Motor Neuron Disease and Delicate Anesthesia Choices

Abstract

Motor neuron diseases (MNDs), two major types of which are amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by upper and/or lower motor neuron degeneration and death. They manifest with progressive skeletal muscle atrophy. Most ALS cases are idiopathic, whereas the cause of SMA is genetic. There is no cure for MNDs and anesthetic management is challenging due to patients’ respiratory dysfunction, abnormal response to muscle relaxants, and high risk of aspiration. General guidelines for this purpose state that intravenous administration of propofol and remifentanil are preferred. Muscle relaxants should be used sparingly due to their causing ventilatory depression, and depolarizing neuromuscular blockers should be avoided entirely for patients’ risk of hyperkalemia. This chapter discusses the etiology of MNDs, their clinical features, disease prognosis, palliative treatments, necessary surgical procedures, and preoperative and postoperative anesthetic management. It covers ALS, SMA, and other less common MNDs.

1. Introduction

Motor neuron diseases (MNDs) are a type of neurodegenerative disease caused by upper and/or lower motor neuron axon demyelination and eventual cell demise. Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) are the two major MNDs. While in ALS both upper and lower motor neurons undergo degeneration [1], SMA results from lower motor neuron loss [2]. The cause of ALS, typically in males aged 50–70 years, is unknown, whereas mutations in Survival Motor Neuron-1 (SMN1) gene trigger SMA starting in infancy. Other MNDs that will be discussed include progressive muscular atrophy, primary lateral sclerosis, Kennedy's disease, pseudobulbar palsy, and hereditary spastic paraplegia.

Based on the Global Burden of Disease, Injuries and Risk Factor (GBD) study, the MND prevalence and attributed deaths in 2019 increased 1.91% and 12.39%, respectively from 1990 [3]. The disease burden of MNDs is increasing; currently, there are an estimated 268,673 MND cases globally [3]. In 2019, MNDs resulted in 1,034,606 disability-adjusted life-years and 39,081 deaths worldwide [3].

The major clinical manifestation of MNDs include progressive muscle weakness and atrophy, muscle fasciculations, spasticity, hyperreflexia, dysphagia, aspiration, dysarthria [4]. Due to severe symptoms and loss of mobility, MND patients require extensive accommodations in surgery. Anesthesia management in these patients is a challenging task because MND patients under anesthesia are at higher risk of respiratory distress, aspiration, and respiratory failure. Thus, anesthetic choices are case-by-case and general guidelines for anesthesia should be adjusted for MND clinical practices.

There are no disease-modifying drugs for ALS. ALS is a rapidly developing disease with an average of few years from diagnosis to death. However, a palliative treatment, Riluzole, can delay ALS progression. Riluzole in combination with stem cell-based therapy may further slow ALS progression [5]. Gene therapy that corrects the Smn1 gene mutation and thus extends the surviving years for SMA patients was approved by the FDA for children in 2019 [6]. Anesthetic drugs and analgesics could potentially worsen the injury or damage of MND-diseased motor neurons and thus accelerate the disease progression in these patients. Therefore, there are paramount challenges for anesthesiologist to optimize the anesthesia management, post-surgical recoveries and avoid to further damage the motor neurons in MND patients.

2. ALS overview

The underlying etiology of ALS is still unknown but likely multifactorial with the combination of genetic and environmental factors. Approximately 10% of ALS cases exhibit dominant or recessive autosomal transmission of a mutation in the superoxide dismutase gene (SOD-1) [7]. Recent studies reveal that mutations in more than ten genes are possibly involved in the pathogenesis of familial ALS [8].

The initial symptoms of ALS include muscle twitching and weakness in extremities, with difficulty moving, speaking, and swallowing. ALS progresses rapidly, with about 70% of patients dying within 3 years of symptom onset [9]. At the advanced stage of ALS, ALS patients experience respiratory distress and complete paralysis, and requiring ventilatory support and gastrostomy.

