Myasthenia gravis and Lambert- Eaton myasthenic syndrome are causes of acquired extraocular muscle weakness and ptosis. Exacerbation of ptosis after sustained upgaze is a clinically useful sign in the diagnosis of myasthenia gravis. A 54-year-old woman with established Lambert-Eaton myasthenic syndrome exhibited transient improvement of her ptosis after sustained upgaze. We suggest that paradoxical lid elevation after sustained upgaze may be a clinically useful sign in distinguishing Lambert-Eaton myasthenic syndrome from myasthenia gravis. Key words: Lambert- Eaton syndrome myasthenic syndrome myasthenia gravis ptosis ophthalmoplegia MUSCLE & NERVE 14:863-866 1991

PARADOXICAL LID ELEVATION WITH SUSTAINED UPGAZE: A SIGN OF LAMBERT-EATON SYNDROME LENORE A. BREEN, MD, LUDWIG GUTMANN, MD, JOHN F. BRICK, MD, and JACK R. RIGGS, MD

Weakness of the external ocular muscles is a much less prominent feature of Lambert- Eaton myasthenic syndrome (LEMS) than myasthenia gravis. I n myasthenia gravis, sustained upgaze is a useful technique to either induce or increase ptosis. We present a patient with LEMS in whom sustained upgaze temporarily abolished the ptosis. CASE REPORT

A 54-year-old women presented with a 6-month history of increasing generalized fatiguable weakness associated with mild incoordination, hoarseness, and episodic diplopia. A 9-pound weight loss, a change in her sense of taste, and a dry mouth occurred over the prior 6 months. She had rheumatoid arthritis, smoked cigarettes, and drank 3 ounces of alcohol daily. Examination revealed a l-mm ptosis of the left eyelid. She had mild proximal weakness and absent tendon reflexes. Exercise led to improvement in the muscle strength and tendon reflexes. When

From the Departments of Neurology and Ophthalmology (Dr. Breen) and Department of Neurology (Drs. Gutmann, Brick, and Riggs), West Virginia University School of Medicine, Morgantown, West Virginia. Address reprint requests to Lenore A. Breen. MD, Department of Neurology, West Virginia University Medical Center, Morgantown. WV 26506. Accepted for publication July 18, 1990. CCC 0148-639W91/090863-04 $04.00 0 1991 John Wiley & Sons, Inc.

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the patient looked up for 20 seconds, the ptosis of the left eyelid disappeared, and then gradually returned over 30 seconds (Fig. 1). Nerve conduction studies were normal except for the presence of small compound evoked muscle action potentials (CMAP) in the right thenar and hypothenar muscle groups (Fig. 2). The baseline-evoked thenar CMAP obtained with stimulation of the right median nerve was 0.9 mV, and increased to 3.8 mV 5 seconds after a 10-second period of exercise. T w o minutes later, the CMAP had returned to 0.9 mV. Stimulating the right ulnar nerve revealed hypothenar muscle action potentials of 0.35 mV and 6.0 mV before and 5 seconds after exercise, respectively. Computerized tomography of the chest revealed a hilar mass. Biopsy of the mass showed small cell carcinoma. Normal studies included: MRI scan of the head, thyroid function tests, CBC, CK, electrolytes, calcium, magnesium, phosphorus, serum protein electrophoresis, liver function tests, B-12 level and CSF studies including cell count, glucose, protein, cultures, and cytology. Acetylcholine receptor antibodies were not present. Other absent antibody tests included: CEA, antiparietal cell, and anti-SSA. Complement levels and C,Q-binding level were normal. Laboratory testing for other autoimmune abnormalities revealed the following results: ESR 52 mm/h, RAJI cell assay elevated at 204 mcg (nmL < loo), and an ANA positive at 1:40. T h e patient's ptosis resolved, prior to the use of radiation and chemo-

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FIGURE l . (A) Ptosis of the left eye prior to exercise. ( 6 ) lmprovement of the ptosis immediately after 20 seconds of exercise. (C) Slight worsening of the ptosis at 20 seconds after exercise, compared with that immediately after exercise, but still improved from pre-exercise position.

therapy, using prednisone 60 mg every other day and azathioprine 100 mg daily. DISCUSSION

LEMS is a rare disease that presents with proximal fatiguable weakness. Autonomic symptoms include impotence, dryness of the mouth, constipation, and blurred vision.’ Ptosis and diplopia also occur but are reported less often than the other symptoms and signs. 1-3,7,8 T h e incidence in men outnumbers women 4.7 to l.3 LEMS is associated with cancer in 62% to 70% of the cases.3z9It has also been reported in association with other autoimmune diseases including: pernicious anemia, rheumatoid arthritis, celiac disease, juvenile-onset diabetes mellitus, psoriasis, scleroderma, multiple sclerosis, vitiligo, Sjogren’s syndrome, and thyroid disease.4273g

