Myasthenia gravis in pregnancy: An update

CURRENT DEVELOPMENTS

Myasthenia gravis in pregnancy: An update WARREN C. PLAUCHE, M.D. Nnl' Orleans, Louisimw Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by the presence of anti-acetylcholine receptor immunogl,obulin G antibodies (anti-AChRigG). This paper contrasts immunologic intervention, particularly long-term glucocorticoid therapy, with standard antichoHne$terase therapy for pregnant MG patients. Ten new cases of pregnancy in myasthenic mothers are reported. A survey of the 40 year anticholinesterase era yielded reports of 292 pregnancies in 202 myasthenia mothers. Instability qf MG during pregnancy is highfighted by gestation related exacerbations identified in 55% of cases. The puerperium appears particularly dangerous. Eight of the nine maternal deaths (4.45%) in this series were from myasthenic complications. Prenatal care and labor management are discussed. The adverse effects of fatigue, analgesic and anesthetic agents, and magnesium sulfate are emphasized. Crisis differentiation and management are outlinEid. Neonatal myasthenic syndromes and their relationship to anti-AChRigG are presented. Neonatal MG occurred in 20.2% of newborn infants in the review series. Six infants were stillborn (2.1%) and 11 died in the neonatal period (3.8%). (AM. J. OBSTET. GYNECOL. 135:691, 1979.)

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MYASTHENIA GRAVIS (MG) has been recognized in man for over 300 years. Willis 1 first published a description of this chronic debilitating neuromuscular disorder in 1672. Weakness and easy fatigability of skeletal muscles, particularly those of the extremities and face, are the hallmarks of this disease. The prevalence of MG has been estimated to be two to 10 cases per I 00,000 population with a marked predilection for young women. 2 A total of 65% to 70% ofMG cases occur in women; 20% experience onset of the disease before age 20.'l Medicine had little to offer patients suffering from MG until the first of two major discoveries led modern medicine's attack on this disease. Walker4 in 1934 and Everts·; in 1935 described control of the muscle weakness of MG with neostigmine. Neostigmine and its From the Departmmt of Obstetrics and Gynecology, Louisiana State University lWedical Crnter. Reprint request<: Dr. Warren C. Plauclui, Department of Obstetrics and G_vnecology, Louisiana State University Medical Center, 1542 Tulane Ave., New Orleans, Loui
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1979 The C. V. Mosby Co.

analogues remain cornerstones in the management of MG to the present day. Tabachnick6 described the first pregnant MG patient to receive neostigmine therapy in 1938. The second breakthrough in the understanding of MG came in 1960 when Simpson 7 and Nastuk and colleaguess introduced the concept of an autoimmune basis for MG. Strauss and associates 9 described a serum globulin fraction in MG patients which could be shown by immunoAorescent techniques to bind to striated muscle. Beutner and associates 10 characterized the factor which stained striations of skeletal muscle as a gamma globulin. Bender and associates 1 1 found that this serum gamma globulin blocked acetylcholine (AC:h) receptors at the myoneural junction in humans. Mittag and co-workers, 12 using I 125 -labeled venom of the krait, Bungarus multicinctus, which specifically binds at ACh receptors of the myoneural junction, demonstrated a reduction of over 70% in available ACh receptors in MG. High titers of anti-ACh receptor immunoglobulin (anti-AChRigG) were identified in both serum and thymic tissue of MG patients. 691

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Table I. Outcome of 10 pregnancies in patients with myasthenia gravis: Charity Hospital, New Orleans, Louisiana, 1969 to 1979 Remissions Exacerbations: Antepartum Postpartum Myasthenic crises (treated in Intensive Care Unit) Premature labor Perinatal deaths Maternal deaths

3 4* 4

2 6 3 0

*Two patients with third-trimester exacerbations experienced further exacerbation post partum.

