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Anesthetic Considerations in Patients Presenting with Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Syndrome

1997; Lippincott Williams & Wilkins; Volume: 85; Issue: 6 Linguagem: Inglês

10.1213/00000539-199712000-00041

1526-7598

Virginia A. Thompson, Joyce A. Wahr,

ATP Synthase and ATPases Research

With the passage of time and the advent of modern technology, new disease entities are constantly being described. It is inevitable that surgical procedures will be performed on patients with these diseases. The anesthetic implications, therefore, need to be addressed. We describe the anesthetic course and raise some anesthetic considerations for a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Case Report A 20-yr-old man presenting for a right cochlear implant had a medical history significant for MELAS syndrome. According to his records, his gestation, delivery, and early development had been normal. Between the ages of 1 and 5 yr, the only possible abnormality was delayed speech development. At the age of 7 yr, he was diagnosed with hearing loss. He began having episodes of dizziness and bilateral leg weakness at the age of 14 yr. Two years later, he experienced a generalized seizure. His continued neurologic deterioration led to his present condition of blindness, deafness, dementia, and severe muscle wasting. Diagnostic testing had been extensive. Blood mitochondrial deoxyribonucleic acid (mtDNA) point mutation analysis was normal for transfer ribonucleic acid leucine (tRNALeu) at positions 3243 and 3271. A normal Southern blot analysis excluded mtDNA deletions and duplications. The oxidative phosphorylation enzyme analysis on a muscle biopsy revealed low specific activities for complexes I and IV consistent with dysfunction of the respiratory chain. His surgical history was significant for two muscle biopsies. The first took place when he was 14 yr old. A review of the anesthetic record indicated that he received intravenous induction with propofol followed by nitrous oxide, oxygen, and a propofol infusion without endotracheal intubation. There were no intraoperative or postoperative events noted. According to his mother, the second biopsy took place at another center and had to be prematurely terminated. The patient was admitted to the intensive care unit, where malignant hyperthermia was excluded. No further details were known by the family, and the anesthetic record was not available. He was currently taking depakote 250 mg bid and had no known drug allergies. Physical examination revealed that he was a young male of slight stature with obvious muscle wasting and profound upper- and lower-extremity contractures. He was both blind and deaf and communicated by signing into his mother's hands. His vital signs, as well as his cardiac, pulmonary, abdominal, and airway examinations, were normal. His complete blood count, liver function tests, and serum lactic acid were normal. Because of his history of anesthetic difficulties, as well as muscle wasting and weakness, a nontriggering anesthetic technique was chosen. After midazolam premedication, anesthesia was induced with propofol and cisatracurium. Tracheal intubation was uneventful, and anesthesia was maintained with propofol and cisatracurium infusions. During the procedure, 50 micro g of fentanyl was given for analgesia, and 0.625 mg of droperidol was given to prevent postoperative nausea and vomiting. The patient was hemodynamically stable throughout, with no changes noted in temperature or electrocardiogram. At the conclusion of the procedure, approximately 3.5 h later, neostigmine and glycopyrolate were given to reverse neuromuscular blockade, and the patient was taken to the recovery room while still tracheally intubated but breathing spontaneously. Within one-half hour, the trachea was successfully extubated. The anesthetic recovery was without complication. Discussion The MELAS syndrome was first described by Pavlakis et al. [1] in 1984. This multisystem disorder is characterized clinically by stroke-like episodes; evidence of mitochondrial dysfunction in the form of lactic acidosis, ragged-red fibers, or both; and at least two of the following: focal or generalized seizures, dementia, recurrent headaches, or vomiting. A review by Hirano and Pavlakis [2] divided clinical characteristics into three categories: cardinal manifestations, frequent manifestations, and other manifestations. All six cardinal manifestations-clinical stroke, seizures, lactic acidosis, ragged-red fibers, exercise intolerance, and onset of symptoms before age 40 years-were noted in more than 90% of patients. Among the frequent manifestations, dementia (90%), normal early development (90%), and limb weakness (89%) were most common. Short stature, hemiparesis or hemianopsia, headaches, nausea or vomiting, hearing loss, and elevated cerebral spinal fluid protein were also considered frequent manifestations. The category of other manifestations included myoclonus, cerebellar signs, peripheral neuropathy, pigmentary retinopathy, ophthalmoplegia, optic atrophy, nephropathy, cardiomyopathy, Wolff-Parkinson-White electrocardiographic syndrome, hirsutism, and cutaneous purpura; these occurred less than 45% of the time. Although the clinical course is unpredictable, patients become progressively disabled and succumb to the disease or a complication directly related to the disease, most frequently respiratory failure. Laboratory values, imaging features, and pathologic findings are variable. Elevated serum and cerebrospinal fluid lactate are found in MELAS patients. Brain computerized tomography studies may demonstrate lucencies consistent with infarcts, cortical atrophy, cerebellar