Critical Events in Patients with Alternating Hemiplegia of Childhood: A Cohort Study Subgroup Analysis

Abstract

People with alternating hemiplegia of childhood undergoing general anesthesia are at risk for severe complications including critical bradycardia and hemiplegic spells. We performed a 10-year historical cohort study and completed a subgroup analysis of patients who specifically underwent general anesthesia. Patients with ATP1A3 positive variants were compared to those without such variants. The 14 patients reviewed underwent general anesthesia a combined total of 39 times. Two patients had a short QTc documented prior to anesthesia and presented with bradycardia in the recovery room. Two other patients experienced a suspected seizure and hemiplegic spell; one of these patients received no facility-administered medications prior to experiencing a hemiplegic spell, and the other experienced a hemiplegic spell on emergence from anesthesia with subsequent cardiac arrest and successful resuscitation. No apparent association was identified between type of anesthesia and the development of bradycardia or hemiplegic spells. Of the four patients experiencing critical events, three had the ATP1A3-D801N variant. Although additional research is necessary to confirm such associations, patients with alternating hemiplegia of childhood, specifically the ATP1A3-D801N variant, appear to be at elevated risk for complications associated with general anesthesia, suggesting the need for an increased anticipation of complications for this population.

Introduction

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder affecting approximately 1:1,000,000 people.¹ AHC was first described in 1971 in a report of eight patients experiencing unusual, intermittent, and alternating hemiplegia episodes lasting a few hours to several days; the authors noted a brief vasomotor prodrome, abrupt onset of hemiplegia, contralateral headaches, and occasional convulsions.² Clinical diagnostic criteria of the syndrome were proposed in 1993 and later termed the Aicardi Criteria.³ These criteria have been supplemented by modifications reflecting evolving knowledge of the syndrome, including genetic mutation etiology and essential major and minor criteria associated with alternating paroxysmal episodes of hemiplegia and abnormal neurological development: Major criteria include onset before the age of 18 months, episodes of dystonia and other types of movement disorder, episodes of abnormal eye movements, presence of the ATP1A3 variant, and improvement of spells with sleep; minor criteria include epileptic seizures, nonepileptic episodes of altered consciousness, and abnormal motor function.^4–7

In 2012, Heizen et al. described de novo variants in the ATP1A3 gene in patients with AHC.⁸ Their analysis found that 74% of 98 patients with AHC had variants of ATP1A3 and identified 18 different ATP1A3 variants, the most prevalent of which was D801N in 36/98 patients (34%); the second most prevalent variant was E815K in 19/98 patients (18%). The ATP1A3 is an α subunit of the sodium potassium ATPase pump, which establishes and maintains the electrochemical gradients of sodium and potassium ions across plasma membranes; variants result in AHC as well as multiple other neurological disorders.⁹ Because genetic variants of ATP1A3 are associated with severe neurologic impairments ^7,9–13 and cardiac repolarization abnormalities,^14–16 they are of particular concern for patients undergoing general anesthesia.^17–20

There is currently no cure for AHC, so medical management involves comprehensive treatment focused largely on symptom modification,^1,3,21–24 including medications for epilepsy and status epilepticus.¹⁰ Flunarizine, a calcium channel blocker, may ameliorate some hemiplegic and possibly dystonic spells.^3,24 Other medications (e.g., benzodiazepines, topiramate, triheptanoin, steroids, amantadine, memantine, aripiprazole, oral ATP, coenzyme Q, acetazolamide, and dextromethorphan) have been proposed to treat symptoms, but their efficacy remains in question.^1,3 Additional therapies include a ketogenic diet and vagus nerve stimulator placement.²³

Information is needed regarding whether the pathophysiology of AHC may predispose patients to complications during general anesthesia.^1,8 The purpose of this subgroup analysis conducted at a leading AHC referral center was to explore types of medications given during general anesthesia, pre-anesthesia QTc intervals, and AHC-related risk factors that could lead to complications among this population.

Methods

This study was approved by the Duke University Health System institutional review board. Written informed consent was granted by patients or their legal guardians. We completed a single-center, historical analysis of patients with AHC who underwent general anesthesia from 2013-2022.

