What is the pathophysiology of nitrous oxide-induced paresthesias?

From the Guidelines

Nitrous oxide can cause paresthesias primarily through its interference with vitamin B12 metabolism, leading to demyelination and axonal degeneration in peripheral nerves and the spinal cord. The pathophysiology of nitrous oxide-induced paresthesias involves the irreversible oxidation of the cobalt ion in vitamin B12, rendering it inactive 1. This inactivation disrupts two critical pathways: methionine synthase activity and methylmalonyl-CoA mutase function, resulting in a vitamin B12 deficiency that impairs myelin formation and maintenance. The risk of developing paresthesias increases with the duration and frequency of nitrous oxide exposure, with chronic recreational users and patients receiving prolonged anesthesia being particularly vulnerable 1. Individuals with pre-existing vitamin B12 deficiency are at heightened risk.

Key Points

• Nitrous oxide irreversibly oxidizes the cobalt ion in vitamin B12, leading to a deficiency that impairs myelin formation and maintenance 1
• The resulting neurological changes manifest as paresthesias, which typically begin in the extremities and can progress proximally with continued exposure 1
• Treatment involves immediate cessation of nitrous oxide exposure and vitamin B12 supplementation, typically with intramuscular injections of 1000 mcg daily initially, then weekly until symptoms resolve
• Early intervention is crucial as prolonged neurological damage may become irreversible

Clinical Considerations

• Patients receiving nitrous oxide should be monitored for signs of paresthesias, such as tingling or numbness in the extremities
• Individuals with pre-existing vitamin B12 deficiency should be cautious when using nitrous oxide, as they are at heightened risk of developing paresthesias
• The use of nitrous oxide should be limited to the minimum effective dose and duration to minimize the risk of paresthesias and other adverse effects 1

From the Research

Pathophysiology of Nitrous Oxide and Paresthesias

• Nitrous oxide abuse can lead to vitamin B12 deficiency, which presents with neurological complications, including paresthesias, ataxia, and muscle weakness 2, 3, 4.
• The mechanism of vitamin B12 deficiency is due to the inactivation of the vitamin B12-dependent enzyme, methionine synthase, by nitrous oxide 5, 6.
• Prolonged recreational use of nitrous oxide can cause symptoms of euphoria and analgesia, but also leads to neurologic complaints secondary to an evoked vitamin B12 deficiency 4.
• The risk of developing peripheral neuropathy and paresthesias is dose-dependent, with heavy users being at a higher risk 6.
• Diagnostic challenges include establishing a diagnosis of vitamin B12 deficiency, as biochemical findings may not always be straightforward, and complementary testing, such as MRI, may be necessary 2.
• Treatment consists of cessation of nitrous oxide abuse and supplementation with intramuscular injections of cobalamin 2.

Clinical Presentation

• Patients may present with progressive ascending paresthesias, lower extremity weakness, and ataxia 3.
• Paresthesias can progress to peripheral neuropathy and megaloblastic anemia if left untreated 5.
• MRI may reveal a longitudinally extensive myelopathy, typically involving the dorsal columns of the cervical cord 2.

Risk Factors

• Recreational use of nitrous oxide is a significant risk factor for developing vitamin B12 deficiency and paresthesias 5, 6.
• Heavy or sustained use of nitrous oxide increases the risk of developing neurological and hematological effects associated with vitamin B12 deficiency 5.
• Age and gender may influence the association between dose and paresthesias 6.