Richman and associates"1 confirmed T cell-mediated immunity to purified ACh receptor protein in MG. They believe this immune response to be responsible for the destructive changes seen by electron microscopy at the myoneural junction in the adult form of the disease. These complex changes are described as an unfolding "simplification" of the usually complex f'oldings of the postsynaptic membraneY Richman's group 1'1 suggested that humoral antibody may also play a role in naturally occurring MG and that the disease indeed reftects two processes which are age dependent: one involving anti-AChRlgG and another related to cell-mediated immune response. The relative importance of cell-mediated versus humoral antibody responses remains unclear. Circulating immune globulins that bind to skeletal muscle acetylcholine receptor protein reduce the number of motor end plates available to bind ACh. 2 Failure to bind ACh inhibits the contractile capability of skeletal muscle but does not affect smooth muscle fibers. Uterine function is unimpaired in this disease since the stimulus for uterine muscle contraction is propagated by ephaptic conduction. 1"' The characterization of MG as an auto-immune disorder led to a change in management of many cases. Richman and colleagues 13 in their discussion of the age dependency of MG, stated that older patients seem to respond reliably to glucocorticoid therapy. The steroid response of younger patients is more unpredictable and many benefit from thymectomy with anticholinesterase drug therapy. Fenichel2 suggested that very young patients with extraocular ~IG should first receive anticholinesterase to avoid the hazards of long-term steroid therapy. He feels that ocular MG responds more reliably to prednisone than to neostigmine. He further suggested that MG patients over 10 years of age be started on a regimen of gradually increasing doses of prednisone to reach optimum control, then remain on a regimen of maintenance steroid therapy. Dalby and associates 1" reported favorably on continuous treat-

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ment of MG with prednisone. Sanders and colleagues"; managed three pregnant patients with :\1(; with highdose prednisone throughout pregnancy 11ith no exacerbation of the disease and no fetal adren
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para 2 woman had well-controlled MG for 3 years prior to the present pregnancy and was maintained on a regimen of 180 mg Mestinon daily in three divided doses. A mild exacerbation of MG symptoms at 30 weeks' gestation required only dose adjustment and increased rest periods. An R pound. 2 ounce male infant was delivered with the use of local anesthesia after a SY2 hour labor. The immediate postpartum course was uneventful; however, 6 months later she was hospitalized in myasthenic crisis. The crisis was successfully overcome and MG is presently well controlled by 180 mg :Vfestinon daily.

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Course of myasthenia in pregnancy McNall and Jafarnia 17 characterized MG m pregnancv bv the statement that "the course of MG is usually not a steady state." The cases presented illustrate courses varying from complete remission to respiratory failure. A previous review of the literature encompassing the years 193R to 1964 revealed similar percentages of cases showing increase, decrease, and no change in the severity of myasthenic symptoms during the antepartum period with a slight edge to the exacerbation course. 14 One third of patients experienced postpartum exacerbations. Three maternal deaths were reported (2.4% ). Scott 1H reported that the mortality risk for myasthenic mothers bears an inverse relationship to the duration of the disease with the greatest risk in the first year and minimal risk after 7 years. He feels that postponement of pregnancy is justified in newly diagnosed MG cases. Revie\\ of the literature since our previous paper adds reports of 164 pregnancies in 113 myasthenic mothers. Antepartum exacerbations occurred in 35.4% of these pregnancies, and postpartum exacerbations occurred in 35.4%. There were 14 spontaneous and 14 "therapeutic" abortions (8.?i% each). Twelve perinatal deaths (7.3%) were reported. Maternal death occurred in six ca~es (?i.3o/c). Neonatal MG was definitely diagnosed in 22 infants and thought probable in four additional cases, for a total of 21% of liveborn infants of mvasthenic mothers.''· 17 --''" Tables I I and I II collat.e the morbidity and mortality statistics for the combined group of 292 pregnancies in 202 myasthenic mothers reported during the anticholinesterase era ( 193R to 1968). Management of MG in pregnancy.