In a case report on an ALS patient undergoing open gastrostomy, the choice of epidural anesthesia over general anesthesia was made to avoid possible respiratory complications [10]. The patient, a 56 year-old female with tetraparesis, also had difficulty speaking, and lung opacities possibly due to microaspiration [10]. The patient was determined to suitable for surgery [10]. For the procedure, epidural anesthesia at the T8-9 epidural space with 0.5% levobupivacaine 40 mg and fentanyl 100 μg was followed by sedation with 1% propofol [10]. The operation and post-operative recovery were uneventful [10]. Although neuroaxial anesthesia may incur further damage on motor neurons, it is ideal compared to general anesthesia for prevention of airway manipulation and respiratory complications. Epidural anesthesia allows the titration of local anesthetic and avoids direct contact between the anesthetic and the heightened susceptible spinal cord. The choice of levobupivacaine in this reported case is due to its lessened motor blockade, as well as low neurotoxicity and cardiotoxicity [10]. Thus, the depth of anesthesia should be closely monitored during the entire surgical procedure.

3. Risks of anesthesia in ALS patients

ALS patients are at a high risk of developing hyperkalemia. Succinylcholine administration to ALS patients induces hyperkalemia, resulting in cardiac dysrhythmias and arrest [11]. In another instance, the depolarizing neuromuscular blocking agent suxamethonium chloride triggered catastrophic hyperkalemia in a patient with undiagnosed ALS [12]. Upper and lower motor neuron injuries or denervation in ALS patients lead to the upregulation of nicotinic α7 acetylcholine receptors, the presence of which enables a larger potassium efflux to the bloodstream [13].

Depolarizing neuromuscular blocker can also cause rhabdomyolysis in ALS patients, a serious medical condition that can results in death or permanent disability. Rhabdomyolysis occurs when damaged sarcomeres release a large amount of dysfunctional proteins and electrolytes into circulation. These harmful substances can cause severe injuries to the heart and kidneys [14]. Due to life-threatening hyperkalemia and potential induction of rhabdomyolysis, depolarizing neuromuscular blocks including succinylcholine, an acetylcholine agonist, and suxamethonium chloride should be contraindicated in ALS patients. In the case of non-depolarizing neuromuscular blocking drugs, short-acting drugs should be chosen to avoid adverse effects and should be used in combination with reversal agents to ensure quick recovery from muscle blocking in ALS patients [15]. Carefully controlling the dose of non-depolarizing neuromuscular blocking drugs is needed to avoid prolonged effects and permanent motor neuron damage.

For ALS patients undergoing surgery, careful consideration of the preoperative, intraoperative, and postoperative phases is essential to achieve successful anesthesia without adverse events. Preoperative respiratory function tests such as spirometry [16] and non-invasive ultrasound assessments [17] can be used to predict respiratory distress perioperatively. In spirometry, if the FEV1 (forced expiratory volume in one second)/FVC (forced vital capacity) ratio, also called as the percentage of the FVC expired in one second [18], is lower than 40%, it indicates a high probability of preoperative ventilatory impairment and that general anesthesia is contraindicated. If possible, a complete neurological examination to determine the presence of impaired bulbar functions such as dysphagia and/or dysarthria is critical [19]. ALS patients with bulbar dysfunction should not be premedicated [10].

Preoperative assessment should include patient history, confirmation of ALS diagnosis, chest radiography, arterial blood gas analysis, liver function test, diaphragmatic function test and videofluoroscopy—an x-ray examination of swallowing. After the preoperative assessment on patients’ general, bulbar, and respiratory function, the next step is to carefully design preoperative management including premedication and monitoring setup. For premeditation, it is best to avoid opioids. Alternatively, small doses of benzodiazepines. Large doses of benzodiazepines also carry risk of dependence like opioids but to a lesser extent. Prophylaxis against pulmonary aspiration in ALS patients such as a peroral 400 mg dose of cimetidine, an H2-receptor antagonists, should be considered at the preoperative stage.

