Although metabolic disorders are uncommon causes of delayed recovery after an anesthetic procedure, it should be considered when unexpected complications arise during and after the anesthetic act. When providing anesthesia to a patient with a mitochondrial disorder, the physician should explain the disease’s complexity and the severe complications and fatal or unpredictable outcomes due to the anesthetic procedure11. In this case, a post-mortem mitochondrial genome evaluation showed a homoplasmic variant of the MT-ND4 gene, in which all mitochondria had the muted gene. Hence, this could be related to the presentation age and outcome, although no surgical stress was present, and no significant hemodynamic changes were observed during the procedure. Even though the patient only manifested acute SNHL and had no positive histological findings, she manifested MELAS symptoms. Typically, MELAS symptoms debuts at early stages; however, onset symptoms may present at age 40 year 11.
Mitochondrial diseases affect the production of energy due to the impairment in the oxidative phosphorylation system2. MELAS is a congenital disease, which is maternally inherited and affects mitochondria and primarily high-energy-demand tissues and organs such as the brain and muscles1,12. The missense mutation, in which there is an adenine to guanine transition at point 3243 of the mitochondrial genome, is the most frequent mutation observed in MELAS13 with a global prevalence of one in 4000 cases reported12 or 236 in 100,000 people14. Usual clinical manifestations include encephalomyopathy, lactic acidosis, and stroke-like episodes with a wide range of presentation; it may even be clinically silent15. Ragged-red fibers, heat CT with radiological signs of stroke, and high levels of lactate are considered diagnostic11.
In this case, a post-mortem mitochondrial genome evaluation was conducted. The patient had a homoplasmic variant of the MT-ND4 gene, in which all mitochondria had the muted gene. Hence, this could be related to the presentation age and outcome, although no surgical stress was present and no significant hemodynamic changes were observed during the procedure. The most common clinical manifestations are migraine, vomit, muscle weakness, and dementia, whereas the least frequent are peripheral neuropathy and functional heart abnormalities11. Although this patient has not presented other symptoms until the neurological manifestation, some reports describe other neurological symptoms in different moments such as hearing loss impairment after age 50 year, acute cortical deafness in an 11 year-old boy16, other stroke-like episodes, hemiplegia, epilepsy, migraine, diabetes, and delay in psychomotor development)17, there are few cases with asymmetrical hearing loss 18 that would allow its suspicion (Table 1).
Thus, when unexpected events occur after anesthesia: patient factors, anesthetic act considerations, or metabolic and pharmacological conditions should be acknowledged as the causes of the delayed patient awakening. Especially in patients with no anesthetic history or diagnostic suspicion related to metabolic disorders, non-diagnosed underlying causes; and in the pediatric population, consider metabolic and medical errors10. Although multiple anesthetic techniques are described (Table 1) in patients with mitochondrial diseases with good outcomes 9,19, patients may present unforeseen severe complications during or after the anesthetic act. Consequently, patients with mitochondrial disease may have an increased risk of complications secondary to surgical stress and anesthesia due to failure, cardiac depression, cardiac conduction defects, and dysphagia. However, almost every anesthetic depresses mitochondrial function, especially volatile anesthetics and propofol, even at usually used doses in healthy patients 19 by blocking different complexes of the electron transport chain. The I and IV complex and acylcarnitine transferase enzyme inhibition20 causes a deviation of energy production into the anaerobic cycle, producing lactate accumulation into the bloodstream1. Furthermore, mitochondrial proliferation has been linked to the proliferation of smooth muscle cells of the microvasculature, causing an arginine and citrulline deficit, reflected in nitric oxide deficiency, promoting oxidative stress and stroke-like episodes. Consequently, the exposition in these components may have triggered the clinical manifestations observed in this patient.19. Consequently, the exposition in these components may have triggered the clinical manifestations observed in this patient.
Although the risk of anesthesia has been established, a specific recommendation in this type of patient has not yet been published. The outcomes seen in each individual are probably explained by the basal metabolic affection of the patient. The anesthetic considerations described in patients with a mitochondrial disorder are based on interventions that avoid metabolic stress in any way, such as; the prevention of prolonged fasting, avoiding hypovolemia and hypoglycemia, minimizing the use of Ringer’s lactate because of hyperlactatemia, avoiding tourniquets and pressure points to minimize low perfusion and oxygenation areas and avoiding abrupt changes in body temperature, cautious titration of anesthetics to prevent abrupt hemodynamic changes and interventions to prevent nausea, and postoperative vomit, as well as multimodal pain management19. Although we may have used all these actions during this patient’s procedure, there were fatal and unexpected outcomes during the postanesthetic recovery, as previously reported in the literature9 that we could not foresee.
