Myasthenia gravis: Case report and analysis CLEMENT J. HANSON, o.o. Crailsheim, West Germany

The abnormal muscular fatigability that characterizes myasthenia gravis may be distinguished from that associated with other neural and muscular diseases by the resolution of weakness after rest, exacerbation after repetitive movement, the muscles preferred, and the reversal of symptoms by anticholinesterase drugs. The disorder affects children in about 20 percent of cases and may be seen in the offspring of mothers with the condition. When anticholinesterase agents, steroids, and thymectomy are not effective, drainage of the thoracic duct, plasmapheresis, and administration of immunosuppressive drugs may be helpful.

Myasthenia gravis is a disorder characterized by fatigability of muscle after repeated or sustained activity and restoration offunction after rest or ad­ministration of an anticholinesterase drug. Its in­cidence has been estimated to be between 2 and 10 per 100,000 population, with onset before age 20 in 20 percent of cases. 1

There are four recognized clinical entities in the childhood period:

The transient neonatal form affects infants born of myasthenic mothers and is manifested as tran­sient weakness in the neonatal period. About 12 percent of infants of myasthenic mothers are af­fected.2 In 78 percent of these, symptoms appear

· within several hours of birth and persist for a mean duration of 18 days. Symptoms include fati­gability of sucking, hypotonia, and weak cry. Death may occur if adequate treatment is delayed. Respiration and feeding must be supported until spontaneous resolution of symptoms.

The infantile or congenital form is rare. It af­fects infants born of nonmyasthenic mothers, and symptoms appear after the newborn period but within the first 2 years of life. Symptoms include

Myasthenia gravis

symmetric ophthalmoplegia, oculomotor muscle palsies, facial weakness, accumulation of pharyn­geal secretions, and occasional progression of symptoms to generalized weakness. Anticholines­terase drugs have been helpful in treatment of weakness of facial and skeletal muscles, but are of limited value in reversing the ophthalmoplegia.

A familial infantile form affects infants of non­myasthenic mothers and manifests itself by severe respiratory and feeding difficulties at birth. There is no evidence of limitation in extraocular func­tion. It differs from the congenital form in the lack of ophthalmoplegia and occasional spontaneous re­mission.3 It has the highest mortality rate among forms seen in the newborn. Treatment involves use of anticholinesterase drugs.

The juvenile form has its onset after age 10 in 75 percent of cases.4 Girls are affected four times as often as boys. The onset of symptoms usually is in­sidious, but they may develop acutely after a fe­brile illness, the so-called myasthenic crisis. Most frequently the presenting symptoms are eyelid ptosis with or without ophthalmoplegia. In many cases weakness of muscle groups in the face, those in speech or swallowing, or the muscles of the neck, trunk, and limbs develops.

Report of case A 16-year-old white girl came to the pediatric neurology clinic in October 1978 with complaints of recent onset of slurring of speech, jaw fatigue during chewing, eyelid ptosis late in the day, dysphagia, and early tiring when she played the piano. She did not recall previous epi­sodes of this complaint. She was a high school student with above average grades.

Her past medical history included mumps, measles, and varicella. She had had an uncomplicated tonsillecto­my at age 6 years. She had not experienced any recent or past diplopia. There was no family history of muscle dis­ease. Her parents were both living and in good health. She said she did not use tobacco or alcohol. Her 14-year­old sister was in good health.

Physical examination showed her to be alert, well ori­ented and slender, with a nasal quality to her voice. Dif­ficulty in enunciating consonants produced slurring. Her blood pressure was 102/84 mm. Hg, her weight 95% pounds, her height 65 Y4 inches, and her temperature 98.8 F. Significant observations were inability to close the eyes completely, difficulty in smiling broadly, show­ing the teeth, and wrinkling the forehead, decreased

378175

movement of the soft palate, and inability to lift the

tongue to the roof of the mouth. Manual muscle testing

of grip strength showed gradually increasing weakness

after five contractions. Otherwise, the physical exami­

nation was unremarkable. The complete blood count, chemical studies (SMA-20),

urinalysis, and x-ray study of the chest showed no ab­

normality, and an electromyogram of proximal muscles

was normal. The Tensilon test (8 mg. given intravenous­

ly) produced marked improvement in symptoms after 1

minute. Mestinon (pyridostigmine), 60 mg. orally four times a

day, was prescribed. Over the next several months the

patient was followed in the outpatient neurology clinic.

