Mitochondrial diseases are a heterogeneous group of metabolic disorders resulting from maternally inherited or sporadic nuclear and mitochondrial DNA mutations that disrupt energy production by the mitochondrial electron transport chain. They occur in approximately 1:5000 of the population and can affect a single organ system or multiple systems, with most causing neurologic and muscle abnormalities.1 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms (MELAS) syndrome is one of these disorders, the cardinal features of which result from a tissue ATP supply and demand mismatch in the central nervous system (CNS) and musculoskeletal system.
Although more than 30 mitochondrial DNA gene mutations have been reported to be associated with MELAS syndrome, a point mutation (m.3243A>G) in the mitochondrially encoded transfer RNA leucine 1 (MT-TL1) gene is found in approximately 80% of cases. The consequence is impaired synthesis of electron transport chain proteins in affected mitochondria and subsequent inadequate energy production to meet metabolic demands. There is a spectrum of signs and symptoms of MELAS syndrome, even in those individuals harboring the same mutation. The clinical diagnosis of MELAS syndrome requires at least 2 category A criteria (headaches associated with vomiting, seizures, hemiplegia, blindness, or focal radiologic supratentorial lesions) and 2 category B criteria (elevated lactate concentration in CNS or plasma, pathologic evidence of mitochondrial injury on muscle biopsy, and a MELAS syndrome-related gene mutation).2 The CNS ischemic lesions, which typically are unique in that they do not have obvious vascular territorial distribution, are thought to result from not only mitochondrial dysfunction but also microangiopathy and impaired nitric oxide synthesis resulting in insufficient vasodilation of the cerebral microcirculation to match neuronal demand.3–5 Thus, a secondary contribution to MELAS syndrome pathogenesis is relative tissue hypoxia. Hypoxia and inadequate ATP production are both responsible for the widespread lactic acidemia resulting from anaerobic metabolism in muscles and other major organ systems. Although the CNS and musculoskeletal systems are most affected, other manifestations include cardiomyopathies, pulmonary hypertension, gastrointestinal dysfunctions, and endocrinopathies.
We report the anesthetic management, including neuraxial blockade, of a patient with MELAS syndrome at a hospital specialized in high-risk obstetrical care. The management included treatment of the typical sequelae of the MELAS syndrome and obstetrical and surgical care during severe postpartum hemorrhage and multiple postoperative complications.
Publication of this report was fully discussed with the patient, and written permission was obtained.
A 36-year-old, gravida 2 para 0 woman was admitted to the hospital at 22 weeks of gestational age. She had signs and symptoms of preeclampsia, MELAS syndrome, and type I diabetes mellitus. She exhibited exertional dyspnea, complete bilateral hearing loss, and anxiety. The patient was diagnosed with MELAS syndrome at 14 years of age via muscle biopsy, and had one previous CNS manifestation—a spontaneously resolving stroke-like event at the age of 23 years. She had a previous general anesthetic for an appendectomy approximately 14 years earlier with no known adverse events and an obstetric history of previous miscarriage at 14 weeks 4 years ago. Notably, she had a hypoglycemic cardiac arrest requiring cardiopulmonary resuscitation 5 years earlier. At admission, she was on insulin pump therapy, and her medications included vitamin D and folic acid. The patient had no known allergies. The genetic service had previously recommended avoidance of lactated Ringer’s solution, aspirin, aminoglycosides, halothane, barbiturates, and other mitochondrial-toxic agents (eg, valproic acid), where possible. Both the patient’s mother and sister had been diagnosed with MELAS syndrome.