Anesthesia records were manually reviewed for method of induction and maintenance of anesthesia, time under general anesthesia, medication dosages and timing of administration, and anesthesia providers’ free text notes detailing any critical events (Table 1). Critical bradycardia was defined as HR <60 bpm or sustained decrease by >20% from baseline HR. A hemiplegic spell was defined as any documentation of a typical AHC hemiplegic spell. The most recent ECG prior to the procedure was reviewed by an independent cardiologist, and pre-anesthetic reports from ambulatory ECG strips were reviewed. In line with the Gollob criteria,²⁵ a borderline short QTc was defined as < 370ms; a QTc < 350ms was considered diagnostic for a short QTc.

Table 1.

Summary of Case Series

Mutation/Variant	Age (years)/weight (kilograms)	Type of Induction	Procedure	Medications/Dose	Critical Events
ATP1A3 D801N	22/48.8	Inhalation	MRI	Dexmedetomidine 20mcg Glycopyrrolate 0.4mg Ondansetron 4mg Propofol 50mg Sevoflurane	Bradycardia in PACU
ATP1A3 EK815K	13/35.6	Intravenous	MRI, dental restoration	Acetaminophen 530mg Cefazolin 1,000mg Fentanyl 50mcg Lidocaine 40mg Midazolam 4mg Propofol 170mg Rocuronium Sevoflurane Sugammadex 150mg	N/A
ATP1A3 D801N	4/17.1	Intravenous	Vagal nerve stimulator	Cefazolin 425mg Dexmedetomidine 20mcg Fentanyl 35mcg Glycopyrrolate 1.7mg Midazolam 2mg Neostigmine 0.85mg Ondansetron 1.7mg Propofol 40mg Rocuronium 20mg Sevoflurane	Bradycardia in PACU
	5/19.9	Intravenous	Central venous catheter insertion	Cefazolin 500mg Fentanyl 30mcg Glycopyrrolate 0.2mg Ketorolac 10mg Neostigmine 1mg Propofol 100mg Rocuronium 10mg Sevoflurane	N/A
	10/36.2	Intravenous	MRI	Atropine 0.4mg Hydrocortisone 40mg Midazolam 2mg Propofol infusion	Bradycardia in PACU
	11/49.8	Intravenous	Central venous catheter removal	Cefazolin 1,000mg Fentanyl 20mcg Hydrocortisone 60mg Methylprednisolone 40mg Midazolam 2mg Propofol 260mg Sevoflurane	N/A
	11/54.7	Intravenous	Liver biopsy	Ondansetron 4mg Propofol 130mg Sevoflurane	N/A
AHC with normal ATP1A3 gene sequencing	1.7/10.2	Intravenous	Lumbar puncture	Dexamethasone 2mg Fentanyl 10mcg Ketorolac 5mg Ondansetron 1mg Propofol 30mg Sevoflurane	N/A
	4/13.5	Inhalation	Muscle biopsy	Cefazolin 280mg Fentanyl 10mcg Ketorolac 7.5mg Ondansetron 1.4mg Propofol 40mg Sevoflurane	N/A
	5/15	Inhalation	Dental restoration	Dexamethasone 3mg Dexmedetomidine 2mcg Fentanyl 35mcg Ketorolac 7.5mg Ondansetron 4mg Rocuronium 10mg Sugammadex 60mg	N/A
AHC with normal ATP1A3 gene sequencing	6/24.5	Inhalation	EEG	Sevoflurane	N/A
	6/24.5	Inhalation	EGD, gastric feeding tube placement	Cefazolin 500mg Fentanyl 25mcg Propofol 40mg Sevoflurane	N/A
	7/28.1	Inhalation	EEG, MRI, EGD, gastric feeding tube placement	Propofol 110mg Sevoflurane	N/A
ATP1A3 de novo gene mutation, T360R	2/9.37	Inhalation	Open hip adductor tenotomy	Cefazolin 250mg Fentanyl 25mcg Glycopyrrolate 0.1mg Neostigmine 0.5mg Ondansetron 1mg Rocuronium 6mg Sevoflurane	N/A
	2/12.4	Inhalation	MRI	Propofol 80mg Sevoflurane	N/A
	3/12.7	Inhalation	Laryngoscopy/ Bronchoscopy	Fentanyl 5mcg Propofol infusion 26.67mg Sevoflurane	N/A
	3/14.1	Inhalation	Ligation of salivary duct	Fentanyl 30mcg Glycopyrrolate 0.12mg Neostigmine 0.5mg Ondansetron 1.4mg Rocuronium 7mg Sevoflurane	N/A
