The diagnostic sensitivity of three laboratory tests [serum antiacetylcholine receptor antibody (AChR-ab) assay, the repetitive nerve stimulation (RNS) test, and, the single fiber EMG (SFEMG)] for myasthenia gravis (MG) was compared in 120 patients. In all cases, at least one of the tests was abnormal. SFEMG was the most sensitive test, being abnormal in 92% of cases, followed by the RNS test (77%) and the AChR-ab assay (73%). SFEMG was abnormal in all cases with negative AChR-ab and RNS tests, in 97% of cases with negative AChR-ab assay, in 89% of cases with negative RNS test, and in 89% of cases with mild MG. We conclude that one of these three tests is abnormal in all cases of MG, and that the SFEMG is most sensitive in the diagnosis of MG. Key words: myasthenia gravis diagnosis electrophysiology MUSCLE & NERVE 15:720-724 1992
DIAGNOSTIC SENSITIVITY OF THE LABORATORY TESTS IN MYASTHENIA GRAVIS SHlN J. OH, MD, D O 0 E. KIM, MD, R. KURUOGLU, MD, RONALD J. BRADLEY, PhD, and DONARD DWVER, PhD
T h e diagnosis of myasthenia gravis (MG) is often challenging. An unequivocally positive edrophonium test has been thought to be diagnostic of MG in the past. However, false positive edrophonium tests have been reported in various diseases including non-neuromuscular diseases.2*6,YThus, in recent years, the diagnosis of MG has been based on clinical features together with edrophonium responsiveness and other laboratory findings. T h e laboratory tests include serum antiacetylcholine receptor antibody (AChKab) assay, the repetitive nerve stimulation (KNS) test, and the single fiber EMG (SFEMG). Among these, the SFEMG is widely thought to be the most sensitive. "*I8 However, not all patients in the previous studies had all three tests performed. We performed all three diagnostic tests in all 120 patients and report the results here.
",' '
From the Department of Neurology (Drs Oh, Kim, and Kuruoglu) and Neuroscience Program (Drs Bradley and Owyer). The University of Alabama at Birmingham, The Veterans Administration Medical Center, Birmingham, Alabama Address reprint requests to Dr. Shin J Oh, Department of Neurology, The University of Alabama at Birmingham, UAB Station, Birmingham, AL 35294. Accepted for publication November 10, 1991.
CCC 0148-639x/92/060720-05$04.00 0 1992 John Wiley & Sons, Inc
720
Diagnostic Tests in MG
MATERIALS AND METHODS
T h e present study is based on 120 MG patients whom we have observed at The University of Alabama at Birmingham MG clinic over the past 10 years. The last 96 patients were studied prospectively. All these patients were symptomatic and had objective evidence of weakness at the time o f evaluation. All three diagnostic tests were performed in the same patient within a 1-month period. The diagnosis of MG was made by a combination of clinical features and positive edrophonium or neostigmine responsiveness. The severity of MC; was graded according to the modified Osserman's classification at the time of evaluation: I, ocular MG; IIA, mild generalized MG; IIB, moderate generalized MG; and IIC, severe generalized MC;. AChR-ab was assayed following the standard immunoprecipitation method using purified human AChR.' When the titer was above 0.05 nmol per '251-&-bungarotoxin-AChRbound per liter of serum, the test was considered abnormal. The KNS test was performed on the abductor digiti quinti (ADQ) and flexor carpi ulnaris (FCU) muscles with stimulating electrodes at the elbow on the ulnar nerve following the previously described method as the first-line test.738If this test showed normal findings, the KNS test on proximal muscles (orbicularis oculi, trapezius, or deltoid muscles) was performed, the muscle being se-
'
MUSCLE & NERVE
June 1992
