Journal of Neuro-Ophthalmology, June 2000, Volume 20, Issue 2

Myasthenia Gravis with a Paraneoplastic Marker

Ocular manifestations of myasthenia gravis are very common. Myasthenia gravis may be associated with lung carcinoma. Lambert-Eaton syndrome is also commonly associated with lung carcinoma and can have ocular manifestations. Overlap of these two entities has been described. The case of a patient with fatigable diplopia and ptosis 3 years after removal of a large-cell lung carcinoma is presented. Tests results for acetylcholine receptor binding and modulating antibodies were positive for myasthenia gravis. Test results for presynaptic voltage-gated calcium channel antibodies of the N-type were also positive. However, test results for the P/Q-type voltage-gated calcium channel antibodies, which are consistent with Lambert-Eaton syndrome, were negative. Autoantibodies can be used to serologically distinguish paraneoplastic myasthenia gravis from Lambert-Eaton syndrome.

Journal of Neuro- Ophlhalmology 20( 2): 102- 105, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Myasthenia Gravis With a Paraneoplastic Marker Jacqueline A. Leavitt, MD Ocular manifestations of myasthenia gravis are very common. Myasthenia gravis may be associated with lung carcinoma. Lambert- Eaton syndrome is also commonly associated with lung carcinoma and can have ocular manifestations. Overlap of these two entities has been described. The case of a patient with fatigable diplopia and ptosis 3 years after removal of a large-cell lung carcinoma is presented. Tests results for acetylcholine receptor binding and modulating antibodies were positive for myasthenia gravis. Test results for presynaptic voltage- gated calcium channel antibodies of the N- type were also positive. However, test results for the P/ Q- type voltage- gated calcium channel antibodies, which are consistent with Lambert- Eaton syndrome, were negative. Autoantibodies can be used to sero­logically distinguish paraneoplastic myasthenia gravis from Lambert- Eaton syndrome. Key Words: Lambert- Eaton syndrome- Myasthenia gravis- Paraneoplastic syndrome. Myasthenia gravis ( MG) is an acquired autoimmune disease characterized by fatigable muscle weakness, which is ameliorated with rest and exacerbated by sus­tained or repetitive contraction. Ptosis and diplopia are present in 70% to 75% of patients at the initial diagnosis of MG and in 90% of patients during the course of the disease ( 1). In distinction, generalized weakness and fatigability of the proximal limb muscles characterize Lambert- Eaton syndrome ( LES), with facilitation after exercise ( 2). Pto­sis, diplopia, blurred vision, and pupillary changes have all been described with LES, but they are uncommon ( 3). About 70% of people with LES have a malignancy, which is usually small- cell carcinoma of the lung. Testing with edrophonium is a common office proce­dure for the diagnosis of MG. Unfortunately, edropho­nium can give a positive result for LES, as well. The two entities have been described as clinically coexisting in the same patients ( 4). Manuscript received October 1, 1998; accepted March 6, 2000. From the Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota. Presented in part at the 1995 meeting of the Frank Walsh Society, April 8- 9, Washington, DC. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, New York. Address correspondence and reprint requests to Jacqueline A. Leavitt, MD, 200 First Street, SW, Mayo Clinic, Rochester, MN 55905. Presynaptic voltage- gated calcium channel ( VGCC) antibodies have been described. Several forms of VGCC antibodies exist, including the N- type and the P/ Q- type. Presence of the P/ Q- type VGCC antibody can help dis­tinguish LES from MG ( 5). CASE REPORT A 46- year- old man was seen in September 1994; he experienced intermittent binocular horizontal diplopia for 7 to 10 days. Additionally, he had blepharoptosis of the right eyelid for the past 3 years that had recently become more pronounced in the evenings. His medical history was significant for large- cell car­cinoma of the right lung. After a needle biopsy of the lung in October 1991, he had 5,000 centigray of radiation to the right upper lung. In November 1991, he underwent a right upper lobectomy and laminectomy with partial resection of the T3 and T4 vertebral bodies, with some residual tumor remaining in the T3 and T4 foramina. Postoperatively, he