The first published case series originating from the Chilean Ministry of Health comprised 6 children (median age 5 years) and 1 young adult (36 years) who underwent a range of outpatient surgical procedures, such as adenotonsillectomy or inguinal hernia repair. Following the procedures, most patients experienced delayed emergence from anesthesia, followed by neurologic sequelae including altered consciousness, abnormal limb movements, cranial nerve deficits, and dysfunction of the corticospinal tract. In most cases, neurologic symptoms were detected immediately on emergence, though their onset was delayed by up to 10 days in some patients. All patients received the volatile anesthetic gas sevoflurane and fentanyl, but many also received the intravenous anesthetic agent propofol. Subsequent neuroimaging revealed bilateral basal ganglion lesions with additional findings involving the cerebellum and deep gray matter structures, suggestive of hypoxic-ischemic encephalopathy. Of the 7 patients, 4 progressed to global cerebral edema and eventual brain death. Although most cases have occurred in children, another recently published case involving a 20-year-old woman confirms that the risk is not strictly limited to the pediatric population.

In response to heightened sensitivity, additional cases have come to light worldwide, including one involving a 6-year-old boy undergoing strabismus surgery who had previously tolerated general anesthesia in his native Venezuela without complications. Despite an uneventful procedure, he never regained consciousness after anesthesia, and neuroimaging revealed evidence of increased intracranial pressure and diffuse hypodensity of the cerebellum and bilateral basal ganglia. Although there is currently only a single reported case during ophthalmic surgery, this topic is evolving at a rapid pace.

There is increasing evidence that these complications are, in part, associated with the presence of the m.11232T>C variant in the mitochondrial gene MT-ND4 , a mutation with a probable founder effect in the Carabobo state in Venezuela. Of the 14 initially reported cases, 10 underwent genetic testing, and all carried this variant, which is extremely rare elsewhere. As more cases are recognized, additional patients are testing positive. The MT-ND4 gene encodes a subunit of complex I of the electron transport chain; importantly, this gene is maternally inherited. Because the MT-ND4 gene is integral to complex I function, the m.11232T>C variant likely impairs oxidative phosphorylation in neurons. This impairment is clinically significant because sevoflurane, an agent widely used for the induction and maintenance of general anesthesia in both children and adults, directly inhibits complex I. In patients carrying this variant, sevoflurane’s inhibition of complex I may compromise mitochondrial function, leading to suppression of mitochondrial oxygen consumption and plausibly explaining the neuroimaging findings of ischemic changes in many of these patients. ^, The selective vulnerability of the basal ganglia and deep gray matter is consistent with the well-established pattern of injury observed in other mitochondrial complex I disorders, such as Leigh syndrome, wherein structures with the highest oxidative metabolic demand are preferentially injured under conditions of impaired mitochondrial respiration.

All reported cases as of April 2026 were exposed to sevoflurane. Although propofol was co-administered in many cases, 1 study published in Anesthesiology revealed that a subset of patients with the MT-ND4 variant had previously tolerated propofol-based total intravenous anesthesia without complications, suggesting that this phenomenon may be specific to halogenated volatile anesthetics (eg, sevoflurane, isoflurane, and desflurane) rather than all inhaled anesthetics, as nitrous oxide does not seem to share this risk. This same study’s in vitro analysis also showed that cell lines with the variant demonstrated significant suppression of mitochondrial oxygen consumption when exposed to sevoflurane but not with propofol or other controls.

Current guidance, therefore, suggests the use of intravenous anesthetic agents such as propofol or ketamine as a safer alternative to volatile agents, although the risk is still considered moderate given propofol’s use in several affected cases. Furthermore, although several cases occurred during a patient’s first exposure to anesthesia, many affected patients, such as the strabismus case discussed earlier, had previously tolerated general anesthesia with volatile agents. These observations suggest that prior tolerance of volatile agents neither excludes the presence of this variant nor eliminates the risk of these neurologic complications. Therefore, neither a negative family history of anesthetic complications nor a personal history of prior general anesthesia should be considered reassuring.

This emerging clinical picture has important implications for ophthalmologists. Although ophthalmologists may be accustomed to reassuring patients based on prior anesthetic tolerance, greater caution is warranted in patients of maternal Venezuelan descent. Unlike emergency surgical settings, many ophthalmic procedures are elective in nature, providing a critical window for risk stratification and intervention. Historically, the literature on ophthalmic anesthesia has suggested that a single brief anesthetic exposure is unlikely to lead to long-term neurodevelopmental deficits in children or young adults. However, the growing recognition of this variant, particularly in the pediatric population, necessitates a reassessment of this assumption in this specific, high-risk subgroup. This reassessment aligns with a broader emphasis in the ophthalmology literature on personalizing anesthetic approaches to the individual patient.