	3/14.1	Inhalation	EEG, Eye exam under anesthesia	Sevoflurane	N/A
	3/14.2	Inhalation	Eye exam under anesthesia	Dexamethasone 2mg Ondansetron 1.5mg Sevoflurane	N/A
	4/14.6	Inhalation	Eye exam under anesthesia	N/A	Event consistent with suspected seizure and AHC spell immediately preceding induction
	4/15.4	Inhalation	Eye exam under anesthesia	Propofol 30mg Sevoflurane	N/A
	5/20.8	Inhalation	CVC insertion	Acetaminophen 310mg Cefazolin 600mg Fentanyl 62.5mcg Glycopyrrolate 0.1mg Ketorolac 10mg Neostigmine 0.5mg Ondansetron 2mg Propofol 10mg Rocuronium 20mg Sevoflurane	N/A
	6/22	Inhalation	Interventional radiology sclerotherapy	Clindamycin 200mg Fentanyl 50mcg Glycopyrrolate 0.3mg Neostigmine 1mg Ondansetron 2mg Sevoflurane Vecuronium 3mg	N/A
	6/24.4	Inhalation	CVC removal and insertion	Clindamycin 240mg Fentanyl 25mcg Ondansetron 2.5mg Sevoflurane	N/A
	8/23.8	Inhalation	CVC – removal and insertion	Acetaminophen 360mg Clindamycin 240mg Fentanyl 25mcg Ondansetron 2.5mg Sevoflurane	N/A
	8/23.8	Inhalation	MRI	Propofol 20mg Sevoflurane	N/A
	8/23.8	Inhalation	Spinal corrective surgery	Acetaminophen 360mg Dexmedetomidine infusion 18.64mg Fentanyl 100mcg Fentanyl infusion 136.06mcg Gentamicin 120mg Ketamine 15mg Ketamine infusion 22.37mg Nicardipine 0.18mg Ondansetron 2mg Phenylephrine 30mcg Propofol 100mg Propofol infusion 591.43mg Sevoflurane Tranexamic acid 1200mg Tranexamic acid infusion 428.21mg Vancomycin 476mg	N/A
	10/31.3	Inhalation	Vagal nerve stimulator	Acetaminophen 470mg Cefazolin 700mg Cisatracurium 9mg Dexmedetomidine 8mcg Fentanyl 25mcg Ketorolac 7.5mg Ondansetron 3mg Propofol 90mg Sevoflurane Vancomycin 500mg	N/A
	10/32.2	Intravenous	EGD	Ondansetron 4mg Propofol 100mg Sevoflurane	N/A
ATP1A3 D801N	13/45.5	Inhalation	MRI	Atropine 0.2mg Dexmedetomidine 24mcg Epinephrine 2,250mcg Epinephrine 80mcg Glycopyrrolate 0.2mg Lidocaine 100mg Midazolam 2mg Ondansetron 4mg Sevoflurane Sodium bicarbonate 50mEq	Event consistent with suspected seizure, AHC spell and cardiac arrest following emergence from general anesthesia with successful resuscitation
AHC ATP1A3 mutation negative	4/29	Inhalation	Tonsillectomy	Dexamethasone 10mg Dexmedetomidine 20mcg Hydromorphone 0.3mg Lidocaine 20mg Ondansetron 3mg Propofol 30mg Sevoflurane	N/A
	6/26.9	Inhalation	EGD	Sevoflurane	N/A
AHC ATP1A3 mutation negative	7/18.1	Inhalation	Muscle biopsy	Acetaminophen 270mg Cefazolin 530mg Dexamethasone 2mg Fentanyl 10mcg Ondansetron 2mg Sevoflurane Tranexamic acid 180mg	N/A
AHC CACA1NA	5/26.8	Intravenous	Vagal nerve stimulator	Cefazolin 700mg Dexamethasone 2mg Dexmedetomidine 8mcg Fentanyl 100mcg Glycopyrrolate 0.3mg Lidocaine 20mg Midazolam 2mg Neostigmine 1.5mg Ondansetron 2mg Propofol 60mg Rocuronium 15mg Sevoflurane	N/A
AHC Deletion seen on chromosomal analysis	40	Inhalation	MRI	Sevoflurane	N/A
AHC p.A333T	2/9.7	Inhalation	MRI	Dexmedetomidine 22mcg Sevoflurane	N/A
SCN1A	26/60.6	Intravenous	Pelvic exam/conization of cervix	Dexamethasone 4mg Doxycycline 100mg Fentanyl 50mcg Hydromorphone 0.4mg Ketorolac 30mg Lidocaine 60mg Midazolam 2mg Ondansetron 4mg Propofol 130mg Scopolamine patch 1.5mg Sevoflurane	N/A
ATP1A2 mutation	6/17.6	Inhalation	MRI	Sevoflurane	N/A
	6/19.8	Inhalation	MRI	Fentanyl 10mcg Propofol 50mg Sevoflurane	N/A