had additional radiation therapy of 2,200 centigray to the entire right lung field. The lung tissue revealed a poorly differentiated ana­plastic malignancy with many bizarre cells and multiple mitoses consistent with large- cell carcinoma of the lung. Special stains were performed. Results of the S- 100 were negative, but results of the keratin stain were positive; this staining pattern is consistent with a carcinoma and excluded melanoma. Despite the aggressive nature of this patient's partially resected tumor, in follow- up, he had no evidence of re­currence. He was placed on prednisone for analgesia control from November 1991 until July 1994. In September 1994, he was refracted to 20/ 20 OU. Confrontation visual fields, color vision, slit- lamp ex­amination, and fundus examination results were all nor­mal. He had 2 mm of ptosis and upside- down ptosis OD. No Cogan lid twitch was ellicitable. The peek sign for orbicularis fatigue was also negative. The pupils mea­sured 2 mm OD and 3 mm OS in the dark and 2 mm and 2.5 mm, respectively, in the light. The responses to light were brisk, and no afferent pupil defect was detected. Lancaster Red- Green testing revealed a large exotro-pia that was worse in lateral gaze to either side with a right hypertropia of 3 prism diopters. Adduction was - 1 bilaterally with saccadic weakness. Abducting nystag- 102 MYASTHENIA GRAVIS WITH A PARANEOPLASTIC MARKER 103 mus was present. The findings were consistent with a bilateral internuclear ophthalmoplegia with skew devia­tion. A magnetic resonance imaging study of the brain with gadolinium- contrast enhancement revealed no intrinsic lesions, abnormal meningeal enhancement, or me­tastases. An eye examination 4 days later revealed a positive Cogan lid twitch OD. Repeated Lancaster Red- Green testing showed more exotropia in primary gaze and a right hypertropia of 18 prism diopters. Intravenous edro­phonium 3 mg was given with development of a large esotropia and a left hypertropia of 10 prism diopters. Results of a neurologic examination were completely normal, including reflexes and systemic muscle strength. He did not have any symptoms of autonomic dysfunc­tion, such as dry mouth or impotence. The consulting neurologist did not feel it was necessary to get an elec-tromyogram because he had typical ocular restriction that variably fatigued, had a positive edrophonium test, and had positive antibodies. Antibody assays were performed: acetylcholine recep­tor ( AChR) binding antibody ( Ab) was 2.64 nmol ( nor­mal, < 0.02 nmol), AChR modulating Ab showed a 77% AChR loss ( normal, < 20%), and testing for AChR block­ing Ab was negative. Testing for striated muscle Ab was negative as well. Testing for anti- neuronal nuclear Ab 1 ( ANNA- 1) was negative. Testing for VGCC Abs of the P/ Q type was negative, but testing for the N- type was positive. The patient was restarted on oral prednisone, 30 mg every other day, but he had worsening of the ptosis. The dose of prednisone was increased to 60 mg/ d, and there was resolution of his diplopia and Cogan lid twitch. One mm of ptosis persisted, and the pupils remained un­changed. The prednisone dose was tapered over a few months, and azathioprine was added 8 months later. One year later, the patient developed adenocarcinoma of the other lung. This tumor was unrelated to the pre­vious carcinoma and was resected along with his thymus gland. There was no evidence of a thymoma, and in fact the thymus gland was atrophic. He died of systemic com­plications of myasthenia gravis about 2 years after the initial diagnosis. DISCUSSION Myasthenia gravis affects the levator palpebrae supe-rioris and/ or the extraocular muscles in 70% to 75% of patients at the time of presentation and 90% of patients during the course of the disease. The ocular symptoms of ptosis and/ or diplopia are typically variable, fatigable, and asymmetric. The pattern of diplopia can mimic any cranial nerve palsy or eye muscle disorder. Bilateral internuclear ophthalmoplegia is most com­monly associated with multiple sclerosis ( 6). However, it has been described in brain stem tumors ( 7), occlusive vascular disease of the brain stem ( 6,8), Chiari malfor­mation, hydrocephalus ( 9), syphilis, trauma ( 10), acute cervical hyperextension ( 11), systemic lupus ( 12), and acquired immunodeficiency syndrome ( 13). Glaser ( 14) first described three patients with MG who had findings