Successful utilisation of epidural analgesia for perioperative pain management in a child with sodium voltage-gated channel alpha subunit (SCN1A) gene mutation

Abstract

Sodium voltage-gated channel alpha subunit (SCN1A) gene mutation is a rare disorder with a large spectrum of clinical presentations. Little is known regarding anaesthetic and analgesic management of these patients. We present a case of a child with SCN1A gene mutation that was successfully managed with an epidural for perioperative analgesia for an abdominal surgery.

Background

Sodium voltage-gated channels play a key role in a cell’s ability to generate and transmit electrical signals in excitable tissue across the nervous system, heart and muscle.¹ Sodium voltage-gated channel alpha (α) subunit (SCN1A) gene is responsible for making one part of the sodium channel called Nav1.1. These Nav1.1 channels are primarily found in the brain and are involved in transmitting signals between neurons.² Mutations in the gene encoding SCN1A are rare and associated with several genetic epilepsy syndromes, ranging from mild febrile seizures to severe myoclonic epilepsy of infancy or Dravet syndrome. There are over 1200 identified SCN1A mutations, with only 18% that are repeated in the population, making the estimate of the probability for disease on the basis of genotype extremely difficult.³

Perioperative pain control is particularly important in paediatric patients since inadequate treatment has been associated with negative development of pain perception and chronic pain in the future.⁴ The voltage-gated sodium channels are well known to be involved in the generation of pain perception, as well as pain disorders. Several of the sodium-gated channels, including Nav1.7, Nav1.8 and Nav1.9, have been associated with multiple severe pain syndromes and neuropathies.⁵ The SCN1A gene mutation has been associated with pain conditions as well, including migraines.⁶

Patients with SCN1A gene mutation are usually taking antiepileptic medications for symptom management, often requiring multimodal therapy to control their seizures.^{7 8} However, little is known regarding anaesthetic and analgesic management for these patients in the perioperative period, including the effect of local anaesthetics, given their abnormal sodium channels. We present the case of a 22-month-old child with SCN1A mutation successfully managed with an epidural for intraoperative and postoperative analgesia.

Case presentation

A 22-month-old 11.4 kg boy baby with a history of SCN1A mutation with associated epilepsy and status post repair of double outlet right ventricle and craniosynostosis presented for ileostomy takedown. His postoperative course following his craniosynostosis repair was complicated by ileus with bowel perforation requiring haemicolectomy and ileostomy. He had severe, uncontrolled pain following this initial abdominal operation. Additionally, he required multiple subsequent operations with general anaesthesia and had developed severe anxiety, eventually being diagnosed with post-traumatic stress disorder (PTSD), even at his young age. Following each of his major operations, the patient had poorly controlled pain, requiring prolonged hospitalizations due to inability to transition to an oral pain management regimen. Our perioperative care team felt epidural analgesia would be optimal, but given his sodium channelopathy, there was concern for the effectiveness of local anaesthetics and no practitioners at our institution had experience with local anaesthetics in this unique patient population.

On the day of surgery, the patient was extremely apprehensive in the preoperative holding area. He was premedicated with oral midazolam 0.5 mg/kg for anxiolysis prior to going to the operating room. After routine inhalational induction of general anaesthesia, an intravenous catheter was placed, and the patient was intubated. A T9 thoracic epidural catheter was placed with the patient in lateral decubitus position using fluoroscopy. The epidural was bolused with 0.5 mL/kg of 0.2% ropivacaine. A continuous infusion of 0.1% ropivacaine with 2.5 µg/mL hydromorphone and 0.5 µg/mL clonidine via the epidural catheter was initiated at rate of 0.35 mL/kg/hour. An intravenous dexmedetomidine infusion at 0.5 µg/kg/hour was also initiated, and he received a total of 1.3 mg/kg of ketamine in divided doses throughout the case. At the end of the surgery, the anaesthetic was discontinued, including the dexmedetomidine infusion, and he was extubated and taken to the recovery room without any evidence or complaints of pain.

Outcome and follow-up

The patient did not have any issues with abdominal pain or agitation for the remainder of his hospitalisation. He did not require any intravenous opioid for analgesia for the duration of the time the epidural was in place. The epidural was removed on postoperative day 4, and he was discharged home with scheduled acetaminophen and ibuprofen. The patient’s parents reported that this was the best analgesia and smoothest postoperative course compared with his previous operations.

Discussion

Epidural analgesia involves the introduction of local anaesthetic into the epidural space, usually via a catheter, providing an infusion mechanism for the local anaesthetic. Local anaesthetics serve to temporarily block neural function at the spinal cord level to reduce or eliminate sensation. They do this by reversibly inhibiting nerve transmission by binding to voltage-gated sodium channels in the nerve plasma membrane. Binding to these channels render them impermeable to sodium, therefore preventing action potential initiation and propagation.⁹ Epidural analgesia is excellent for patients with known pain issues, as it is localised to the area of pain and one can avoid the utilisation of systemic opioids, which have significant side effects and potential long-term complications. The Pediatric Regional Anesthesia Network recently published a study using the multicenter database that included 13 120 neuraxial continuous catheters placed in paediatric patients.¹⁰ Serious complications, although rare, included sensory issues that resolved within weeks to months (0.02%–0.04%), local anaesthetic toxicity presenting as cardiac arrest or seizure (0.02%), epidural abscess (0.01%) and local cutaneous infections (0.6%). No epidural hematomas or permanent motor deficits were reported. The more common and less serious adverse events were catheter-related issues (4%—dislodgement, occlusion or disconnection) and respiratory depression that resolved with pausing the continuous infusion (0.14%). Unintentional dural puncture occurred in 0.86% of lumbar and 0.66% of thoracic epidurals that were placed.¹⁰ There is a high level of safety for regional anaesthesia techniques, including epidurals, in children.

