; therefore, activation of the
NMDA receptors requires both membrane depolarization and binding of both l-glutamate and glycine at their extracellular binding sites. [10] Membrane depolarization, usually provided by activation of adjacent AMPA receptors, results in the displacement of Mg2+ from within the NMDA receptor channel allowing cations to enter the cell. [10,11]. Binding of the phencyclidine binding site within the NMDA receptor channel by polyamines such as phencyclidine and ketamine causes a blockade of cation influx through the channel and inactivation of the NMDA receptor. This binding at the phencyclidine binding site can only occur when the channel is opened through activation of the NMDA receptor. [11] It is through this mechanism that ketamine exerts its NMDA receptor antagonistic activity. [1]
In the newborn, seizures are the most frequent manifestation of neurological disease and are usually symptomatic secondary to an underlying cerebral insult. Hypoxic-ischemic encephalopathy and hypoglycaemia are two of the most common causes of neonatal seizures in most case series. [12] Several developmental features of the neonatal brain not only predispose towards seizures but also make seizures more resistant to standard anticonvulsants that act on the GABAergic system. [13] In the neonatal brain there is a relative excess of excitatory activity relative to inhibitory GABAergic activity. Concentrations of extracellular glutamate are higher in the neonatal brain due to increased release into and decreased reuptake of glutamate within the synaptic cleft. [13,14] In the setting of a cerebral insult such as perinatal hypoxic ischemic encephalopathy, the concentrations of extracellular glutamate increase even further. [13] The relative expression of neurotransmitter receptors in the neonatal brain also predisposes to seizure activity with NMDA and AMPA receptors being the
predominant receptor types expressed. [14,15] The NMDA receptors themselves also display several maturational changes in the neonate enhancing their excitatory function. These include reduced voltage gating mediated by Mg2+, a greater sensitivity to glycine enhancement and prolonged excitatory post-synaptic potential duration following activation of the receptor. [14,15] In contrast, concentrations of GABA are decreased in the neonatal brain compared to those of adults and older children. Moreover, activation of GABA receptors can have a paradoxical excitatory effect on the post synaptic neuron due to a developmental mismatch between the NKCC1 and KCC2 Cl-cotransporters. This mismatch results in a higher intracellular concentration of Cl- at resting state, Activation of the GABA receptors then results in an efflux of Cl- from the neurons and resultant depolarization. [14,15] This in part explains why GABAergic medications can have limited efficacy in treating neonatal seizures. [13,14]
The maturational changes seen in NMDA and GABA receptors in the neonatal brain would make a NMDA receptor antagonist such as ketamine an attractive therapeutic option for neonates with refractory seizures. To date, there are two reports of ketamine being used to abort refractory status epilepticus in neonates. Taroco et al. reported using ketamine successfully to abort status epilepticus in a preterm infant born at 34 weeks gestation with Pierre-Robin sequence, polymicrogyria and lissencephaly. After failing several anticonvulsants including phenobarbital, midazolam and levetiracetam the patient received two boluses of ketamine followed by a ketamine infusion that was gradually increased to 24 mcg/kg/min (1.44 mg/kg/hr). The patient remained seizure free while the ketamine infusion was maintained from days 82-103 of life approximating a corrected gestational age of 40-63 days. Following
withdrawal of ketamine the patients’ seizures recurred despite re-initiating the ketamine infusion with a maximum dose of 60 mcg/kg/hr (3.6 mg/kg/hr) and the patient subsequently died. [7] Freibauer and Jones reported using ketamine in a 2 day-old male infant with Encephalopathy of Infancy with Migrating Focal Seizures secondary to a KCNQ2 mutation. After having failed treatment with phenobarbital, phenytoin and midazolam, a ketamine infusion (dosage not specified) was successful in controlling both clinical and electrographic seizures. Due to the poor prognosis, care was withdrawn soon after and the patient subsequently died. [8] Our case demonstrates excellent clinical efficacy in stopping seizures after several appropriate anticonvulsants at appropriate doses failed. There are however some concerns about long term neurodevelopmental sequelae of ketamine exposure in the developing brain. Along with several other commonly used anaesthetics including midazolam and isoflurane, ketamine exposure can induce neuronal degeneration and apoptosis in several brain regions in immature rodents and non-human primates. [16,17,18] With exposure to ketamine this is thought to be secondary to upregulation of NR1 NMDA receptors on neural cell membranes. Because ketamine has rapid clearance from blood and brain its withdrawal then allows for glutamate induced activation of these excessive NMDA receptors. This results in accumulation of excessive intracellular Ca2+ which activates apoptotic cascades and neuronal death. [16] In in vivo animal models the ketamine induced neuronal death was seen predominantly in the frontal cortices but only when they were exposed to repeated high doses of ketamine suggesting that brief treatments with low doses may not be enough to induce upregulation of NMDA receptors. In 24 human infants undergoing cardiopulmonary bypass randomized to receive either a single pre-surgical dose of ketamine at 2 mg/kg or normal saline placebo,
ketamine did not show any neuro-protective or neuro-toxic qualities with postsurgical near infrared cerebral spectroscopy and developmental follow up using the Bayley Score of Infant Development 2-3 weeks post surgery. [19] Mitochondrial dysfunction seems to play a pivotal role in the neuronal apoptosis seen with ketamine exposure. Several in vitro studies have shown that the addition of carnitine blocks the neurotoxic effects of ketamine. [16] This suggests that if ketamine is chosen as an anticonvulsant in a newborn carnitine supplementation may allay some of the concerns regarding potential neuro-toxic effects of the ketamine. However, this has yet to be proven in human models and the appropriate dose of carnitine supplementation has yet to be determined.
Conclusion: Ketamine’s antagonistic activity on the NMDA receptor renders it an attractive potential anticonvulsant for use in neonates with refractory seizures. The fact that our patient responded well to ketamine therapy and demonstrated no evidence of neurotoxicity at tenmonth follow up further supports its use in this clinical situation. Concerns regarding potential neuro-toxic effects and the possible role of carnitine supplementation in preventing ketamineinduced neuro-toxicity in the immature brain warrant further investigation.
References:
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Legend: Figure 1: Neonatal polygraphic EEG showing seizure arising from right temporal head region at electrode T4. The patient is on phenobarbital monotherapy and therapeutic hypothermia at the time of this recording. Figure 2: Neonatal polygraphic EEG showing burst suppression pattern. The patient is on phenobarbital and topiramate as well midazolam infusion at 0.15 mg/kg/hr and ketamine infusion at 1.5 mg/kg/hr.