There was considerable improvement in hand weakness

but little change in slurring of speech or jaw fatigue dur­

ing chewing. Mestinon was gradually increased to 180

mg. four times a day. Reevaluation in March- 19.'79 revealed-persistence of

slurred speech, eyelid ptosis, inability to close the eyes

tightly, and diminishing hand grip strength after re­

peated contractions. The patient was referred to a tho­

racic surgeon for thymectomy. At admission for thymectomy on April16, 1979, labo­

ratory studies gave normal results. With the patient un­

der general anesthesia, thymectomy was performed by

median stemotomy on April19. The patient was kept in

surgical intensive care for 24 hours and then transferred

to the ward. On April 22 a small area of pneumothorax

developed at the right apex after removal of the medias­

tinal tube. This resolved without treatment over several

days. Facial weakness and slurred speech persisted, and

Mestinon was continued. Pathologic examination of the

surgical specimen showed a normal-appearing thymus

without evidence of microscopic abnormality or thy­

moma. The patient was discharged April 24.

On April 30 she was readmitted for initiation of ster­

oid therapy. At that time she said that all her preoper­

ative symptoms persisted. Physical examination showed

weakness of ocular and facial muscles and slurred nasal

speech. Measurement of thyroid in the serum, complete

blood count and chemical studies (SMA-20), urinalysis,

cultures of urine, and an x-ray film of the chest gave nor­

mal results. Prednisone in a dose of 80 mg. orally every

moming with antacids was prescribed. Over the next

several days there was some improvement in dysarth­

ria. Pulmonary function tests showed a mild decrease in

forced vital capacity. She was instructed to take Mes­

tinon 120 mg. every 6 hours as needed for acute symp­

toms, but required only 60 to 120 mg. per day. She was

sent home May 9 on these dosages.

She was followed as an outpatient through the pediat­

ric neurology clinic over the next several months. After

several weeks prednisone was decreased gradually to 80

mg. every other day. Serial measurements of hematocrit

and serum electrolytes were made and remained nor­

mal. Further tapering of prednisone led to an, exacerba­

tion of dysarthria and facial weakness by September

1979, and the dose was increased to 80 mg. daily. By No­

vember cushingoid fa:cies was evident, and the patient

began complaining of pain in the left shoulder and left

379176

ankle. X-ray examination showed mild osteoporosis of

these areas. The prednisone was decreased to 80 mg. ev­

ery other day. At the time of this report mild dysarthria

and facial weakness persisted.

Comment This case demonstrates the slowly progressive

clinical course of juvenile myasthenia, with its

marked fluctuations and tendency to relapse and

remission. Management was difficult, and the pa­

tient was unable to lead a near-normal life despite

administration of the recommended first-line drug

and surgical therapy.

Clinical manifestations

The clinical presentations of juvenile myasthenia

vary widely. They depend on the age of the child.

- Infants may demonstrate fat-igability of sucking,

hypotonia, weak cry, accumulation of airway se­

cretions, facial weakness, poor feeding, eyelid pto­

sis, weakness of extraocular muscles, and occa­

sional generalized weakness. Symptoms may

appear within hours of birth, as in the transient

neonatal type, or not until the second year of life,

as in the persistent neonatal type. Older children initially have ptosis of the eyelids

with or without weakness of extraocular muscles.

Symptoms may progress to involve the muscle

groups of the face, those used in speech and in

swallowing, and those of the extremities. Proximal

limb muscles are affected more than distal ones,

and the upper limbs more than the lower limbs. In

the most severe forms of juvenile myasthenia

there may be weakness of virtually all muscles.

