Amyotrophic Lateral Sclerosis

Introduction

• ALS, otherwise known as Lou Gehrig’s disease, is one of the most common progressive neurodegenerative disorders that involves both the upper and lower motor neurons. ALS exhibits significant clinical heterogeneity and occurs in both sporadic and familial forms.^1-3
• ALS most commonly presents with signs of lower motor neuron degeneration affecting the upper extremities, but can also present as bulbar symptoms or upper motor neuron (UMN) symptoms. There is no cure currently for ALS, and treatment is focused on symptom management.
• Jean Martin Charcot was the French neurologist who first described ALS in 1869 and is otherwise known as Charcot disease in her honor.² Lou Gehrig was a famous baseball player who was diagnosed with this disease in 1939.
• Four other motor neuron diseases exist, including primary lateral sclerosis, progressive muscular atrophy, progressive bulbar palsy, and pseudobulbar palsy.
• The prognosis of ALS is poor currently, with a mean survival of 2-4 years from onset.³ Outcomes are worse in patients with early bulbar symptoms, especially when respiratory involvement occurs, with a mean survival of about 1.5 years.³

Etiology

• Like many other neurodegenerative diseases, ALS results from a combination of genetic components, environmental components, and age-related dysfunction.2 About 90-95% of cases of ALS, however, do occur sporadically.¹
• Symptoms typically first appear between the ages of 50 and 65. These symptoms include muscle cramping, twitching, and weakness, which may eventually lead to muscle impairment. In the later stages of ALS, patients can develop dyspnea, dysphagia, and ultimately respiratory weakness due to UMN involvement.^1,3 Electromyographic findings can confirm the diagnosis.

Environmental Components

• Environmental factors may contribute to the development of ALS. Previous epidemiological studies have suggested exposure to smoking, heavy metals, pesticides, solvents, and dust/fumes from different materials may be associated with the development of ALS. Most research on these risk factors is inconclusive. Physical activity has also been mentioned in many studies, and its potential link to ALS.
• Cigarette smoking is a common habit that leads to inflammation, oxidative stress, and even neurotoxicity from exposure to heavy metals and compounds. Smoking increases the probability of developing ALS, and the risk is highest in individuals who began smoking earlier in life, but does not appear to depend on smoking duration or intensity. Smoking is regarded as the most consistently reported environmental risk factor for ALS.²
• Overall, research on heavy metal exposure, particularly lead, selenium, mercury, cadmium, and iron, has produced conflicting and inconclusive results, with some experimental evidence of neurotoxicity but limited epidemiological confirmation.
• Research studies have also looked at the relationship between pesticide exposure and ALS. This link was brought to light amongst Gulf War veterans when an increased incidence of ALS was observed in this population. Specifically, organophosphate pesticides are known to cause neurological damage via inhibition of acetylcholinesterase, leading to both muscarinic side effects (salivation, lacrimation, urination, defecation, gastrointestinal cramping, and emesis) and nicotinic side effects (hypertension, muscle weakness, twitching, and muscle paralysis).
• Merwin et al. state that exposure to high doses of organophosphates can give rise to “organophosphate-induced delayed neuropathy,” which is a condition like ALS characterized by similar motor dysfunction and paralysis.6 However, no clear link has been found between organophosphate exposure and the development of ALS. Further research is needed to elucidate these risk factors and their contributions to the development of such severe medical conditions.
• Studies that examine physical activity, sports, and the development of ALS have been conducted over the past 20 years. Given that there are professional athletes who have developed ALS, studies were done to look at the relationship between physical activity, supplements, and ALS. It was concluded that while athletes do exhibit a higher risk of developing ALS than the general population, light to intense physical activity or exercise has not been shown to increase the risk of developing ALS.
• It has been shown that genes such as ciliary neurotrophic factor, leukemia inhibiting factor, and vascular endothelial growth factor, which are associated with exercise, are potential risk factors for ALS.⁵ Moreover, several studies have reported inconsistent findings regarding an increased risk of developing ALS among athletes, challenging the notion of a relationship between physical activity and ALS. Therefore, physical activity itself has not been confirmed to cause ALS. The elevated incidence observed in athletes may instead be partly explained by underlying genetic factors.

Genetic Components

• Genetics has been known to play a role in the development of ALS. Familial ALS (FALS) occurs due to mutations in specific genetic loci.2 More than 60 genes identified are linked with ALS.⁴ Genes that are known to cause FALS include: SOD1, TARDBP, FUS, ANG, OPTN, and C9orf72. SOD1 encodes superoxide dismutase, a copper/zinc ion-binding SOD. This gene accounts for 20% of cases of FALS and 5% of cases of SALS due to its cytotoxic effects on cells; its pathophysiology remains unclear. This mutation is associated with either very slow or very rapid disease progression. TARDBP encodes TAR DNA-binding protein 43, which is involved in DNA repair. This mutation accounts for approximately 5% of FALS cases. This gene is involved in gene expression and contributes to transcription, RNA splicing, and translation. In ALS, abnormally ubiquitinated TDP-43 forms inclusions in motor neurons. ANG causes about 1% of FALS, and codes for an angiogenic factor that responds to hypoxia. FUS codes for fusion in sarcoma; ANG, which codes for angiogenin, ribonuclease, and the RNAase A family.⁵
• Mutations in this gene are associated with young-onset, rapidly progressing ALS. OPTN codes for optineurin, a gene implicated in open-angle glaucoma; mutations in this gene disrupt the inhibition of nuclear factor kappa-beta activation, altering the distribution of OPTN in the cytoplasm.² C9orf72 is normally involved in RNA processing, protein production, and transport. Mutations in this gene are associated with a combination of ALS and frontotemporal dementia.²