Mg may occasionally remit after spontaneous abortion but there is no evidence that therapeutic abortion beneficially alters the course ofthis disease. 14 • 19 • 21 • 32 • 33 The use of steroids for long-term therapy of adult MG introduces the problem of the pregnant myasthenic patient on a regimen of steroids. The use of brief courses of steroids to promote pulmonary stn·fac-

Table II. Outcome of infants of 292 pregnancies in 202 myasthenic mothers Outcome Abortion: Spontaneous Therapeutic Stillbirth Neonatal deaths Live-born .Veonatal myasthenia: Definite Probable

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249 44

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Table III. Outcome of 202 myasthenic mothers in 292 pregnancies % Antepartum course*: Remission Exacerbation No change Postpartum exacerbation t Maternal death

S7 131 103

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29.8 44.9 35.3 30.8 4.4

*Some patients experienced exacerbation in one trimester. remission in another. tSome patients with postpartum exacerbation had also experienced worsening of myasthenia during pregnancv.

tant development has raised the issue of diminished fetal brain cell production, possiblv related to inhibition of the enzyme thymidine kinase.' 14 · 'l' This phenomenon, 11·hich was demonstrated in the rat fetus, has not been documented in the human.'w Steroid induction or inhibition of other fetal enzyme s1·stems is the subject of intense investigation at present. Greengaard17 described abnormalities of carbohydrate metabolism competence in rats exposed to steroids in utero. Swimming ability is reported to be lost in similarly exposed young rats. 17 Gluck3~ warned of the possibilitv of tampering with normallv synchronized sequential enzvme induction and therefore potentiallv disordering the development of various organs and behavioral patterns. Bongiovanni and McPaddena 9 and Schapiro~ 0 made excellent pleas for caution in the use of steroids in pregnancy, citing anatomic. biochemical. behavioral, and immunologic alterations related to such use. It is mv content.ion that myasthenic patients are best placed on a regimen of anticholinesterase medication and weaned from steroid therapy before pregnancy is contemplated. If the disease remains stable on this program. pregnancy can be expected to progress with relative safety. The patient must understand the possibility of exacerbation of her disease and the threat of crisis during and after pregnancy. The mvasthenic patiem who is on a rq.,>imen of steroids 1\'ht·n pregnann·

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occurs can be hospitalized for changeover to anticholinergic drug maintenance. Steroids should be reserved for pregnant myasthenic patients who are unresponsive to anticholinesterase therapy. Transient worsening of MG commonly occurs when steroids are begun. This therapy should be initiated with the patient under hospital surveillance. 16 The keys to prenatal management of MG remain increased rest, prompt treatment of infections, careful titration of cholinergic medication, and alertness for exacerbations. Anticholinesterase drugs are managed identically for pregnant and nonpregnant MG patients. Perhaps the most useful and time tested of these quaternary ammonium compounds is neostigmine.*41 Neostigmine may be initially given in doses of 15 mg every 2 to 3 hours and dosage adjusted to levels at which the patient's skeletal muscle strength is optimal. Serial recording of vital capacity or hand strength measurements is a useful guide in initial adjustment of dose. 14 · 17 Many clinicians find pyridostigminet to be a more ideal maintenance drug because of its longer duration of action (3 to .4 hours), reduced muscarinic side effects, and "smoother" control of symptoms. 41 Usual initial dosage is 60 mg every 4 to 6 hours. Dose adjustments are accomplished by first reducing the dose interval, then increasing the quantity by 15 to 30 mg per dose to optimum levels. 17 The patient should be warned that increasing drug dosage above optimum will not further increase strength but will risk a cholinergic crisis. When optimal doses are ascertained, many patients prefer pyridostigmine in "Timespan" form which may allow a full night's sleep without arising for medication. Equivalent doses are as follows: 0.5 mg intravenous neostigmine = 1.5 mg intramuscular neostigmine = 15 mg oral neostigmine = 60 mg oral pyridostigmine. 41 The appearance of a "crisis" poses a major problem in the management of myasthenic mothers. Three types of crises may befall the myasthenic patient. True myasthenic crises reflect exacerbations of the disease; cholinergic crises are precipitated by drug overdose and nonreactive crises occur when the patient develops progressive resistance to anticholinesterase medication. Articles by Osserman and Genkins41 and Hay' 9 contain comprehensive discussions of the differentiation and management of myasthenic crises. An essential point is the differentiation of true myasthenic crisis from cholinergic crisis. Both syndromes display similar progressive muscle weakness which often progresses to respiratory insufficiency. *Prostigmin, Roche Labs, Nutley, New Jersey. tMestinon, Roche Labs.