(PACU = post anesthesia care unit; MRI = magnetic resonance imaging; AHC = alternating hemiplegia of childhood; CVC = central venous access; EEG = electroencephalography; EGD = esophogastroduodenoscopy)

Results

Patient Demographics

This study included 14 patients who underwent a total of 39 general anesthetics (patient demographics are summarized in Table 2). Patients were a median age of 6.8 years old, with three patients over the age of 18 (22, 26, and 40 years), and 71% were female. Most (8) had a single general anesthetic during the study period, although one had 16. Six of the 14 patients (43%) hosted variants in the ATP1A3 gene, including D801N (n = 3), E815K (n = 1), T360R (n = 1), and A333T (n = 1). Only one patient had an ATP1A2 variant; the rest had normal gene sequencing.

Table 2:

Overview of Patient Demographics, Anesthetic Characteristics, and Critical Events by AHC Genotype

	ATP1A3 Variant n=6 patients, n=25 anesthetics	Other Variant or Normal Gene Sequencing n=8 patients, n=14 anesthetics	All Patients n=14 patients, n=39 anesthetics
Patient Demographics
Age (years)	6.3 [3.8 - 10.4]	6.8 [5.0 - 7.4]	6.8 [4.1 - 10.1]
Gender (% female)	50.0	87.5	71.0
Weight (kg)	22.0 [14.2 - 33.9]	24.5 [17.0 - 28.3]	23.8 [14.6 - 31.3]
Number of Anesthetics per Patient	1.0 [1.0 - 7.8]	1.5 [1.0 - 2.8]	1.0 [1.0 - 3.0]
Anesthetic
Route of Induction via Inhalation Agent (%)	70.8	78.6	73.7
Maintenance of General Anesthesia with Inhaled Agent (%)	87.5	100.0	92.1
Time Under General Anesthesia (minutes)	84.0 [49.0 - 113.0]	69.0 [46.0 - 105.5]	78.0 [46.0 - 113.0]
Dexmedetomidine Administered (%)	24.0	21.4	23.1
Dexmedetomidine Dose (mcg/kg)	0.65 [0.37 - 1.44]	0.30 [0.13 - 0.69]	0.53 [0.28 - 0.98]
Neostigmine Administered (%)	24.0	7.1	17.9
Glycopyrrolate Administered (%)	32.0	7.1	23.1
Atropine Administered (%)	8.0	0.0	5.1
Complications
Critical Bradycardia (n)	3*	0	4
AHC Spells (n)	2†	0	1
Cardiac Arrest (n)	1	0	1

Patients were divided by the genetic etiology of alternating hemiplegia of childhood (AHC): ATP1A3 variant versus other variant or normal gene sequencing. Patient demographics and anesthetic methods were similar across groups. All observed perioperative critical events occurred in the ATP1A3 group.