The next step is to induce and maintain anesthesia in ALS patients and this step depends on the types of chosen anesthesia. For the induction of epidural anesthesia, propofol is used for sedation [10]. In a case of a 63 year-old female ALS patient undergoing open reduction and internal fixation of the right tibia, intravenous administrations of propofol and remifentanil without any muscle relaxants were chosen for the anesthesia method [20]. This anesthetic method effectively avoided the occurrence of ALS exacerbation and ventilatory depression induced by abnormal responses to muscle relaxants [20]. After standard and neuromuscular monitoring devices were placed on the patient without any pre-anesthetic medications, anesthesia was induced by infusing 3 ng/ml remifentanil and 3.0 μg/ml propofol [20]. The maintenance of anesthesia in this patient was achieved by propofol and remifentanil with 100% oxygen [20]. The intubation was successful and the patient was discharged postoperative day 3 [20]. In a 48-year-old male with a 5 year history of ALS, general anesthesia was selected for his laparotomy because of dysphagia and dysarthria [15]. This patient was induced by 80 μg fentanyl and 2 mg/kg of propofol, and 10 mg of rocuronium was administered before endotracheal intubation [15]. Continuous infusion of propofol at 0.05–0.1 mg/kg/min was used for anesthesia maintenance [15]. No additional muscle relaxant was administered to the patient and surgery was successfully completed without any significant sequelae [15]. In the above case, the endotracheal tube was placed prior to anesthesia induction, and extubation was performed with the patient fully awake [15]. For ALS patients, while regional anesthesia is generally a less risky choice than general anesthesia, general anesthesia can be done safely in advanced-stage ALS patients.

4. Propofol and remifentanil in induction and maintenance of anesthesia in ALS patients

For the induction and maintenance of anesthesia in ALS patients, combined propofol and remifentanil are frequently used. Propofol is the most popular intravenous sedation drug. Early pharmacological studies have shown quick whole body distribution and relatively fast clearance [21]. Compared to traditional anesthetics such as barbiturates, thiopental and methohexital, patients under propofol show rapid recovery from anesthesia and significantly lower incidence of postoperative side effects including nausea, vomiting, and cognitive impairment, collectively termed “hang-over effects”. Furthermore, patients under propofol exhibit relatively quick recovery in cognitive and psychomotor function [22]. The benefits of propofol also include earlier discharges from the post-anesthesia care unit and higher patient satisfaction for their anesthetic experience [23]. Because of these features, propofol has become the primary choice for an induction agent via intravenous bolus administration and a volatile anesthetic for anesthesia maintenance. With improved drug delivery systems and monitoring, the use of propofol can further benefit high-risk patients such as ALS patients undergoing complex procedures [24].

Remifentanil is a synthetic and short-acting mu-opioid receptor agonist. Other opioids including morphine, fentanyl, alfentanil and sufentanil are also used for pain relief and the use of these opioids is associated with a range of adverse effects. The adverse effects of morphine manifest with histamine release, pruritus, constipation, and the accumulation of metabolite morphine-6-glucuronide in patients with renal impairment [25]. Drug accumulation is a serious concern when opioids are used in surgical procedures. Remifentanil has an ultrashort clearance profile because it can be rapidly metabolized by unspecific blood and tissue esterases [25]. In contrast, fentanyl, alfentanil and sufentanil are all metabolized in the liver. Continuous infusions of these opioids result in drug accumulation and prolonged offset effects. The accumulation of these opioids can cause respiratory depression/failure alongside significantly delayed and unpredictable recovery in ALS patients. The simultaneous use of remifentanil and propofol has unique beneficial effects. Studies comparing the sedative effect of these two drugs in regional anesthesia have demonstrated that remifentanil is more effective than propofol in decreasing pain but has a higher incidence of nausea and respiratory depression [26, 27]. A study on combining propofol or midazolam with either sufentanil or remifentanil reveals that either <3 mg/kg/h propofol, 0.5–3 mg/h midazolam with 5–10 μg/h sufentanil, or 0.05 μg/kg/min remifentanil can achieve successful sedation in regional blocks with a low incidence of adverse events [28]. Further studies in using different administration methods identify that a bolus administration for induction along with continuous infusion of propofol for maintenance is ideal for successful sedation and quick recovery [29]. It has been shown that remifentanil is associated with development of hyperalgesia in patients [30]. However, propofol infusion decreases the incidence of remifentanil-induced hyperalgesia [31]. Therefore, the combination of remifentanil and propofol can overcome the adverse effects of remifentanil including respiratory depression and nausea while keeping the advantage of remifentanil in effectively blocking pain during surgeries. This method should be recommended for ALS patients undergoing either regional or general anesthesia.