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Myasthenic crisis usually occurs in patients 1\·ith severe forms of MG. They experience sudden exacerbation of their illness or the crisis may be precipitated by intervening infection or severe emotional or physical stress. As the crisis builds, patients become unable to swallow medication and become progressively weaker. Hypoventilation, failure to clear bronchial secretions, and increasingly poor gaseous exchange result in respiratory failure! 4 Access to intensive care facilities capable of prompt and long-term support of the patient with respiratory failure is of paramount importance. Endotracheal intubation may suffice in the initial crisis phase but tracheostomy and respirator support with constant attendance to bronchial toilet are often required. Cautious increase in anticholinesterase medication may restore myasthenic control. Cholinergic crisis is characterized by tearing, ptyalism, abdominal cramps, diarrhea, nausea and vomiting, and generalized muscle weakness which may also progress to respiratory failure and death.'L 22 · 2 ' All anticholinesterase drugs must be temporarily stopped, atropine adminstered to reverse muscarinic effects, and respiratory support instituted!'' Para-amino-aldoxine* reactivates cholinesterase 17 but Osserman and Genkins41 reported unfavorable side effects, including vascular collapse. Muscarinic gastrointestinal symptoms are more characteristic of cholinergic crisis than of myasthenic exacerbation crisis but the essential differentiation is made by administering a test dose of 2 to I 0 mg of edrophonium.t. Tensilon elicits an improvement in strength and condition only in the myasthenic crisis. Nine deaths occurred among the 202 myasthenic mothers whose cases were reviewed (4.45%). One death was attributed to cholinergic overdose crisis, four to nonreactive crisis, three to exacerbation of the myasthenic state, and one death was of unknown cause. There are no reports of the use of glucocorticoids to treat the nonreactive myasthenic crisis in pregnant patients. Osserman and Genkins41 described the use of adrenocortirotropic hormone (ACTH) to induce remission in nonpregnant patients with severe myasthenia. Considerable success was reported but patients often became worse initially and strict hospital observation, respiratory support, and tracheostomies were frequently necessary. Immunosuppressive drugs such as 6-mercaptopurine, azathioprine, cyclophosphamide, and methotrexate have been tried in myasthenic crises with inconclusive results and frequent complications! 1 These drugs are contraindicated in the pregnant pa*Protopam chloride, Ayerst Labs., New York, New York. tTensilon, Roche Labs.

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tient. Plasmapheresis (plasma exchange transfusion) has recently been recommended for management of recalcitrant myasthenic crises. 16 • 44 • 45 Cautions have been expressed regarding both the cost and the efficacy of this mode of therapy. 46 Plasmapheresis has not been reported in pregnant patients. Thymectomy and thymic irradiation for MG were extensively discussed in the monographs of Simpson and associates20 and Osserman and Genkins. 41 These controversial therapeutic modalities are principally used in young patients with demonstrated thymoma and arc rarely indicated in the management of the pregnant myasthenic patient. Management of MG during labor.