The pathognomonic features of this weakness are

its exacerbation on repetitive movement and its

resolution after rest. The diagnosis is confirmed by the striking re­

sponse to anticholinesterase drugs. A pharmacolog­

ic method of diagnosis involves intravenous injec­

tion of0.2 mg. ofTensilon (edrophonium chloride)

per kilogram. This produces reversal of symptoms

within 1 minute, an effect which lasts up to 10

minutes. Alternatively neostigmine may b.e given

intramuscularly in a dose of 0.04 mg. per kilo­

gram. This produces reversal of symptoms in 10 or

15 minutes. Atropine may be used to treat side ef­

fects.

Pathophysiology .

Myasthenia is an autoimmune disease resulting

from a localized defect in neuromuscular transmis­

sion at the neuromuscular junction. Eighty-seven

percent of patients with myasthenia have been

shown by an immunoprecipitation technique5 to

have antibodies to acetylcholine receptors. More-

Feb. 1982/J ourna l of AONvol. 81/no. 6

over, immunoglobulin G and the C3 component of the complement system have been visualized at the postsynaptic membrane by the use ofimmuno­pharmacologic techniques. 6 The antibody to ace­tylcholine receptor attaches near the active bind­ing site,7 producing steric hindrance, so that acetylcholine cannot attach to its end-plate recep­tors. Myasthenia has been observed in association with other diseases presumed to be of autoimmune origin. Elias and Appel8 estimated that more than 5 percent of myasthenic patients may have an as­sociated endocrine disease in which autoimmunity plays an important role and cited the study by Os­serman and associates9 of the incidence of thyroid disease in myasthenia gravis.

Differential diagnosis Myasthenia gravis, one of several diseases· affect­ing the neuromuscular junction, must be distin­guished from other neuropathies and muscular disorders, all of which may appear as muscular weakness in children. Among the possibilities are anterior hom cell diseases, polyneuropathies, mononeuropathies, and intrinsic muscle diseases. The physician should eliminate the possibility of these other diseases through appropriate history taking and physical examination. The striking features of myasthenia include the resolution of the weakness after rest, exacerbation after repet­itive movement, propensity to involvement of the ocular, facial, trunk, and proximal limb muscles, and immediate reversal of symptoms after admin­istration ofTensilon or neostigmine.

Two other neuromuscular junction disorders may mimic myasthenia. One disorder has been caused by a number of antibiotics. These disturb neuromuscular transmission and cause marked generalized weakness. Neomycin, streptomycin, dihydrostreptomycin, kanamycin sulfate, poly­myxin B sulfate, bacitracin, colistin sulfate, 10 and lincomycin hydrochloride monohydrate1 have been implicated.

The other disorder has been caused by ingestion of spores of Clostridium botulinum, which produce a toxin which interferes with neuromuscular and autonomic synaptic transmission. Fenichel1 said that affected infants are believed to have ingested the spores or vegetative cells which colonize the in­testinal tract and produce the toxin in situ. Botu­lism may be the cause of undiagnosed transient hypotonia in infancy in many cases.

Treatment Anticholinesterase agents provide the first line of treatment for myasthenia.11 Pyridostigmine (Mes­tinon) is the most frequently used oral agent and

Myasthenia gravis

begins to act in from 10 to 30 minutes, with a peak effect in 2 hours, and continued action for 4 hours. It is given in a dose of 1.0 mg. per kilogram by mouth every 4 hours. Neostigmine may be used in a dose of0.3 mg. per kilogram every 3 hours. These agents have adverse effects, however. Excessive doses can cause increased weakness, 1·11 and long­term use has been shown12 to have an adverse ef­fect on the neuromuscular junction itself by de­creasing acetylcholine receptors, damaging post­synaptic folds, and reducing amplitude of end­plate potentials. Many myasthenic patients need additional therapy.

More than 85 percent of patients with myas­thenia have abnormalities of the thymus. Of these, 15 percent have thymomas and 70 percent have histologic hyperplasia. 13 Thymectomy has been shown14·15 to produce clinical improvement in from 57 to 86 percent of patients and induce remis­sion in from 20 to 36 percent. The most widely ac­cepted indication for surgery is thymoma, but thy­mectomy may be done for patients without thymoma if medication, including steroids, does not produce a response, and some physicians have advocated it for all patients with generalized symptoms. Improvement after surgery may take as long as 10 years, and many patients continue to need drug therapy after surgery.