5. Intraoperative nondepolarizing neuromuscular blockers in ALS patients

While depolarizing neuromuscular blockers are contraindicated, nondepolarizing neuromuscular blockers such as rocuronium has been successfully used along with propofol and remifentanil. In a case of a 47 year-old ALS patient with a humerus fracture, general anesthesia was induced by propofol, rocuronium and remifentanil [32]. At the end of an uneventful operation, TOF (train-of-four) was great than 0.90 but muscle strengthen and tidal volume were not sufficient [32]. Rocuronium and other nondepolarizing neuromuscular blockers are competitive antagonists of the post-synaptic acetylcholine receptor, leading to prolonged weakness or flaccid paralysis. In the above case, 2 mg/kg sugammadex was given intravenously to quench the residual remifentanil in the patient [32]. Suggammadex rapidly forms a complex with free rocuronium, which is quickly filtered by the kidney. Thus, the duo of rocuronium and sugammadex has been frequently and safely used in general anesthesia of ALS patients.

6. Postoperative care for ALS patients

Tracheal extubation should be done after the patient is fully awake. This will maximize the laryngeal reflex function. Regardless, the respiratory status of the patient needs be closely monitored. In some cases, postoperative ventilation is needed, and weaning ventilation should be prolonged. Patients who had noninvasive positive-pressure ventilation (NPPV) preoperatively require NPPV being placed once again postoperatively [33]. There is a need for effective pain relief but the use of agents that depress respiration should be avoided. It is recommended to use peripheral nerve blockers and local or regional approaches to manage postoperative pain. Postoperative oxygen use is not recommended due to the instability of respiratory control in ALS patients. When opioids are used, the dosages should be tightly controlled in conjunction with monitoring methods such as pulse oximetry to reduce morbidity and mortality.

In case of an ALS patient with rectal cancer, laparoscopic low anterior resection with diverting loop ileostomy and total abdominal hysterectomy were performed under general anesthesia using the combination of propofol and rocuronium for induction and the regime of sevoflurane and remifentanil for maintenance [34]. After the surgery, glycopyrrolate and pyridostigmine bromide were used to reverse the muscle relaxant effects of rocuronium [34]. Postoperative use of fentanyl controlling analgesia in the patient consisted of intermittent low doses within 48 hours, and the patient recovered uneventfully [34]. The use of fentanyl should be cautioned against as it causes respiratory muscle rigidity and subsequent respiratory dysfunction in ALS patients. Postoperative pain should be carefully managed based on the unique circumstances of ALS patients.

7. Anesthesia during labor and delivery in ALS patients

Because ALS onset is usually late in life, there are few cases associated with labor and delivery in ALS patients. How pregnancy affects the progression of ALS is still unclear. It has been reported that ALS patients have successfully carried pregnancies to term [35]. The timing and the methods of delivery are chosen based on the disease stage. The perineum and the uterine musculature are not affected by ALS, and thus vaginal delivery is a preferred method for labor. Progressive shortness of breath or respiratory distress during pregnancy are indicators for emergency Caesarean section [35]. ALS patients are often unable to increase respiration to match oxygen need in labor. As respiratory burden worsens at the end of pregnancy, anesthetic management during Caesarean section becomes increasingly challenging.

There is no formal recommendation for anesthesia management of Caesarean section in women with ALS. It has been reported that epidural anesthesia has been used successfully with no evidence of anesthesia complications in ALS patients. In a case of 38-week pregnant woman with 10-year history of ALS, sequential combined spinal-epidural anesthesia was successful for Caesarean section [36]. Before delivery, neurological assessment on the patient showed progressive muscle weakness, severe dysarthria and dysphagia. The patient presented with quadriparesis, hypotonia, and hyperreflexia, and severe restriction on spirometry with a high risk of respiratory failure. Prior to anesthesia, doses of ranitidine, metoclopramide and dexamethasone are given. Hyperbaric bupivacaine 6 mg plus fentanyl 10 μg were given through the spinal needle and 5 minute later with 0.25% isobaric bupivacaine in 10 ml through the epidural catheter to block T5. The surgical procedure was uneventful. Thus, while vaginal delivery is ideal, delicate regional anesthesia can achieve good outcomes for Caesarean section.