atrophy, and basal ganglia calcification. Muscle fibers with an abnormal proliferation of mitochondria can be detected histochemically with modified Gomori trichrome stain as ragged-red fibers. More recently, genetic testing has evolved. Three point mutations within mtDNA have been associated with MELAS, the most prominent being an A-to-G transition at nucleotide 3243 of tRNALeu, which occurs in approximately 80% of typical MELAS patients. Less than 10% of patients have a mutation at nucleotide 3271, and one patient has had a mutation at nucleotide 3291. Three other point mutations have been proposed as candidate mutations for MELAS: 3252 and 3256 in the same tRNA, and 11084 in the ND4 subunit of mtDNA. No molecular abnormality has yet been found in approximately 10% of typical MELAS patients [3]. The MELAS 3243 mutation has been shown to result in severe defects in the translation of mitochondrially encoded proteins and to reduce the capacity for oxygen consumption. However, there is no consistent correlation among genetic defect, mitochondrial biochemical derangement, and clinical manifestation. Since MELAS was first described, the clinical course, laboratory findings, and diagnostic testing have been better elucidated. However, the etiology and pathophysiologic mechanisms of the disease remain unclear. Consequently, the anesthetic implications in a patient with MELAS are unknown. Based on the clinical manifestations and case reports of patients with other mitochondrial myopathies, we had the following concerns: 1. The physical appearance, exercise intolerance, and limb weakness are indicative of muscle wasting, arousing concerns for succinylcholine-induced hyperkalemia and sensitivity to neuromuscular blocking drugs. Robertson [4] described sensitivity to d-tubocurarine in a 7-year-old boy with ocular muscular dystrophy, Lessell et al. [5] reported sensitivity to succinylcholine in a 48-year-old woman with progressive ocular myopathy, and Naguib et al. [6] demonstrated sensitivity to mivacurium in a 16-year-old boy with the diagnosis of mitochondrial myopathy. In contrast, D'Ambra et al. [7] reported a normal response to both succinylcholine and pancuronium in a patient with Kearns-Sayre syndrome. Because this issue remains controversial, it would be advisable to closely monitor neuromuscular blockade and to use drugs with a short duration of relaxation. 2. There is an association between muscle abnormalities and malignant hyperthermia. Patients described in articles by Maslow and Lisbon [8], D'Ambra et al. [7], and Burns and Shelley [9] have received triggering drugs without sequelae. However, Ohtani et al. [10] reported a case of malignant hyperthermia in a patient with mitochondrial myopathy after induction with succinylcholine. It therefore seems prudent to avoid the use of known triggering drugs. 3. In a single case report by James [11], a 56-kg male patient with ophthalmoplegia plus required only 75 mg of thiopentone for loss of eyelid reflex. The possibility of such extreme sensitivity to intravenous induction agents should be kept in mind. 4. These patients often have elevated serum lactate levels, most likely resulting from defects in the respiratory chain necessitating anaerobic metabolism of glucose. Maintenance of normal serum glucose levels, adequate oxygen balance, stable cardiovascular function, and good gas exchange should help to prevent or minimize acidosis. Electrolyte shifts as a result of lactic acidosis must also be considered. 5. Cardiac abnormalities include cardiomyopathies and conduction defects. A preoperative electrocardiogram should be considered. Electrocardiographic and blood pressure monitoring is essential throughout the anesthetic. Avoidance of drugs that depress cardiac function is advised. It may also be beneficial to have external or intravenous pacing capabilities, as well as various inotropic, chronotropic, and antiarrhythmic agents, available. 6. Because decreased ventilatory response to both hypoxia and hypercarbia (unrelated to muscle weakness) has been described [12], cautious titration of sedatives and opioids is necessary. However, our patient tolerated both narcotics and sedatives without ventilatory problems. 7. Other manifestations of concern include seizures, nephropathy, peripheral neuropathy, and sensory deprivation. Sensory deprivation is significant in that it makes communication and, therefore, psychologic preparation of the patient more difficult. For our patient, the presence of his mother during induction was believed to be beneficial. Although more information is available regarding anesthesia and mitochondrial myopathies, a MEDLINE (1966-1997) search found only one article regarding MELAS and anesthesia, published in Japanese. In an effort to further our knowledge of the anesthetic issues related to this disease entity, a MELAS Anesthesia Registry has been established at the University of Michigan. Anesthesiologists who care for patients with this disease are requested to obtain permission from the patient or guardian to forward the medical information and to forward blind copies of the anesthetic work-up and both intraoperative and postanesthesia recovery records. Information should be forwarded to Joyce A. Wahr, MD, Department of Anesthesiology, University Hospital, 1G323-0048, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0048. Further information can be obtained from Dr. Wahr at 313-936-4280 or [email protected], or on the University of Michigan Department of Anesthesiology home page at http://www.med.umich.edu/anes/melas. In this way, we can expand our knowledge of this disease, share accumulated experience as it is gained firsthand, and better understand the anesthetic implications of this disease.