Most myasthenic patients show clinical im­provement during oral administration of corticos­teroids. The indication for steroid therapy is fail­ure to respond adequately to thymectomy or anticholinesterase medication. It may be given also in conjunction with thymectomy, since clini­cal improvement after surgery often is delayed. Beginning steroid therapy with high doses (from 10 to 100 mg. daily) of prednisone has been report­ed16 to cause exacerbation of weakness in some cases. To avoid this problem, treatment may be be­gun with a relatively small dose (25 mg. daily) of prednisone and the amount increased gradual­ly.1·11 As the condition improves on steroids, anti­cholinesterase medication can be decreased ac­cordingly.

Immunosuppressive drugs, such as 6-mercapto­purine11 and azathioprine, 17 are helpful when the condition does not respond to thymectomy and steroids. Plasmapheresis and thoracic duct drain­age have been reported to be helpful for resistant disease.8

•11

1. Fenichel, G.M.: Clinical syndromes of myasthenia in infancy and childhood. Arch Neurol35:97-103, Feb 78 2. Namba, T. , Brown, S.B., and Grob, D.: Neonatal myasthenia gravis. Report of two cases and review of the literature. Pediatrics 45:488-504, Mar70 3. Conomy, J.P., Levinsohn, M. , and Fanaroff, A.: Familial infantile

380/77

myasthenia gravis. A cause of sudden death in young children. J Pediatr

87:428-30, Sep 75

4. Millichap, J .G., and Dodge, P.R. : Diagnosis and treatment of myas­

thenia gravis in infancy, childhood, and adolescence. Neurology

10:1007-14, Nov 60

5. Lindstrom, J .M., eta!.: Antibody to acetylcholine in myasthenia gra­

vis. Prevalence, clinical correlates, and diagnostic value. Neurology

26:1054-9, Nov 76

6. Engel, A.G., Lambert, E.H., and Howard, F.M., Jr.: Immune com­

plexes (IgG and C3) at the motor end-plate in myasthenia gravis. Ultra­

structural and light microscopic localization and electrophysiologic cor­

relations. Mayo Clin Proc 52:267-80, May 67

7. Lennon, V.A.: Immunology of the acetylcholine receptor. Immunol

Commun 5:323-44, 1976

8. Elias, S.B., and Appel, S.H.: Current concepts of pathogenesis and

treatment of myasthenia gravis. Med Clin North Am 63:745-57, Jul 79

9. Osserman, K.E., Tsairis, P ., and Weiner, L.B. : Myasthenia gravis and

thyroid disease, clinical and immunological correlation. Mt Sinai J Med

NY 34:469-83, Sep-Oct 67

10. McQuillen, M.P., Cantor, H.E. , and O'Rourke, J.R. : Myasthenic

syndromes associated with antibiotics. Arch Neurol18:402-15, Apr 68

11. Drachman, D.P.: Myasthenia gravis (second of two parts). N Eng! J

Med 198:186-93, 26 Jan 78

12. Engel, A.G~mbert, E.H., and Santa, T~:-Study-oflong-term anti­

cholinesterase therapy. Effects on neuromuscular transmission and on

motor end-plate fine structure. Neurology 23:1273-81, Dec 73

381178

13. Appel, S.H., Almon, R.R. , and Levy, N.: Acetylcholine receptor anti­

bodies in myasthenia gravis. N Eng! J Med 293:760-1, 9 Oct 75

14. Buckingham, J .M., et al.: The value of thymectomy in myasthenia

gravis. A computer-assisted matched study. Ann Surg 184:453-8, Oct 76

15. Fraser, K., Simpson, J.A., and Crawford, J.: The place of surgery in

the treatment of myasthenia gravis. Br J Surg 65:301-4, May 78

16. Jenkins, R.B. : Treatment of myasthenia gravis with prednisone.

Lancet 1:765-7, 8 Apr 72

17. Matell, G., et al.: Effects of some immunosuppressive procedures on

myasthenia gravis. Ann NY Acad Sci 274:659-76

Drachman, D.B.: Myasthenia gravis (first of two parts). N Eng! J Med

298:136-42, 19Jan 78

Accepted for publication in March 1981. Updating, as neces­

sary, has been done by the author.