lected on the basis of clinical involvement.8 In 46 cases (38%),the KNS test on proximal muscles was performed in at least one musle. When decremental response was more than the mean value plus 2 SD, the test was considered abnormal. Normal limits of decremental response varied from 5% to 13c-/o,depending on the rate of stiniulation and muscles tested: 5% to 10% for the ADO, 8% to 11% for the FCU, 7% to 9% for the orbicularis oculi and the trapezius, and 12% to 13% for the deltoid muscles.8 The SFEMG was performed on the extensor digitorum communis (EDC) muscle following the standard method.* T h e test was considered abnormal when any one of the following three criteria was met""': (1) mean MCD (mean consecutive difference) was longer than 40 ps; (2) more than 10% of potential pairs had blocking or jitter greater than 54 ks; or ( 3 ) blocking was so frequent that it was impossible to calculate the MCD in the majority of potential pairs. I n addition, the SFEMG was performed on the cranial muscles in 8 cases. RESULTS
In all cases, one of these tests was positive. Among these tests, the SFEMG was most sensitive, being positive in 92% of cases. The RNS test was positive in 77%)of cases, while the AChR-ab assay was positive in 7370 of cases (Table 1). All three tests were more sensitive in generalized MG than in ocular MG. However, the difference in the diagnostic sensitivity between ocular and generalized MC; was almost negligible for the AChR-ab assay, but was significant ( P = 0.0002) for the RNS test. The RNS test and the SFEMG became more sensitive with increasing severity of
MG. However, for the AChR-ab assay, there was no such clear relationship. T h e least-sensitive test for ocular MG was the RNS test but, for generalized MG, the AChR-ab assay was least sensitive. In any form of MG, the SFEMG was most sensitive. In mild MG (I and IIA), the SFEMG was abnormal in 89% of cases, the AChR-ab assay and the RNS test each in 69% (Table 2). In severe MG (IIB and IIC), the SFEMG was abnormal in all cases, while the RNS test was abnormal in 97% of cases, arid the AChR-ab assay in 88%. In 32 patients with negative AChR-ab assay, the SFEMG was most sensitive in diagnosis of MG, being positive in 97% of cases, in contrast to 66% for the RNS test (Table 2). It should be noted that 88% of patients in this group had mild MG. In 28 patients with a negative RNS test, the SFEMG was positive in 89% of cases, in contrast to 61% for the AChR-ab assay. All patients in this group had mild MG and about 31% of patients with mild MG had negative RNS tests. Of 10 patients with negative SFEMG, the AChR-ab assay positive in 80% and the KNS test in 60%. All of these patients had mild MG. In 1 1 patients with negative AChR-ab assay and RNS test, the SFEMG was abnormal in all cases. All of these patients had mild MG. In 1 case with a negative AChR-ab and SFEMG assay, the RNS test was abnormal. This case had ocular MG. In 4 patients with negative RNS and SFEMG test, the AChR-ab assay with positive. All of these patients had mild MG. DISCUSSION
Our study showed that one of the three tests is abnormal in all patients with symptomatic MG. Conversely, it can be said that, if none of these tests
Table 1. Diagnostic sensitivity of three laboratory tests in MG according to severity. Number of cases
Subgroup
AChR-ab assay
RNS test Proximal
Distal
SFEMG
9 (4q$ 83 (83)$
7 (35) 66 (66) 37(552) 24 (85 7) 5 (100) 74 (61 6)
16 (80j-t 94 (94) 61 (91) 28 (100) 5 (100) 110 (91 7)
~
Ocular (I) Generalized ( 1 1 ) Mild (IIA) Moderate (IlB) Severe (IIC) Total
20 100 67 28
5 120
14 (70)* 74 (74) 46(687) 25 (89 2) 4 (80) 88 (73 3)
51 (761) 27 (96 4) 5 (100) 92 (76 6)
*Number of cases (%/ t o n e patient bad abnormal SFEMG ln the orbicularis ocuh muscle whde SFEMG was normal in the EDC muscle #Difference between these two hgure IS stafistically s i g n h x n t (P = 0 0002)
Diagnostic Tests in MG
MUSCLE & NERVE
June 1992
721
~
~
~~
Table 2. Diagnostic sensitivity of the laboratory tests in MG subgroups Subqroups Mild MG (I and HA) AChR-ab assay (-)* RNS test ( - ) SFEMG (-) AChR-abISFEMG (-) AChR-ab/RNS test (-) RNS test/SFEMG (-)
Number of cases
AChR-ab assay
87
60 (68 9%)
32t 28$
10
17 (607%) 8 (80%)
1 11 4
4 (100%)
RNS test
SFEMG
60 (68 9%) 21 (659%)
77 (88 5%) 31 (96.9%) 25 (89 3%)
6 (60%) 1 (100%) 11 (100%)
‘Negative fTwenty-nine cases had mild MG (/ and / / A ) #Twenty-seven cases had mdd MG