Pathophysiology and Clinical Features

• ALS affects the entire motor neuron system, with degeneration occurring at both the upper and lower motor neurons. The UMNs are located in the precentral gyrus and prefrontal cortex. The lower motor neurons in the anterior horn of the spinal cord and brainstem are also affected. There have been multiple molecular pathways associated with ALS, involving failure of proteostasis, excitotoxicity, neuroinflammation, mitochondrial toxicity and oxidative stress, defective neurofilaments, and abnormal RNA processing and protein aggregation.
• Aggregates of proteins and their oligomeric complexes disrupt cellular homeostasis and function, causing cellular stress. When the cell is overloaded with misfolded proteins, they are targeted for ubiquitination and subsequent degradation. Many ALS genes are involved in this pathway and function as key components of ALS pathogenesis. Genes like TDP-4, FUS and ANG are responsible for dysregulation of RNA metabolism in ALS. Mutations in these genes can cause transcriptome abnormalities, including disruption of transcription and splicing, and cytoplasmic mislocalization, ultimately leading to cell toxicity.²

Early Clinical Features

• ALS is characterized by progressive muscle weakness, atrophy, fasciculations, and cramps. Early symptoms typically begin focally in one limb, then spread to all extremities, and, after months to years, affect the respiratory system.
• Upper limb involvement is most commonly in the dominant hand, with thenar muscle involvement greater than hypothenar muscle involvement (commonly referred to as the split hand sign). This is due to degeneration of the lateral portion of the anterior horn of the spinal cord. In the lower limb, the anterior tibial muscle is most commonly the first muscle affected before the gastrocnemius, hamstrings, or quadriceps muscles.
• Bulbar palsy is observed in approximately 25% of patients at disease onset. Hyperreflexia, fasciculations, clonus, and muscle spasticity are also seen. Bulbar symptoms of ALS include dysarthria or dysphagia. Dysphonia is less common but can also be seen in this subtype. Early bulbar and/or respiratory symptoms are associated with worse disease prognosis.¹

Late Clinical Features

• About 15% of patients with ALS may also develop frontotemporal dementia.¹ Constipation, neurogenic bladder, and other dysautonomic symptoms are also seen late in the disease process. Severe dysphagia will lead to weight loss and malnutrition. Respiratory muscle weakness with dyspnea, hypoxia, and hypercarbia are also common late in ALS. This compromise in respiratory status commonly leads to pulmonary complications and ultimately respiratory failure, which is the main cause of death in patients with ALS.¹

• ALS is a clinically diagnosed disease, made after excluding other potential diseases that cause motor neuron dysfunction.
• Treatment for ALS is based on monitoring for disease progression, management of symptoms, prevention of complications associated with these symptoms, and mainly supportive care.
• There is little role for pharmacological intervention in this disease; some drugs help alleviate symptoms and slow disease progression. One drug used is riluzole, which is thought to slow down functional decline in patients with late-stage ALS. Riluzole is a sodium channel blocker that inhibits glutamate release in the CNS and decreases glutamate excitotoxicity. The benefits of this drug may prolong life expectancy to about 2-3 months on average. Ultimately, ALS is incurable, and median survival is approximately 3-5 years after symptom onset.¹

Anesthetic Considerations

• A variety of anesthetic considerations should be discussed prior to undergoing anesthesia in a patient with ALS. Given the heterogeneous nature of ALS, a thorough preoperative assessment should be performed, and a systematic approach to the patient’s current symptoms should be adopted. A lengthy risk-benefit discussion should occur between the physician and the patient, given that patients with ALS are at higher risk for undergoing general anesthesia. With the high risk of respiratory muscle weakness, the patient’s respiratory status must be reviewed, as postoperative ventilatory support and an intensive care unit may be necessary if extubation is not feasible.
• These patients are at a higher risk for aspiration if they experience bulbar dysfunction. Patients with bulbar dysfunction may have difficulty managing secretions, and therefore, a protected airway may be indicated. Rapid sequence intubation is often warranted to minimize the risk of aspiration. Suctioning the oral cavity multiple times during the surgery and before extubation is imperative to control copious secretions and prevent aspiration.^6,10
• Patients with preoperative respiratory involvement may exhibit exaggerated ventilatory depression with the use of neuromuscular blockade due to abnormal responses to these medications. In ALS, denervation-induced upregulation of acetylcholine receptors predisposes patients to profound hyperkalemia following administration of neuromuscular blockers; hence, succinylcholine is often avoided. Administration of depolarizing muscle relaxants can trigger neuromyotonic-like contractions, rhabdomyolysis, and severe hyperkalemia. Patients also exhibit a sensitivity to nondepolarizing neuromuscular blockers, typically requiring lower doses with risk of prolonged muscle paralysis.⁶
• The use of regional or neuraxial blocks in patients with ALS is also controversial. Neuraxial anesthesia has been found to cause exacerbations and even relapses of the disease due to needle trauma or drug toxicities. The mechanism of disease exacerbation remains unknown; however, it is hypothesized that the lack of a protective sheath around the spinal cord and demyelination can render the spinal cord more susceptible to neurotoxic effects of local anesthesia.⁶ Due to the markedly lower concentrations of local anesthetic reaching the spinal cord white matter after epidural administration, epidural anesthesia is generally favored over intrathecal approaches.
• Some patients with ALS also experience chronic pain that is largely related to immobility. Paying close attention to the patient’s positioning on the operating room table will help minimize the risk of positional injury. A postoperative pain plan can be developed based on preoperative assessment, surgical type, surgical duration, and postoperative expectations.⁹
• There are no official guidelines for anesthetizing patients with ALS. Patients and physicians should discuss risks and benefits at an individualized approach, given the heterogeneity and variations in presentations of ALS.