^*One event occurred after new vagal nerve stimulator activation and therefore omitted from analysis

^†AHC spell occurred prior to induction

Procedures and General Anesthetics

The most common procedure requiring general anesthesia was magnetic resonance imaging (MRI) (11). Other procedures included central venous catheter insertion or removal (5); eye exam under anesthesia (5); esophagogastroduodenoscopy (4); electrocephalogram (EEG) (3); vagal nerve stimulator placement (3); ear-, nose-, and throat-related procedures (3); dental restoration (2); muscle biopsy (2); spinal corrective surgery (1); liver biopsy (1); lumbar puncture (1); sclerotherapy (1); hip tenotomy (1); and pelvic examination (1).

Key components of the general anesthetic were comparable between patients with ATP1A3 variants and those without (see Table 2). Anesthesia was most frequently induced (74%) and maintained (92%) with inhaled sevoflurane. Patients with ATP1A3 variants received dexmedetomidine in 24% of cases (median [IQR] dose of 0.65 [0.37-1.44] mcg/kg) as compared to 21% of genotype negative cases (dose of 0.30 [0.13-0.69] mcg/kg).

Critical Events

All observed perioperative critical events occurred in patients with ATP1A3 variants. Events are summarized in Table 3. Three of four events occurred in patients with the ATP1A3-D801N variant. Three patients experienced isolated bradycardia in the post-anesthesia care unit (PACU); one of these had a vagal nerve stimulator activated and was excluded from further analysis. A separate patient had a suspected AHC spell immediately prior to induction of anesthesia, and another experienced a suspected seizure, bradycardia, and subsequent cardiac arrest with successful resuscitation following emergence from anesthesia.¹⁸

Table 3:

Individual-Level Anesthetic Details and Critical Events

Patient #/variant/age at event	Procedure	Method of Anesthesia Induction/Maintenance/Airway	Pre-medication	Other IV Medications and Dosages	Dexmedetomidine Administered	Preoperative Heart Rate from Outpatient visits (bpm)	Preoperative Heart Rate from Holter Monitor (bpm)	Preanesthetic QTc (msec)	Intra-procedure Heart Rate Nadir (bpm)	Critical Events
#1 ATP1A3-D801N 22 years	MRI	Inhalation/Sevoflurane/LMA	Midazolam PO 20mg	Glycopyrrolate 0.4mg Ondansetron 4mg Propofol 50mg Sevoflurane	20mcg (0.4 mc/kg)	69-91 (1 week before procedure)	N/A	378	53	Bradycardia in PACU
#2 ATP1A3-D801N 10 years	MRI	Intravenous/Propofol infusion/Native	Midazolam IV 2mg	Atropine 0.4mg Hydrocortisone 40mg 320.91mg	None	73 (2 days before procedure)	Mean 87, minimum 55 (2 days before procedure)	323	65	Bradycardia in PACU
#3 ATP1A3-T360R 4 years	Eye exam under anesthesia	N/A	None	N/A	None	118 (1 day before procedure	Mean 106, Minimum 62 (16 hours before procedure)	434	N/A	Event consistent with suspected seizure and AHC spell immediately preceding induction
#4 ATP1A3-D801N 13 years	MRI	Inhalation/Sevoflurane/LMA	Midazolam PO 15mg	Atropine 0.2mg Epinephrine 80mcg bolus Epinephrine 2,250mcg infusion Glycopyrrolate 0.2mg Lidocaine 100mg Midazolam 2mg Ondansetron 4mg Sodium Bicarbonate 50mEq	24 mcg (0.5 mcg/kg)	96 (2 months before procedure	Mean 134, Minimum 90 (7 days before procedure)	364	56	Event consistent with suspected seizure, AHC spell and cardiac arrest following emergence from general anesthesia with successful resuscitation

In total, four significant clinical events were observed over the course of the study period. In one case, a suspected seizure and alternating hemiplegia of childhood (AHC) spell occurred prior to administration of any medication. In the remaining three cases, complications occurred following emergence from general anesthesia. All three patients who experienced bradycardia harbored the ATP1A3-D801N variant. Since dexmedetomidine is a medication that can decrease heart rate its administration is reported separately. (MRI = magnetic resonance imaging; PACU = post anesthesia care unit; LMA = laryngeal mask airway; IV = intravenous; PO = per os)