The patient was admitted to the high-risk antenatal ward with hypertension (blood pressure [BP] 186/97 mm Hg), proteinuria, and an elevated serum uric acid concentration of 365 μmol/L (normal range 140–360 μmol/L). On the initial examination, she appeared anxious with a difficult airway (Mallampati score 4, restricted mouth opening, decreased thyromental distance, and facial edema) but with no obvious cardiorespiratory abnormalities. Platelet counts and liver enzymes were normal. Hypertension was treated but refractory to labetalol, hydralazine, and nifedipine. Antenatal ultrasound revealed a live, small-for-gestational age fetus (estimated fetal weight 300–400 g) with absent end-diastolic flow in the umbilical artery and increased vascular resistance in the uterine artery. Repeat blood test revealed developing metabolic derangements in the mother—notably marked hyperkalemia with a K+ of 7.0 mmol/L and metabolic acidosis (HCO3 = 15 mEq/L). The right radial artery was cannulated for continuous hemodynamic monitoring, and 1 g of calcium gluconate was administered intravenously for myocardial membrane stabilization. Intravenous administration of insulin, glucose, and bicarbonate and inhalation of salbutamol caused a decrease in serum potassium concentration. Despite these measures, blood glucose concentration, lactic acidosis, and hyperkalemia were difficult to control during the subsequent 36 hours (Figure 1).
Shortly thereafter, a repeat ultrasound revealed worsening fetal status consistent with impending intrauterine fetal demise. As the patient was contemplating medical induction of labor, she developed a sudden neurologic event with headache, hypertension, lip tingling, dysphasia, and limb weakness. She remained fully conscious and followed commands but developed an expressive dysphasia, unable to respond verbally to questions, or count to 10. On examination, her cranial nerves were grossly intact, but she had 0/5 power in the right upper and lower extremity (in all muscle groups), with 3/5 power in the left leg. She had bilaterally brisk knee jerks, an equivocal right plantar reflex, and a down going left plantar reflex. A differential diagnosis of eclampsia or stroke was made.
The patient was taken for urgent computed tomography of the head in consultation with the stroke team, and her refractory hypertension was treated with intravenous hydralazine in aliquots of 5 mg for a total of 20 mg and 2 g magnesium sulfate. Imaging of the head was negative for a cerebrovascular event but did reveal marked chronic cortical and cerebellar atrophy with cisterna magna enlargement (Figure 2). After spontaneous resolution of her symptoms within 20 to 30 minutes, the patient was transferred to the intensive care unit (ICU) to begin medical induction of labor with misoprostol and oxytocin for a stillborn fetus. The exact timing of the intrauterine fetal demise was unknown. She was counseled appropriately and agreed to this decision.
The patient’s metabolic condition improved, and she was transferred back to the obstetric unit with an intravenous fentanyl patient-controlled analgesia pump for management of labor pain. The stillborn fetus was delivered uneventfully; however, after delivery, the anesthesiologist was called urgently to the patient’s room, where the obstetrician was attempting manual removal of the placenta. The obstetrician reported an estimated blood loss of 300 to 500 mL during this maneuver. Arterial blood gas analysis revealed pH 7.34, Paco2 43 mm Hg, hemoglobin 98 g/L, and a serum lactate concentration of 1.4 mmol/L.
Because intravenous analgesia was inadequate, the decision was made to transfer the patient to the operating room for instrumental delivery of the placenta. The patient was both a potentially difficult intubation and difficult bag mask ventilation as the result of marked edema of the face and tongue. Despite sacral edema, neuraxial anesthesia was performed with one attempt in the lateral decubitus position with a single shot spinal. On consideration of the patient’s short stature (147 cm), concern about less predictable distribution of anesthetic, and a desire for limited rostral spread with hemodynamic stability, 10 mg of isobaric bupivacaine was administered intrathecally, resulting in effective anesthesia to the T10 dermatome. After administration of the spinal anesthetic, the patient developed persistent hypotension requiring repeated boluses of phenylephrine (0.1 mg × 12 doses) and calcium chloride 1 g to maintain a systolic BP >100 mm Hg. The spinal anesthetic was otherwise well tolerated and provided adequate anesthesia without persistent neurologic sequelae for the patient.