Mitochondrially encoded nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 4 (MT-ND4). Subunit fourth is one of the seven mitochondrial DNAs (mtDNAs) encoding MTND1-6. This gene complex includes approximately 41 polypeptides of respiratory complex I. Complex I accepts electrons from NADH and transfers them to ubiquinone (coenzyme Q10) and uses the energy released to pump protons out across the mitochondrial inner membrane 21. Post-mortem genomic analysis in our patient reveals a novel missense variant in MT-ND4: m.11232T > C, which is likely pathogenic. This variant affects the fourth transmembrane domain of the protein due to an amino acid substitution of leucine to proline at 158 position (L158P). We analyzed the hydrophobicity affection by the change in the mutant protein, finding a decline in the hydrophobicity of the transmembrane domain 22, which might result in altered folding and insertion of the protein 23. Additionally, this gene is highly expressed in the most affected tissues of MELAS (brain, endocrine tissue, lung, small intestine, heart, muscle, and kidney) according to the GTEx significant expression 24, which might be correlated with the phenotype observed in the present case and in others reported in the literature (Table 1 and Fig. 1).
Neuroimaging plays an essential role in diagnosing MELAS as it may confirm or differentiate from other similar clinical presentations. Usually, head computed tomography (CT) is the initial study when a stroke is suspected. Two different cortical and subcortical lesions simulate an ischemic event and are located in the parietal, temporal, and occipital lobes; the other lesion reported in the deep white matter compromises highly basal ganglia and thalamus and showing in some cases basal ganglia calcification 25,26. Head computed tomography (CT) is usually the initial study when an acute stroke is suspected, in which hypodensities are present, and it may show bilateral basal ganglia calcification frequently observed in these cases25. However, head MRI is the gold standard 25–27 showing hyperattenuating lesions in T2 and Fluid Attenuated Inversion (FLAIR) in cortical and basal ganglia are present in unifocal or multifocal areas; it may also start in one territory, and in a lapse of weeks, it may migrate to a different one. Variable presentation in diffusion sequences are observed, which may show vasogenic vasospasms, and the Apparent Diffusion Coefficient (ADC) is predominantly facilitated. Still, high metabolic areas with prolonged time of evolution may restring, which traduces into vasogenic edema. These cases correlate with greater severity and worse prognosis 25–28.
Gangliobasal impairment and hypoattenuation in CT starts with the globus pallidus, caudate nuclei, and putamen. In MRI, hyperintensities in T1 sequence and hypoattenuation in T2 are also present. This compromise is observed in other mitochondrial diseases such as Leigh syndrome. Other compromises in the occipital white matter and cerebral atrophic in posterior fossa have been reported and in a fewer frequency, these impairments are seen in the cerebral hemispheres. Perfusion imaging in MELAS, besides stroke-like episodes, show hypoperfusion in the perfusion maps with prolonged median transit time, cerebral blood volume, and cerebral blood flow27–29.
Spectroscopy may help with the diagnosis because it shows a slight decrease in the N–acetyl–aspartate peak, reflecting a reduction of the neuronal population without significant changes in the choline (Cho) and creatine (Cr) peaks. Thus, the significant difference is evident with the double lactate peak in an intermediate time eco (TE: 135–144 ms). These changes are similar to those observed in acute ischemic lesions. However, in patients with MELAS, brains analyzed via spectroscopy showed a lactate increase that suggests anaerobic metabolism and global acidosis. They’re also related to lactic acid levels in spectroscopy with the illness’s severity and lower supervivency27–29. In this case, this finding was present in the ganglia basal nuclei and the posterior fossa with diffusion restriction, with no enhancement, and with an increase in the perfusion sequences in the ganglia basal nuclei and posterior fossa with lactate increase and double-peak as previously reported in the literature.
Before anesthetic induction, clinicians raised no alarms regarding the possibility of a mitochondrial disease because the clinical manifestation did not allow to suspect it only with its presentation. Therefore, this case report adds on to the previously reported cases with successful, fatal, or unpredicted outcomes, which, as a suggestive clinic manifestation was not present, could not be foreseen before the anesthetic act. Acute SNHL might be a sign of alarm for MELAS, as observed in other studies (Table 1). Patients with MELAS have an increased risk of developing cardiac peri-operatory dysrhythmias and myocardial dysfunction and have increased pre-existing cardiac conduction defects, especially atrioventricular and branch blocks. They mainly show electrocardiographic changes that affect PR interval and supraventricular tachycardia (Table 1). Additionally, patients with MELAS often present electrolytic disturbances such as hyponatremia and hyperkalemia associated with a high risk of developing metabolic acidosis during the peri-operatory period. The multi-organ involvement in this pathology increases the risk of suffering multiple peri-operatory complications 13,30,31 (Table 1).
To conclude, mitochondrial diseases are heterogeneous disorders with wide clinical variability in the presentation dependent on the mutated genome’s severity and the tissue threshold to manifest clinically for each individual. The anesthetic considerations of patients with mitochondrial diseases rely on the anesthesiologist’s need to prevent metabolic stress secondary to the surgical and anesthetic act. In most cases, clinicians cannot predict the response to anesthetic exposure. Finally, although these alterations present a considerable incidence and prevalence, national health care programs should include public health policies such as neonatal screening in the future.