are abnormal, the diagnosis of MG should be doubted even in the presence of objective weakness. We have observed one asymptomatic MG patient who showed negative results on all three tests, but this rule has heen held true in all symptomatic MG patients so far in o u r experience. O u r study showed that the SFEMG is the most sensitive of the three tests, followed by the KNS test and the AChR-ab assay in that order. O u r results are different from two previous studies which showed that the AChK-ab assay was su >e rior to the RNS test in diagnostic sensitivity.’ , I x O u r study is also unique in that we performed all three laboratory tests in all of our patients, whereas, in two previous studies, the AChK-ab assay was tested in only one third, and the KNS in only one third to one half of patients in whom the SFEMG was tested.’’.” T h e reason for the selection of a specific test was not given. However, it seems apparent that the SFEMG was heavily used for confirmation of diagnosis of MG in these studies and, therefore, it is possible that these results may not represent a genuine comparison. O u r study showed that all three tests are more sensitive in generalized MG than in ocular M G and also with increasing severity of disease. ‘ i h e difference in sensitivity between ocular and generalized MG is least in the AChK-ab assay and greatest in the KNS test, indicating that the f’ormer is relatively uniform in diagnostic sensitivity regardless of severity of MG, while the KNS test is least helpful in the diagnosis of ocular MG. Similar observations were made by St%lbergand Sanders.Ix O u r study f o u n d that the SFEMG was the crucial objective test in the 11 (9%) MG patients in whom the AChK-ab assay and KNS test were both negative, thus the SFEMG was the only test confirming diagnosis of M G in this group. O u r study also identified groups o f MG pa-
8-
722
Diagnostic Tests in MG
tients in whom the SFEMG is most helpful in confirmation of diagnosis: (1) patient with negative AChR-ab assay; (2) patients with negative RNS test; and ( 3 ) patients with mild MG ( I and IIA). In these groups, the SFEMG was the most sensitivie test, being abnormal in more than 89% of cases, indicating the great usefulriess of SFEMG in the diagnosis of MG. Traditionally, clinicians have had the greatest diagnostic difficulty in the mild MG group, because the majority of patients in this group have either a negative AChK-ab assay or normal RNS test. In Stilberg’s series, the SFEMG was abnormal in all of 17 MG patients who had a negative AChK-ab assay.” In our series, the SFEMG was abnormal in 97% of patients with negative AChR-ah assay. In 58 patients with mild MG in Kelly’s series, in whom the RNS test was normal, the SFEMG was abnormal in 92% of cases and the AChR-ab assay was positive in 80% of cases.4 In the present study, in 27 patients with mild MG, in whom the KNS test was normal, the SFEMG was abnormal in 89% of cases and the AChR-ab assay was positive in 59%. In recent years, the AChK-ab assay has been the single most useful clinical test in MG because of its relative specificity. ’Though this test is easily available, the test results may not be available for days o r weeks. ‘The most commonly available AChK-ab assay is one using purified human AChR. This test is positive in 70% to 87%) of patients with MG. 1 .:
DIAGNOSTIC SENSITIVITY OF THE LABORATORY TESTS IN MYASTHENIA GRAVIS SHlN J. OH, MD, D O 0 E. KIM, MD, R. KURUOGLU, MD, RONALD J. BRADLEY, PhD, and DONARD DWVER, PhD
T h e diagnosis of myasthenia gravis (MG) is often challenging. An unequivocally positive edrophonium test has been thought to be diagnostic of MG in the past. However, false positive edrophonium tests have been reported in various diseases including non-neuromuscular diseases.2*6,YThus, in recent years, the diagnosis of MG has been based on clinical features together with edrophonium responsiveness and other laboratory findings. T h e laboratory tests include serum antiacetylcholine receptor antibody (AChKab) assay, the repetitive nerve stimulation (KNS) test, and the single fiber EMG (SFEMG). Among these, the SFEMG is widely thought to be the most sensitive. "*I8 However, not all patients in the previous studies had all three tests performed. We performed all three diagnostic tests in all 120 patients and report the results here.