8. SMA overview

SMA is a spectrum of MNDs occurring predominantly in infants and children. The primary causal factors for this inherited disease are deletions or mutations of the Smn1 gene. Generally, Smn1 gene deficiency causes the degeneration and eventual death of spinal anterior horn neurons with decreased brainstem nuclei. SMA type I (Werdnig-Hoffmann) shows symptoms before 6 months of age and progresses rapidly in the first year of life. SMA types II and III (Kugelberg-Welander) manifest at 6–18 months of age and later in childhood, respectively. SMA type 0, the most severe and earliest onset form, is fatal without respiratory support. The symptoms of SMA type IV first appear in adulthood, presenting with minimal disability.

Infants and children with SMA often need anesthesia because of diagnostic procedures and surgical treatments. Common procedures associated with SMA type I patients are gastrostomy, fundoplication, tracheotomy, and muscle biopsy. Common procedures for SMA type II and III patients include correction of scoliosis and club foot, joint contracture release, and muscle biopsy. SMA type III patients can reach reproductive age and thus cesarean sections may be performed on these patients.

9. Anesthetic management of SMA patients

SMA patients have prominent spinal and other bone deformities that require surgical correction to improve patients’ quality of life and extend their survival time. In a case of a 14-year-old SMA type II male patient with a previous operation for scoliosis, the patient was scheduled for an implant removal because of infection [37]. General anesthesia was used and 2 mg dormicum, 20 mg lidocaine, 80 mg propofol, 25 μg fentanyl were used for the induction of anesthesia [37]. No neuromuscular blockers were used [37]. The patient was intubated with a spiral cuffed number 5 tube with direct laryngoscopy when his Bispectral Index Score, which monitors consciousness, was 46 [37]. Foe anesthesia maintenance, one percent sevoflurane and remifentanyl infusion of 0.1–0.2 mg/kg/min were used [37]. The surgery was uneventful and an intravenous administration of 25 mg dexketoprofen was given for postoperative analgesia [37]. The patient was successfully extubated and followed up in intensive care for one day postoperatively [37]. As in this case study, general anesthesia for major surgery in SMA patients should be performed using minimal opioids, whereas muscle blockers are to be used judiciously. Combining sevoflurane with remifentanil, which quickly reverses the muscle relaxant effect of sevoflurane, can achieve optimal anesthesia management and postoperative recovery.

Likewise, there are two cases of general anesthesia for surgical correction of heart defects in SMA type II patients [38]. A 23-day-old SMA type 2 patient successfully underwent pulmonary banding and patent ductus arteriosus ligation with 4 mg thiopental, 4 mg fentanyl, and 1.5 mg rocuronium being used for anesthesia induction and maintenance [38]. Atrial and ventricular septal defect closure and pulmonary artery reconstruction were performed on a 17-month-old patient using rocuronium, pentothal, dormicum, and fentanyl, with maintenance via 0.1 mg/kg/h precedex and 0.6–0.7 minimum alveolar concentration (MAC) of sevoflurane [38]. Both patients were extubated and recovered uneventfully [38].

In a case of an 8 year-old SMA type II patient, a dislocated hip was corrected with a combination general and local anesthesia regimen [39]. Similar to the aforementioned cases, the patient was induced by sevoflurane followed by intravenous administration of fentanyl and propofol [39]. Spinal anesthesia was achieved with 2 ml 0.5% hyperbaric bupivacaine with an epidural catheter in the L3–L4 space [39]. The patient successfully recovered.

Graham et al. summarizes anesthesia induction and management for 56 cases of SMA types I, II and III [40]. Midazolam via both enteral and intravenous routes or a combination of ketamine and midazolam were used for premedication [40]. The most common method for airway support is standard endotracheal intubation. Propofol-based intravenous anesthesia is the most common approach during the procedure. Cisatracurium is the first line neuromuscular blocker, while fentanyl and remifentanil are the two most commonly used intraoperative opioids.

10. SMA patient perioperative care essentials

In a retrospective chart study, thoracolumbar spinal deformity corrections were performed in 34 SMA type I and II patients in a single medical center from 1990 to 2015 [41]. The study reported that in the 34 patients, there were two occurrences of pneumonia (6%), no postoperative re-intubation or unplanned tracheostomies, and no deaths [41]. Because SMA is associated with impaired gastrointestinal function and malnutrition, most SMA patients need perioperative total parenteral nutrition (TPN), whichbypasses the gastrointestinal tract and delivers nutrients to the venous system. Additionally, these patients must be on continuous NPPV for adequate respiratory support.