SCN1A gene mutation is a rare disease with a wide array of clinical severity. Literature for anaesthetic management in paediatric patients with sodium channelopathies is sparse, including the use of regional anaesthesia techniques. Our patient had significant issues with poorly controlled pain in the past following his multiple operations, requiring large doses of opioids and even a prolonged intensive care unit stay due to inadequate analgesia. In a recent study, performed in paediatric patients, there was a high prevalence of PTSD and anxiety in children adolescents with severe chronic pain.¹¹ However, this study was conducted in children aged 8–17 years old; our patient is unique in that he was only 22 months old with PTSD and anxiety. Further research is needed to evaluate the association between PTSD and chronic pain and anxiety in the younger paediatric population.

Reduction in gut motility often seen with opioids is not ideal for a patient undergoing a bowel operation secondary to the risk of a postoperative ileus. Opioids also have many other untoward side effects, including respiratory depression, sedation and pruritus. We therefore chose to use an opioid-sparing technique for this patient, including epidural analgesia, along with intravenous ketamine and dexmedetomidine. Ketamine is a non-opioid anaesthetic and analgesic agent, working as a noncompetitive antagonist at the N-methyl d-aspartic acid receptor. It has the advantages of preserving airway and respiratory function, while effectively providing analgesia.¹² Dexmedetomidine is an α2 adrenoceptor agonist that works centrally to reduce sympathetic tone, reduce opioid and anaesthetic requirements and also provide analgesia, without untoward effects on the respiratory system.¹³ The epidural formulation consisted of a local anaesthetic, ropivacaine, along with an α2 agonist, clonidine and a low concentration of hydromorphone. The epidural, along with the intravenous ketamine and dexmedetomidine, allowed us to minimise intravenous opioid administration intraoperatively and avoid systemic opioid usage altogether postoperatively.

The gene encoding for the SCN1A Nav1.1 channel is mainly expressed in cerebral tissue, hence the major clinical effect of the mutation being seizure disorders of varying severity, along with autism and migraines. Available evidence indicates that there is substantial functional heterogeneity among mutant SCN1A channels associated with distinct epileptic syndromes, revealing a complex relationship among clinical and biophysical phenotypes.¹⁴ Common functional biophysical abnormalities observed in the mutant Nav1.1 include a compromised channel inactivation leading to increased persistent current, a decreased entry into the channel, and an increased rate of recovery from slow inactive states. This persistent current is the likely cause of the epileptiform activity, and it is suppressed by antiepileptic medications.¹⁵ With this heterogeneity, it is extremely difficult to determine the subclinical effects, such as those in the cardiovascular and peripheral nervous systems. Despite it being known that mutant SCN1A channels exist in both the spinal cord and peripheral nerves, there is a paucity of information about the effects of these channels in nervous tissues.

While there might be concerns about lowering the seizure threshold by using local anaesthetics in patients with this type of mutation, the risk of significant systemic absorption of local anaesthetics from an epidural infusion is extremely low. A study in paediatric patients who received a 0.5 mL/kg bolus followed by a continuous infusion at 0.25 mL/kg/hour of 0.25% bupivacaine had only trace plasma concentrations (0.27–0.67 µg/dL) of local anaesthetic, well below the toxic dose of 2 µg/dL, with no clinical evidence of local anaesthetic toxicity.¹⁶

It is theoretically possible for local anaesthetics to cause further hypofunction in these cells, leading to seizure activity. Therefore, one would have to closely monitor for symptoms suggestive of seizure activity in susceptible patients. At present, there are no available data providing information on the effects of local anaesthetics on mutated SCN1A channels. Fortunately, our patient had no episodes of seizures or seizure-like activity for the duration that the epidural was in place.

There are reports of cases using neuraxial and/or regional anaesthesia in patients with hyperkalemic periodic paralysis, a mutation of SCN4A, and in SCN5A gene mutations causing cardiac conduction disturbances.¹⁷ To the best of our knowledge, this is the first reported case of a paediatric patient with SCN1A mutation successfully managed with an epidural for analgesia. Although some anaesthesiologists may be hesitant to use regional analgesic approaches in this patient population, our case demonstrates that when clinically appropriate, neuraxial analgesia is safe and effective and should be considered.

Patient’s perspective.

This was by far the best pain control and smoothest recovery (my child) has ever had. Between open heart surgery, two brain/cranial surgeries, 45 days in the hospital and two stomach surgeries, this was by far the best possible stay we could have had. I would recommend anyone with a complex history like (my child’s) or related to this gene mutation to give the epidural a chance. It was the best decision we could have ever made. (Patient’s mother; 11 November 2019)

Learning points.

• Sodium voltage-gated channel alpha subunit (SCN1A) gene mutation is a rare disorder with a large spectrum of clinical presentations.

• Given their effect on sodium channels, local anaesthetics and regional anaesthesia may be withheld by anaesthesiologists in the perioperative period in paediatric patients with this disorder due to unknown side effects or efficacy.

• Our case demonstrates that epidural analgesia with local anaesthetics can be safe and effective for analgesia in patients with SCN1A gene mutation in the perioperative period.