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When labor begins, parenteral neostigmine is the drug of choice for myasthenic controL Oral medication is poorly absorbed and the unreliability of dosage has led to myasthenic crisis under the stress of labor. 19 Induction of labor at a time when hospital facilities are at peak efficiency should be considered. 14 MG patients are quite sensitive to sedative, narcotic, and tranquilizer medications. 17 Respiratory depression is a particular danger to be guarded against by using these agents only when necessary and then in small doses carefully budgeted to patient need and response. Magnesium sulfate is frequently used for treatment of pre-eclampsia in this country. Magnesium ion has been shown to diminish the depolarizing action of ACh, decrease the amount of transmitter substance at the motor end plate, and depress muscle membrane excitability .47 Cohen and associates 22 described a myasthenic patient with pre-eclampsia in whom a severe crisis was precipitated by the intramuscular injection of magnesium sulfate. This reaction was unresponsive to calcium ion therapy but did respond to Tensilon and atropine. Hayl 9 and Burkett and Roderique23 concur in denigrating the use of magnesium in MG patients. The choice of regional anesthesia for delivery is almost unanimous in the literature. 3 • 14 ' 17 • 19 Procaine and similar drugs do require liver and plasma cholinesterases in their hydrolytic metabolism. 19 McNall and Jafarnia 17 caution us regarding the extreme sensitivity of MG patients to curare-like drugs. Ether, chloroform, trichlorethylene, and Fluothane are said to be contraindicated in myasthenic patients. 19 · 4 '· 4 H Burkett and Roderique23 reported a case illustrating the danger of general anesthesia and curare administration in a patient with previously undiagnosed myasthenia. Delivery usually progresses without complication in MG mothers. There are many cases in the literature documenting shorter than average labors, though this is not a constant finding. 3 · 14 · 49 • :;o Instrumental assis-

tance in the second stage is recommended to lessen the mother's exertion and fatigue and to overcome diminished strength of the expulsive •·ffort due tu weakened abdominal muscles." The first three weeks of the puerperium arc particularly dangerous for the MG patient since a third of patients will experience exacerbations that may be quite sudden and severe at this time.'!. 2' 1 After delivery the patient returns to her former oral medication rygimen, often requiring a slight increase in dose because of the increased activity related to the care of her newborn infant. Regular periods of rest arc essentiaL Puerperal endometritis, breast inflammation, urinarv tract infections, and respiratory infections are special hazards requiring prompt recognition and treatment. Certain antibiotics (kanamycin, neomvcin. streptomycin, colistin, and sulfonamides) mav increase mvasthenic wcakness.'11 11 Breast-feeding in myasthenic mothers poses the potential hazard of further passage of anti-AChRigC to the infant in breast milk. Osserman"' 11 arned of the passage of cholinergic drugs taken bv the mother to the infant as well as the possible transmission of a then unidentified ''curare-like substance.·· Though it was once thought that breast-feeding adversely affected the myasthenic mother, Viets and associates 1" ;,·ere unable to confirm this assertion. Gunn and Sanderson;;o reported one case of postpartum exacerbation believed due to breast-feeding, which responded lO cessation of lactation. Neonatal myasthenia

Strickroot and co-workers28 reported the first case of neonatal myasthenia in 1942. MG has been recognized for centuries but no cases were described in newborn infants until the era of anticholinesterase drug therapy. One might speculate that prior to this therapy pregnancy among patients with severe m\asthenia mav have been a rare phenomenon. FenicheP 2 distinguished several forms of myasthenia which may appear in the neonatal period. Most common is the acquired, transient neonatal nwasthenia of infants born to myasthenic mothers. The congenital form of myasthenia occurs in babies whose mothers arc free of the disease. Ophthalmoplegia and weakness of extraocular facial muscles without generalized weakness characterize this disorder. Familial infantile myasthenia cases are also associated with normal mothers, although the family history usually reveals other cases of myasthenia. These babies have generalized weakness, poor feeding, and respiratory difficulty but lack the facial muscle weakness of the congenital type. The rarest form is juvenile myasthenia. which i' identical in

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manifestation to adult myasthenia. This type is usually not manifest before 2 years of age although Osserman and associates 53 reported a case with onset in the neonatal period. Transient neonatal myasthenia results from transplacental passage of antiacetylcholine receptor antibodies from the myasthenic mother to her baby. 30 The onset of characteristic weakness in the infant may be delayed as long as 48 hours by coincident acquisition by the baby of anticholinesterase drugs given to the mother. Dunn26 described a case of neonatal myasthenia which cleared completely following exchange transfusion performed at 48 hours of age for hyperbilirubinemia. Nakao and associates/A using antihuman immunoglobulin G assays, identified anti-AChRigG in neonatal MG. High titers were found up to 12 days of life, reducing to minimal levels by day 21. This finding confirmed the long-held clinical impression that the condition lasts an average of 3 weeks, though anticholinesterase therapy is occasionally required for as long as 5 weeks. 41 In the currently reviewed group of cases, acquired neonatal myasthenia was diagnosed with certainty in 22 (17.7%) newborn infants. Four other babies were identified as being "probable" cases (3.2%).