Pulmonary disease and bulbar dysfunction are strongly associated with SMA and pose anesthetic risks. Preoperatively, pulmonary consultation should be done in all SMA patients. Pulmonary function tests should be conducted. Most SMA patients have difficulties with intubation and thorough evaluations on indicators for intubation should be considered. Preoperative training on NIPPV should be conducted if the patient currently does not have respiratory support. Preoperative airway evaluation is mandatory and establishes a plan for intubation difficulties due to. SMA patients are susceptible for to hypo- and hyperglycemia. Thus, blood glucose levels should be closely monitored. Cardiac function needs to be evaluated preoperatively because SMA is often associated with cardiac malformations. SMA type I and II patients often have gastroesophageal reflux and should be evaluated accordingly.

Intraoperatively, endotracheal intubation with positive pressure ventilation should be applied as respiratory support. Depolarizing muscle relaxants such as succinylcholine should be constrained and the dose of nondepolarizing muscle relaxants should be tightly controlled. If nondepolarizing muscle relaxants are used, neuromuscular function should be monitored. Inhaled anesthetics should be avoided in favor of the intravenous route. Short acting opioids are used intraoperatively when opioids are needed. TPN infusion should be maintained to avoid hypoglycemia. SMA patients typically have 2 more hours of anesthetic time than healthy patients.

Postoperatively, SMA patients should be monitored in the intensive care unit. Generally, these patients require 5–7 days of intensive care even with minor procedures. Most SMA type I patients need postoperative ventilatory support. Postoperative oxygen supplementation is needed for the first 24 hours. Opioids, acetaminophen, and NSAIDs, or all three in combination should be used as postoperative pain management. Opioids may induce respiratory distress in SMA patients. Benzodiazepines are used to manage muscle spasms and discomfort. However, postoperative pain management can largely be tailored to the individual.

11. Kennedy’s disease overview and anesthetic management

Kennedy’s disease (KD), also known as spinal and bulbar muscular atrophy, is a rare adulthood-onset X-linked disease that results in the degeneration and eventual death of lower motor neurons. The major symptoms of KD are tongue atrophy, dysarthria, dysphonia and dysphagia, along with limb and bulbar muscle atrophy, weakness and fasciculations [42]. KD is a CAG trinucleotide expansion repeat disorder in the androgen receptor gene. Anesthetic management can be challenging. Laryngospasm and pulmonary aspiration have been reported as primary anesthetic risks in KD patients. Both nondepolarizing and depolarizing neuromuscular blockers induce hyperkalemia in KD patients [42]. In a 71-year old KD male patient who underwent a tracheotomy, the surgical procedure was performed under local anesthesia by ultrasound-guided superior laryngeal nerve block and superficial cervical plexus block via 2% lidocaine [42]. The procedure was uneventful and the patient reported no discomfort [42]. In a 61-year-old male KD patient who underwent a left thigh sarcoma excision, general anesthesia with endotracheal intubation was induced by 150 mg propofol and 100 μg fentanyl, and maintained with inhalational anesthesia [43]. The patient recovered without any postoperative complications.

12. Isaacs’ syndrome overview and anesthetic management

Isaacs’ syndrome, a peripheral MND, manifests with peripheral nerve hyperexcitability. Symptoms include cramps, muscle stiffness, muscle twitching, and pseudomyotonia. The major cause of Isaacs’ syndrome is antibodies against the voltage-gated potassium channel complex in the peripheral nerves. Anticonvulsive medications and immunomodulation therapy are used to control the progression of this disease. The onset of Isaacs’ syndrome is mainly in early adulthood or onwards.

In a 74-year-old female Isaacs’ syndrome patient who underwent a surgery for open rotator cuff repair, total intravenous anesthesia with propofol, remifentanil, and atracurium was used under continuous neuromuscular monitoring [44]. The surgical procedure and postoperative recovery were smooth without any anesthetic complications. Because Isaacs’ syndrome is a rare disorder, anesthetic management and outcomes have not been extensively explored in literature.

Conflict of interest statement

The authors have declared that no conflict of interest exists

Declaration of interests

The author declares no competing interests.