Bradycardia

Notably, both patients who experienced bradycardic events in the PACU had the ATP1A3-D801N variant and a documented short QTc on pre-anesthetic ECGs. The first, age 22, was under general anesthesia for a total of 74 minutes for an MRI scan. This patient was administered a single 20 mcg (0.41 mcg/kg) IV bolus of dexmedetomidine shortly after induction and 4 mg of IV ondansetron prior to emergence. His documented outpatient heart rate over the preceding week ranged from 69 to 91 bpm, with a nadir of 53 bpm. His heart rate on arrival to the PACU was 41-45 bpm, with a blood pressure of 99/44.

The second patient, age 10, had general anesthesia (via propofol infusion) for 84 minutes for an MRI scan, during which she received 2 mg IV midazolam and 40 mg IV hydrocortisone. Preoperative twenty-four hours of Holter monitoring showed a mean heart rate of 87 bpm and a minimum rate of 55 bpm. Upon arrival to the PACU, her heart rate was 53 bpm with a non-invasive blood pressure of 94/56; the intraoperative nadir was 65 bpm. Neither patient received neostigmine, and in both cases, bradycardia was responsive to an intravenous anticholinergic medication administered in the PACU.

Hemiplegic Spells

Two separate patients experienced a suspected seizure and hemiplegic spell. The first, who had the ATP1A3-T360R variant, presented for an eye exam under anesthesia. While supine for a planned inhalational induction, she experienced spastic movements, increased secretions, coughing, gagging, difficulty breathing, and a drop in measured oxygen saturation to 80%. The case was canceled prior to induction. The second patient had the ATP1A3-D801N variant. Following emergence from general anesthesia for an MRI scan, he experienced bradycardia, agitation, seizure activity, hemiplegic spell, and subsequent cardiac arrest due to ventricular fibrillation, with successful resuscitation.¹⁸

Discussion

Our current study is a subanalysis describing a cohort of patients with AHC undergoing general anesthesia at our institution. Prior to this review, descriptions of experiences of patients undergoing general anesthesia have been limited to letters to the editor or case reports,^18–21 including one report on a combined group of patients from our center and outside hospitals which did not specifically analyze individual complications during general anesthesia.¹⁷ This combined sedation/anesthesia study of 34 patients who underwent 129 procedures with either sedation or anesthesia reported that 35% experienced complications during at least one procedure, and 14 (11%) manifested one or more complications, 64% of which were severe enough (apnea, severe laryngeal dystonia requiring tracheostomy, seizures, AHC type spells and cardiac rhythm problems [mostly bradycardia]) to require intervention. Because the combined study reported results in aggregate, we sought to explore the general anesthesia population exclusively, focusing specifically on relationships between the perianesthesia environment, preoperative QTc, medications used with general anesthesia (propofol infusion and inhalation agents), and critical events in this population. Our current subanalysis describes details associated with the four critical events manifested in relation to general anesthesia; no relationship between type of general anesthesia and critical event was found.

Short QT syndrome is a cardiac disease characterized by ventricular tachyarrhythmias that can lead to syncope and death with a prevalence of 0.05% in the pediatric population.²⁶ Anesthesia risk implications of a patient with a short QTc interval include increased risk of sudden cardiac death. The management of a patient hosting an ATP1A3 variant, which conveys risk of developing either bradycardia, short QT interval, and/or ventricular arrhythmias, requires specialized diagnostics and management. Electrical health of the heart should be evaluated at diagnosis with a 12-lead ECG to quantify cardiac repolarization time in the form of a corrected QT calculation, an echocardiogram to determine whether any structural abnormalities are present, and an ambulatory heart rhythm monitor (for example a 24-hour Holter).^26,27 Some patients may need a longer duration of monitoring to adequately quantify their symptom and disease burden.²⁸ When abnormalities are identified, any reversible condition that can cause bradycardia (such as thyroid disturbance, metabolic derangements, or sleep apnea) should be evaluated and managed.²⁹ Short QT is typically defined as a corrected QTc of <350, with a QTc of <370 considered borderline. Its presence reflects higher risk for developing ventricular arrhythmias and should, therefore, trigger careful evaluation of presyncope, syncope, and arrhythmias to ensure that there are no concerns for cardiogenic syncope. Given early evidence that bradycardia can compound arrhythmogenesis, chronotropic drugs should be avoided in the setting of short QT. The use of implantable cardioverter defibrillators for primary or secondary prevention of arrhythmias is a nuanced discussion that should take into account the goals of the family. ²⁹