of unilateral or bilateral internuclear ophthalmoplegia with adduction deficits and abducting nystagmus. He proposed the term " pseudo- internuclear ophthalmople­gia." Since then, others have described pseudo-internuclear ophthalmoplegia in myasthenia gravis ( 6, 15- 19). Bilateral internuclear ophthalmoplegia has also been described secondary to carcinomatous meningitis from oat- cell carcinoma of the lung ( 20). Paraneoplastic ef­fects on the brain stem, causing bilateral internuclear ophthalmoplegia in addition to other neurologic abnor­malities, have been described in a case of small- cell car­cinoma ( 21) and in a case of bronchial carcinoma ( 22). The pathology of the brain stem involvement in the small- cell carcinoma revealed extensive bilateral demy-elination of the medial longitudinal fasciculus in the up­per pons- caudal midbrain. Lambert- Eaton syndrome may have ocular involve­ment in up to 20% of cases. Manifestations may include ptosis, extraocular eye muscle weakness, autonomic pu­pillary changes, and intermittent blurred vision ( 3,23). One of the classic diagnostic tools for MG is the edro­phonium test ( 24). Intravenous edrophonium improves the ptosis, extraocular muscle weakness, or orbicularis oculi weakness. The use of edrophonium with the Lan­caster Red- Green test was first described by Retzlaff et al. ( 25). Horizontal measurements may vary with myas­thenia or with the adrenergic or cholinergic effects of edrophonium, but vertical improvement after the use of edrophonium, as in our patient, is most attributable to a positive response ( 26). Unfortunately, false- positive edrophonium test results have been described in many different entities, including parasellar tumors and aneurysms ( 27), brainstem glioma ( 28), amyotrophic lateral sclerosis, botulism, Guillain- Barre syndrome ( 29), multiple sclerosis, end stage renal disease ( 30), and LES ( 31), as well as in normal patients. Electromyography ( EMG) is another tool to aid in the diagnosis of MG. Electrical stimulation of a motor nerve at a high rate will cause a progressive decrement in the amplitude of the motor action potential. Any decrement is considered consistent with MG, and a 10% decrement is considered significant. Unfortunately, this decremental response is not specific for MG; it can occur in LES, botulism, and amyotrophic lateral sclerosis. Repetitive stimulation causing a decremental response is found in 65% to 85% of patients with systemic MG, but only in 33% to 50% of patients with ocular MG ( 32,33). A more sensitive test for MG than repetitive stimula­tion is single- fiber EMG ( 34). Variable interfiber firing intervals will cause jitter due to poor synaptic efficiency. Occasionally, the single fiber may not depolarize when the motor unit fires and is considered blocked. Up to 90% of patients with systemic MG and 60% to 70% of patients with ocular MG may have abnormal jitter and blocking ( 33). This test is much more difficult to perform and is rarely done on the orbicularis oculi. Again, test J Neuro- Ophthalmol, Vol 20, No. 2, 2000 104 J. A. LEAVITT results can also be positive in LES, amyotrophic lateral sclerosis, and botulism, as well as in some muscular diseases. In our patient, the neurologist felt that the di­agnosis was established, without the need for an EMG. The classic EMG findings in LES are reduced muscle action potential after supramaximal nerve stimulation, further depression with low repetitive stimulation, and marked facilitation at high rates of stimulation or after voluntary contraction for a few seconds ( 35) ( Table 1). Serologic testing to confirm the diagnosis of MG con­sists of AChR binding, modulating, and blocking Abs ( Table 2). Test results for AChR binding Abs are positive in 86% of patients with MG, in 71% of patients with ocular MG, and in only 5% to 13% of patients with LES ( 36,37). The titer of AChR binding Abs does not corre­late with the clinical severity. This test is most helpful in detecting subclinical MG. Our patient had an abnormal binding Ab of 2.64 nmol ( normal, < 0.02 nmol). Acetylcholine receptor modulating Abs have the po­tential to attach to the AChR in a way to cause degrada­tion of the receptor. This test is most helpful as a screen for MG when the AChR binding Abs are not detectable. The test result is reported in terms of loss of AChR. This test correlates with the severity of disease. The percent­age of