Delivery of the placenta resulted in a further 500-mL estimated blood loss. Intraoperatively, the patient received approximately 1.5 L of normal saline and 2 units of packed red blood cells for a decrease in hemoglobin concentration to 75 g/L. At the end of placental extraction, the patient developed copious secretions, crackles at the bases of her lungs, and increasing fraction of inspired oxygen requirements (peripheral capillary oxygen saturation 82% on room air), likely indicative of pulmonary edema. Ultrasound revealed ascites and fluid in the pouch of Morison consistent with volume overload. Oxytocin (40 U/L at approximately 120 mL/h) was continued postoperatively, and the patient was transferred back to the ICU, given her deteriorating respiratory status. A chest radiograph confirmed pulmonary edema.
Postpartum, pulmonary edema was responsive to diuresis and fluid restriction in the ICU. She did not require supportive ventilation. She continued to have labile blood glucose control, with an episode of hypoglycemia (glucose = 1.5 mmol/L) accompanied by loss of consciousness. This was treated with intravenous dextrose, and the patient recovered promptly; however, she subsequently developed ongoing vaginal bleeding requiring further transfusion and hemodynamic instability (systolic BP < 90 mm Hg) with tachycardia, thought to be related to postoperative endometritis. She required aggressive fluid resuscitation but no vasopressor support. She was treated with piperacillin/tazobactam and eventually responded well. She was discharged 25 days after her admission with oral labetalol, antibiotics, and enoxaparin. Follow-up appointment with obstetric medicine 10 days later found the patient normotensive without medication with a normal neurological examination.
We described the in-hospital course of a complicated mitochondrial disorder in pregnancy, which encompassed metabolic, neurologic, and obstetrical emergencies due, in part, to the sequelae of her disease. Our literature search identified numerous case reports and series of the obstetric and anesthetic management of MELAS syndrome.6,7 In the setting of general anesthesia, hyperkalemia, hyponatremia, and postoperative renal dysfunction (the latter following major surgery) were reported to be the most frequent complications, with otherwise good tolerance of frequently used general anesthetics as well as lactated Ringer’s solution.8 Interestingly, our case also illustrates hyperkalemia as the most severe metabolic complication. In a retrospective analysis of a cohort of women carrying the m.3243A>G mutation,6 the most common peripartum complications were premature delivery, preeclampsia, and gestational diabetes. Nevertheless, many patients underwent uneventful deliveries.
Thus, it is important to recognize that MELAS syndrome represents a continuum of diseases with varying symptomatology and complication rates. Although rare, this case confirms the observations from previous case series that the MELAS syndrome confers a high risk of both obstetrical and medical complications, including postpartum hemorrhage, pulmonary edema, new-onset neurologic symptoms, hyperkalemia, and acidosis. Two additional case reports reported pregnancy-induced worsening of CNS function in MELAS syndrome. One described new-onset neuropathy and myopathy and the other status epilepticus.9,10 Although one must anticipate peripartum deterioration of neurologic function in patients with MELAS syndrome, our particular case is on the more severe end of the spectrum.
Notably, many of the complications observed here occur in patients with severe preeclampsia, and it is unclear as to whether these metabolic derangements represented preeclampsia versus MELAS syndrome. Although the exact pathophysiology of preeclampsia and mitochondrial disease require further clarification, previous studies have demonstrated links between preeclampsia and mitochondrial dysfunction, with a reported odds ratio for preeclampsia development in patients with MELAS syndrome of 7.0.11 It has been suggested that at its core, preeclampsia results from mitochondrially derived oxidative stress, a phenomenon that would be worsened in patients with MELAS syndrome. Proteomics have revealed that preeclampsia causes placental apoptosis (evidenced by cytochrome c release and activated caspase-3) and upregulation of peroxiredoxin 3, an antioxidant protein generated in the face of reactive oxygen species.12,13 It also is possible that mitochondrial proliferation in vascular wall smooth muscle in MELAS syndrome leads to placental and cerebrovascular breakdown common to both preeclampsia and mitochondrial disorders. In our case, endotheliopathy and glycocalyx breakdown may have been further complicated by disseminated intravascular coagulation and hemodynamic instability, both of which cause capillary leak and fluid extravasation. Pregnancy-induced increase in metabolic demand and relative hemodilution may have exacerbated these derangements.