Because AHC is associated with developmental delay and behavioral issues, general anesthesia is often required for exams and procedures that would otherwise be performed without it,¹³ thus these patients have a disproportionately high number of exposures to general anesthesia. Research suggests that patients with an ATP1A3 variant on chromosome 19 are at increased risk while undergoing anesthesia due to the impact on the alpha-3 subunit of the sodium-potassium ATPase pump, which may predispose this population to AHC-type spells, cortical irritability, and agitation that can trigger spells, seizures, abnormal brainstem function, and cardiac arrythmias.^10,14–16

Our cohort included patients who met the clinical criteria for AHC, including both variant positive and variant negative genotypes. Our review supports the hypothesis that there is an increased risk for complications during anesthesia in variant positive AHC. As mentioned above, one patient with the ATP1A3-T360R variant had a suspected AHC spell which led to cancellation of their case prior to induction of anesthesia or any drug administration; this suggests that factors such as psychological stress should be considered potential triggers for an AHC spell, which anesthesia providers must be prepared to manage. Symptomatic bradycardia was observed in 3 of the 14 patients during 4 general anesthetics; all had the ATP1A3-D801N variant. These observations may indicate an association of bradycardia with the D801N variant and suggest the need for caution in using medications known to significantly decrease heart rate such as alpha-2 agonists and beta-blockers.

It is well-described in the neurology literature that AHC-related hemiplegic spells can be precipitated by stress.³ Despite similarities in phenotype, patients with ATP1A3 variants may manifest different, more severe complications due to anesthesia and stress than those with the negative variants.¹⁵ There are currently no detailed recommendations regarding whether specific anesthesia medications or techniques are safer for this population. Perioperative management may focus on removing or limiting known triggers of stress (e.g., temperature extremes, medications, food dyes, crowds) that might potentiate a hemiplegic attack. At our institution, such measures include provision of a quiet, private preoperative holding room with a closable door, which allows parents/caregivers to remain with the patient as long as possible; avoidance of preoperative oral medications with dyes; and allowing patients to wear to headphones/sunglasses as desired. The association of the ATP1A3-encoded sodium-potassium ATPase subunit D801N variant with shortened QTc interval places patients with this variant at risk for bradycardia, and likely also for ventricular fibrillation preceded by bradycardia.^14,17,18 Careful preoperative assessment with a focus on cardiology evaluation is advisable.^14–16 Because about half of patients with AHC have epilepsy, it is essential that their anti-seizure medication be administered on schedule and that the team be ready to recognize and manage seizures or status epilepticus. Lastly, it should be noted that patients with AHC have a predisposition to obstructive and central sleep apnea as well as apneic episodes during anesthesia, which has been associated with seizures or other spells.^1,11,17

Limitations

This descriptive, historical case series provides information about trends and types of complications that may occur in patients with AHC undergoing general anesthesia. Although this review shows possible genetic associations and contributes to the existing body of literature, results are only associative, and so far, we cannot definitively recommend specific anesthesia techniques as safer than others. The cohort size of 14 is not large enough for statistical analysis to indicate significance. Referral bias may have played a role in the type of patients with AHC seen at our institution.

Conclusions

Patients with AHC frequently require general anesthesia to undergo diagnostic or therapeutic procedures; however, the pathophysiology of AHC suggests an increased risk with general anesthesia. Hemiplegic spells and bradycardia may occur in the perioperative environment. Examination of the ECG and QTc can guide medication choices. The majority of patients with AHC in this review tolerated inhaled and/or intravenous anesthesia techniques. Given the need for anesthesia for patients with AHC, an understanding of the gene variants and associated risks is important. This review supports the hypothesis that patients with the ATP1A3 variants are at increased risk for bradycardia and/or AHC spells that require intervention and supportive care in the peri-anesthesia period.