AChR loss is usually very high in generalized MG or in MG associated with thymoma (> 90% loss of AChR) ( 36). Our case had 77% AChR loss ( normal, < 20%). Blocking Abs to AChR are rarely found in any con­dition other than MG. Test results for the blocking Ab are only positive when the results for modulating Ab are also positive; they are positive in 52% of all patients with MG and in 30% of patients with ocular MG ( 35). How­ever, results for the blocking Ab are only positive in 1% of patients with nondetectable binding Abs. The blocking Ab titer may be used for academic purposes to correlate titer with clinical severity. Test results for our patient's blocking Ab were negative. Antistriational muscle antibodies are also useful in the diagnosis of MG. These Abs cross- react with the con­tractile elements of skeletal muscle. Thirty percent of adult patients with MG, 80% of patients with MG with thymoma, and 24% of patients with thymoma without TABLE 1. Myasthenia gravis ( MG) versus Lambert- Eaton syndrome ( LES) Finding Ptosis Diplopia Tensilon response Autonomic abnormalities Repetitive- stimulation EMG Single- fiber EMG MG +++ +++ +++ - * $ 90- 95% ( ref. 43) LES + + +/- ++ t jitter, blocking * Decremental response in 65% to 85% of systemic MG, 33% to 50% of ocular MG ( 32, 33). t Postactivation facilitation. i Decremental response. +++, very common; ++, fairly common; +, can occur; +/-, may occur; EMG, electromyography. TABLE 2. Antibodies in myasthenia gravis ( MG) and Lambert- Eaton syndrome ( LES) Antibody Binding AChR AB Modulating AChR AB Blocking AChR AB Antistriational muscle AB| MG (%) 86 * 52 30/ 80 Ocular MG (%) 71 30. LES (%) 5- 13 * High with systemic MG or with thymoma. t 30% positive in MG, 80% positive in MG with thymoma. AChR, acetylcholine receptor; AB, antibody. clinical evidence for MG will test positive for antistria­tional muscle Abs ( 36). Our patient tested negative for antistriational muscle Abs. All of the AChR antibody tests are less frequently positive in the first year of onset of purely ocular MG and can also be falsely negative in patients treated with im­munosuppressive drugs. Recently, presynaptic VGCC antibodies have been de­scribed ( 8,9,40). There are three identified types of VGCC Abs that relate to MG or LES: L- type, N- type, and P/ Q- type ( 41). ( Other VGCCs include R- type and T- type, but these do not pertain to this discussion.) The distribution of each of the VGCCs is different. The P/ Q-type VGCC mediates transmitter release at the neuro­muscular junction. N- type Abs are found in 33% to 45% of patients with LES. Low titers of P/ Q- type and N- type Abs have been found in 54% of paraneoplastic encephalomyeloneuropa-thy- complicating lung, ovarian, or breast carcinoma, in 24% of patients with cancer without neurologic compli­cations, in 23% of patients with sporadic amyotrophic lateral sclerosis, and in less then 3% of patients with MG, epilepsy, or scleroderma ( 42,43). Our patient did have a positive N- type VGCC Ab. The P/ Q- type VGCC is probably the primary mediator of neuromuscular transmission. P/ Q- type Abs have been detected in 100% of patients with LES with lung cancer and in 91% to 92% of patients with LES without cancer ( 42,43). The pathophysiology of Lambert- Eaton syn­drome is felt to be specifically related to the P/ Q- type VGCC antibodies and their role in the presynaptic re­lease of acetylcholine. Our patient did not have measur­able P/ Q- type VGCC Abs. L- type VGCC Abs have been TABLE 3. Calcium- channel antibodies in myasthenia gravis ( MG) and Lambert- Eaton syndrome ( LES) Patient group LES without lung cancer LES with cancer Myasthenia gravis Small cell lung cancer Controls Calcium- channel AB P/ Q- type (%) 96 88 0 0 0 N- type (%) 40 22 0 0 0 Data from Motomura et al. J Neurol Sci 1997; 147: 35-^ 2. AB, antibody. J Neuro- Ophthalmol. Vol. 20, No. 2, 2000 MYASTHENIA GRAVIS WITH A PARANEOPLASTIC MARKER 105 described only in patients with LES with high titers of N- type VGCC Abs. Our patient had fatigable ptosis, Cogan lid twitch, and a edrophonium- responsive hypertropia. His serologic profile included positive binding and modulating anti­bodies to the AChR, which are both markers of MG. Test results for the VGCC N- type antibody were also positive. The absence of the P/ Q- type VGCC Ab essentially ex­cludes Lambert- Eaton syndrome. 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