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Ocular involvement in LEMS is not as prominent a feature as in myasthenia gravis, nonetheless, it occurred commonly in the review of 50 cases by O’Neill et al.’ Ptosis occurred in 54% of the patients. Twenty-five patients had diplopia, but clinical examination showed no eye movement abnormalities. Six patients had sluggish pupil reactions to light. T w o patients tested for pupil sphincter supersensitivity using Mecholyl and dilute pilocarpine had positive results. There was no difference in the incidence of ocular involvement in the patients who had cancer and those without cancer. Two studies using quantitative oculography in LEMS patients showed improvement of eye movements after exercise. 1,2 Cruciger and associates reported 5 patients who underwent neuroophthalmic examination. Three patients had ptosis on examination and 1 had slowed abduction saccades documented. Three patients underwent testing of eye movements using oculography. After baseline measurements, the patients exercised their ocular muscles by doing back-to-back saccades of 40” for 20 seconds (about 2 saccadeslsec). Two of the patients had a significant increase in their saccadic velocity after exercise. The second study by Dell-Osso et a1.2 reported 5 patients with no eye movement abnormalities on clinical examination. All the patients had abnormal quantitative oculography with hypometric saccades. Two patients had facilitation of saccades with exercise converting their hypometric saccades to hypermetric saccades and increasing the peak saccadic velocities. Patients with LEMS can be misdiagnosed as having myasthenia gravis.’ In O’Neill’s series of 50 patients, the diagnosis of myasthenia gravis had been made in 10 patients, and 2 patients had undergone thymectomy. T h e similarity of the clinical presentation with fatiguable weakness and ptosis in the 2 diseases causes this confusion. In addition, patients with LEMS can show improved muscle strength with edrophonium tests.2” Features which differentiate LEMS from myasthenia gravis include increasing strength with sustained activity over the initial 30 seconds, autonomic symptoms, and the absence of acetylcholine receptor antibodies in LEMS. The diagnosis often depends on the characteristic electrophysiologic features of each disease, including small singleevoked CMAPs, postexercise facilitation of CMAP amplitude, and an incremental response with 20 to 50 Hz repetitive nerve ti mu la ti on.^ Ptosis is a common finding in LEMS.’ Our pa-

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before exercise

I

30

5

10 second

seconds

60

o f ter exercise

I

exercise

ImV

FIGURE 2. Two-hertz supramaximal median nerve stimulation (recording thenar muscle) before and after a 10-second maximal exercise. Note small muscle action potential with decrernental response before exercise, and marked facilitation of the muscle action potential amplitude 5 seconds after exercise. The facilitation gradually subsided by 60 seconds.

tient had obvious improvement in her ptosis with sustained upgaze. This finding was consistently present. Care was taken to prevent the patient from contracting the frontalis muscle during elicitation of this sign. T h e elevation of the lid most likely represents facilitation of the levator muscle following exercise. T h e electrophysiologic results reported by Cruciger et al., Dell’Osso et al., and the clinical findings in this patient demonstrate that the muscles in the lid and ocular motor system respond to exercise in the same manner as the muscles in the extremities in LEMS. Transient lid retraction after upgaze occurs in other diseases including hyperkalemic and hypokalemic periodic paralysis, Grave’s ophthalmopathy, and acquired synkinesis of the oculomotor In periodic paralysis, myotonic contracture of the levator causes the lid retraction. Grave’s ophthalmopathy causes fibrosis and shortening of the levator resulting in the staring ex-

pression and the Graefe sign, lid retraction on downgaze. If the ophthalmopathy is associated with hyperthyroidism, overactivity of Mueller’s muscle plays a role. Rarely, ptosis is present in Grave’s ophthalmopathy. Clinical findings of proptosis, conjunctival injection, and mechanical restriction of extraocular muscles would differentiate thyroid eye disease from LEMS. The pseudoGraefe sign, seen in acquired oculomotor synkinesis, is a result of abnormal rerouting of regenerating nerve fibers to the levator muscle. We suggest that paradoxical lid elevation after sustained upgaze is a sign of LEMS. Based on the electrophysiologic characteristics of LEMS and myasthenia gravis, facilitation of the levator muscle after exercise is much more likely in LEMS. In the evaluation of patients with ptosis and fatigability, demonstration of paradoxical lid elevation after sustained upgaze would help diagnose Lambert- Eaton myasthenic syndrome.

REFERENCES

1 . Cruciger MP, Brown B, Denys EH, Magoon E, Wasson PJ, Newnian NM, Scott AB: Clinical and subclinical oculomotor findings in the Lambert-Eaton syndrome. J Clin Neuro-ophthalmol 1983;3: 19- 22. 2. Dell’Osso LF, Ayyar DR, Daroff RB, Abel LA: Edrophonium test in Lambert-Eaton syndrome: Quantitative oculography. Neurology 1983;33:1157- 1163. 3. Elmqvist D, Lambert EH: Detailed analysis of neuromus-

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cular transmission in a patient with the myasthenic syndrome sometimes associated with bronchogenic carcinoma. Mayo Clin Proc 1968;43:689-713. 4. Gutmann L, Crosby TW, Takamori M, Martin JD: The Eaton-Lambert syndrome and autoimmune disorders. Am J Med 1972;53:354-356. 5. Keesey JC: Electrodiagnostic approach to defects of neuromuscular transmission. Muscle Nerve 1989;12513-626.

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6. Layzer RB, Lovelace RE, Rowland LP: Hyperkalemic periodic paralysis. Arch Neurol 1967;16:455-472. 7. Miller NR: Walsh and Hoyt’s Clinical Neuro-Ophthalmology, 4 ed. Baltimore, Williams and Wilkins, 1985, pp 866-867. 8. Oh SJ: The Eaton-Lambert syndrome in ocular myasthenia gravis. Arch Neurol 1974;31:183-186.

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9. O’Neill JH, Murray NMF, Newsom-Davis J: The LambertEaton myasthenic syndrome. Brain 1988;l 11:577-596. 10. Resnick JS, Engel WK: Myotonic lid lag in hypokalemic periodic paralysis. J Neurol Neurosurg Psychiatry 1967;30:4751.

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