**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.

**Keywords:** motor neuron disease, muscle atrophy, muscle weakness, general anesthesia, regional anesthesia, muscle relaxants, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA)

### **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 caseby-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 nondepolarizing 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

*Motor Neuron Disease and Delicate Anesthesia Choices – Anesthesia for Motor Neuron Disease… DOI: http://dx.doi.org/10.5772/intechopen.113276*

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 remifentanilinduced 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.