Summary and conclusions Recent evidence confirms that the adult form of MG is an autoimmune disorder characterized by the presence of anti-AChRigG which blocks the formation of ACh at the motor end plate and causes anatomic deterioration of this structure. The end result is defective neuromuscular transmission manifested by progressive skeletal muscle weakness. Therapy of the autoimmune aspect of MG has led to trials of ACTH, glucocorticoids and immunosuppressive drugs, and plasma exchange transfusion. Glucocorticoids have found therapeutic popularity particu-

REFERENCES I. Willis, T.: DeAnima Brutorum, Oxford, 1672, Theatro Sheldoniano, p. 404. 2. Fenichel, G. M.: Clinical syndromes of myasthenia gravis in infancy and childhood, Arch. Neurol. 35:97, 1978. 3. Chambers, D. C., Hall,]. E., and Boyce, J.: Myasthenia gravis and pregnancy, Obstet. Gynecol. 29:597, 1967. 4. Walker, M. D.: Treatment of myasthenia gravis with physostigmine, Lancet 1: 1200, 1934. 5. Everts, W. H.: The treatment of myasthenia gravis by the oral administration of Prostigmin, Bull. Neurol. lnst. N. Y.4:523, 1935. 6. Tabachnick, H.: Myasthenia gravis-consideration of recent advances and influence of pregnancy. Report of case,J. A.M. A. 110:884, 1938.

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larly for treatment of ocular myasthenia and in patients over 10 years of age. The obstetrician thus must fac<' the problem of pregnant myasthenic patients on steroid therapy. A management program is recommended for the pregnant myasthenic patient consisting of increased rest periods, carefully adjusted anticholinesterase drug dosage, and vigilant attention to infections and exacerbations. Steroid therapy is not recommended at present for pregnant patients with myasthenia well-controlled because of potential risks to the fetus. Classification of various forms of crisis, their differentiation, and their management are discussed. Crises present the greatest challenge to the skill of physicians caring for MG patients. The puerperal crisis is the patient's greatest pregnancy risk. Management of myasthenia using anticholinesterase drugs during pregnancy, delivery, and the postpartum period is described. Careful consideration of sedative, anesthetic, and pre-eclamptic medications and employment of the parenteral route for anticholinesterase therapy during labor are identified as critical facets of management. The English language literature is reviewed from the beginning of anticholinesterase therapy in pregnancy to the present. The parameters of morbidity and mortality rates associated with MG are tabulated. The unpredictable course of the disease in pregnancy is emphasized. Exacerbations related to some phase of gestation occurred in 55% of reported cases. Crisis in the puerperium progressed to maternal death in 4.4% of cases. A safe outcome for the myasthenic patient contemplating pregnancy depends upon adherence to the meticulous details of MG management by both physician and patient. Immediate access to hospital facilities capable of both immediate and long-term respiratory support in crisis is imperative.

7. Simpson, ]. A.: Myasthenia gravis: A new hypothesis, Scott. Med. J. 5:419, 1960. 8. Nastuk, W. L., Plescia, 0. J., and Osserman, K. E.: Changes is serum complement activity in patients with myasthenia gravis, Proc. Soc. Exp. Bioi. Med. 1051:177, 1960. 9. Strauss, A . .J., Seegal, B. C., Hsu, K. C., et a!.: Immt~< noflorescence demonstration of a muscle binding, complement fixing, serum fixing serum globulin fraction in myasthenia gravis, Proc. Soc. Exp. Bioi. Med. 105: 184, 1960. I 0. Beutner, E. H., Witebsky, E., Rich en, D., eta!.: Studies on autoantibodies in myasthenia gravis, ]. A. M. A. 182: 4558, 1962. II. Bender, A. N., Ringel, S. P., Engel, W. K., eta!.: Myas-

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