In conclusion, MELAS syndrome in pregnancy can present with profound complications. Throughout the peripartum period, close monitoring of acid–base status, electrolytes, and neurologic function are essential. Judicial fluid management also is critical, because patients can be prone to pulmonary edema and respiratory complications. Although it may be technically difficult due to edema and short stature, neuraxial anesthesia can be performed safely without risk of neurologic complication. Lastly, effective interdisciplinary cooperation is crucial for care coordination of these high-risk patients.
Name: Josh D. Bell, MD, PhD.
Contribution: This author helped compile the figures, write the manuscript, and with operative care of the patient.
Name: Kushlin Higgie, MBChB, FANZCA.
Contribution: This author helped collect the data, edit the manuscript, and with clinical care of the patient.
Name: Mital Joshi, MD, FRCPC.
Contribution: This author helped edit the manuscript, and with operative care of the patient.
Name: Joshua Rucker, MD, FRCPC.
Contribution: This author edit the manuscript, and with clinical care of the patient.
Name: Sahar Farzi, MD.
Contribution: This author helped collect the data and edit the manuscript.
Name: Naveed Siddiqui, MD, MSc.
Contribution: This author helped edit the manuscript and with clinical care of the patient.
This manuscript was handled by: Hans-Joachim Priebe, MD, FRCA, FCAI.
1. Parikh S, Goldstein A, Koenig MK, et al.Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17:689701.
2. El-Hattab AW, Adesina AM, Jones J, Scaglia FMELAS syndrome: clinical manifestations, pathogenesis, and treatment options. Mol Genet Metab. 2015;116:412.
3. El-Hattab AW, Emrick LT, Chanprasert S, Craigen WJ, Scaglia FMitochondria: role of citrulline and arginine supplementation in MELAS syndrome. Int J Biochem Cell Biol2014;48:8591.
4. El-Hattab AW, Emrick LT, Hsu JW, et al.Impaired nitric oxide production in children with MELAS syndrome and the effect of arginine and citrulline supplementation. Mol Genet Metab 2016;117:407412.
5. El-Hattab AW, Emrick LT, Williamson KC, Craigen WJ, Scaglia FThe effect of citrulline and arginine supplementation on lactic acidemia in MELAS syndrome. Meta Gene2013;1:814.
6. Maurtua M, Torres A, Ibarra V, DeBoer G, Dolak JAnesthetic management of an obstetric patient with MELAS syndrome: case report and literature review. Int J Obstet Anesth. 2008;17:370373.
7. Sasano N, Fujita Y, So M, Sobue K, Sasano H, Katsuya HAnesthetic management of a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) during laparotomy. J Anesth. 2007;21:7275.
8. Gurrieri C, Kivela JE, Bojanić K, et al.Anesthetic considerations in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: a case series. Can J Anaesth. 2011;58:751763.
9. Sikdar S, Sahni V, Miglani A, Daga MKPregnancy-precipitated status epilepticus: a rare presentation of MELAS syndrome. Neurol India. 2007;55:8284.
10. Yanagawa T, Sakaguchi H, Nakao T, et al.Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with deterioration during pregnancy. Intern Med. 1998;37:780783.
11. de Laat P, Fleuren LH, Bekker MN, Smeitink JA, Janssen MCObstetric complications in carriers of the m.3243A>G mutation, a retrospective cohort study on maternal and fetal outcome. Mitochondrion2015;25:98103.
12. Shibata E, Nanri H, Ejima K, et al.Enhancement of mitochondrial oxidative stress and up-regulation of antioxidant protein peroxiredoxin III/SP-22 in the mitochondria of human pre-eclamptic placentae. Placenta. 2003;24:698705.
13. Shi Z, Long W, Zhao C, Guo X, Shen R, Ding HComparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia. PLoS One2013;8:e64351.