At the time this paper was written, Dr. Hanson was a resident

in pediatrics at Walter Reed Army Medical Center, Washing­

ton, D.C. He is now a general medical officer and health clinic

commander, U.S. Army Health Clinic, Crailsheim, Federal Re­

public ofWest Germany.

Dr. Hanson, Box 858, 16th Med. Det., APO, New York 09751.

Feb. 1982/Joumal of AOA/vol. 81/no. 6

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CORGARD® nadolol tablets

40 mg, 80 mg, 120 mg, 160 mg scored tablets

CORGARJ)® TABLETS greater (on a mglkg basis) than maximum indicated human dose; no teratogenic poten-Nadolol Tablets tial was seen in any of these species. There are no well-controlled studies in pregnant DESCRIP110N: Corgard (nadolol) is a synthetic nonselective beta-adrenergic receptor women; therefore, use nadolol in pregrtant women only if potential benefit justifies blocking agent. potential risk to the fetus. CONTRAINDICATIONS: Bronchial asthma, sinus bradycardia and greater than frrst Nursing Mothers- It is not known whether this drug is excreted in human milk. Because degree-conduction-block,-cardiogenic.shock, and overt-cardiae-failure (see.-WARNIN<JS).--many-drugs.are.excreted in human-milk,-exercise caution-when nadolol is administered to a WARNINGS: Cardiac Failure-Sympathetic stimulation may be a vital component sup- nursing woman. Animal studies showed that nadolol is found in the milk of lactating rats. porting circulatory function in congestive heart failure, and its inhibition by beta- Pediatric Use - Safety and effectiveness in children have not been established. blockade may precipitate more severe failure. Although beta-blockers should be avoided ADVERSE REACTIONS: Most adverse effects have been mild and transient and have in overt congestive heart failure, if necessary, they can be used with caution in patients rarely required nadolol withdrawal. with a history of failure who are well-compensated, usually with digitalis and diuretics. Cardiovascular - Bradycardia with heart rates of Jess than 60 beats per minute occurs Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart commonly, and heart rates below 40 beats per minute and/ or symptomatic bradycardia muscle. IN PATIENTS WITHOUT A HISTORY OF HEART FAILURE, continued were seen in about 2 of 100 patients. Symptoms of peripheral vascular insufficiency, usually use of beta-blockers can, in some cases, lead to cardiac failure; therefore, at frrst sign or of the Raynaud type, have occurred in approximately 2 of 100 patients. Cardiac failure, symptom of heart failure, digitalize and/or give diuretics, and closely observe response, hypotension, and rhythm/conduction disturbances have each occurred in about I of 100 or discontinue nadolol (gradually if possible). patients. Single instances of first degree and third degree heart block have been reported;

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intensification of AV block is a known effect of beta-blockers (see also CONTRAIN­DICATIONS, WARNINGS, and PRECAUTIONS). Central Nervous System­Dizziness or fatigue reported in approximately 2 of 100 patients; paresthesias, sedation, and change in behavior reported in approximately 6 of HXXl patients. Respiratory -Bronchospasm reported in approximately I of HXXl patients (see CONTRAINDICA­TIONS and WARNINGS). Gastrointestinal- Nausea, diarrhea, abdominal discom­fort, constipation, vomiting, indigestion, anorexia, bloating, and flatulence each reported in I to 5 of H:XXl patients. Miscellaneous - Each of the following reported in I to 5 of HXXl patients: rash; pruritus; headache; dry mouth, eyes, or skin; impotence or decreased libido; facial swelling; weight gain; slurred speech; cough; nasal stuffmess; sweating; tinnitus; blurred vision. Although relationship to drug usage is not clear, sleep disturbances have been reported. The oculomucocutaneous syndrome associated with practolol has not been reported with nadolol.

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