",' '
From the Department of Neurology (Drs Oh, Kim, and Kuruoglu) and Neuroscience Program (Drs Bradley and Owyer). The University of Alabama at Birmingham, The Veterans Administration Medical Center, Birmingham, Alabama Address reprint requests to Dr. Shin J Oh, Department of Neurology, The University of Alabama at Birmingham, UAB Station, Birmingham, AL 35294. Accepted for publication November 10, 1991.
CCC 0148-639x/92/060720-05$04.00 0 1992 John Wiley & Sons, Inc
720
Diagnostic Tests in MG
MATERIALS AND METHODS
T h e present study is based on 120 MG patients whom we have observed at The University of Alabama at Birmingham MG clinic over the past 10 years. The last 96 patients were studied prospectively. All these patients were symptomatic and had objective evidence of weakness at the time o f evaluation. All three diagnostic tests were performed in the same patient within a 1-month period. The diagnosis of MG was made by a combination of clinical features and positive edrophonium or neostigmine responsiveness. The severity of MC; was graded according to the modified Osserman's classification at the time of evaluation: I, ocular MG; IIA, mild generalized MG; IIB, moderate generalized MG; and IIC, severe generalized MC;. AChR-ab was assayed following the standard immunoprecipitation method using purified human AChR.' When the titer was above 0.05 nmol per '251-&-bungarotoxin-AChRbound per liter of serum, the test was considered abnormal. The KNS test was performed on the abductor digiti quinti (ADQ) and flexor carpi ulnaris (FCU) muscles with stimulating electrodes at the elbow on the ulnar nerve following the previously described method as the first-line test.738If this test showed normal findings, the KNS test on proximal muscles (orbicularis oculi, trapezius, or deltoid muscles) was performed, the muscle being se-
'
MUSCLE & NERVE
June 1992
lected on the basis of clinical involvement.8 In 46 cases (38%),the KNS test on proximal muscles was performed in at least one musle. When decremental response was more than the mean value plus 2 SD, the test was considered abnormal. Normal limits of decremental response varied from 5% to 13c-/o,depending on the rate of stiniulation and muscles tested: 5% to 10% for the ADO, 8% to 11% for the FCU, 7% to 9% for the orbicularis oculi and the trapezius, and 12% to 13% for the deltoid muscles.8 The SFEMG was performed on the extensor digitorum communis (EDC) muscle following the standard method.* T h e test was considered abnormal when any one of the following three criteria was met""': (1) mean MCD (mean consecutive difference) was longer than 40 ps; (2) more than 10% of potential pairs had blocking or jitter greater than 54 ks; or ( 3 ) blocking was so frequent that it was impossible to calculate the MCD in the majority of potential pairs. I n addition, the SFEMG was performed on the cranial muscles in 8 cases. RESULTS
In all cases, one of these tests was positive. Among these tests, the SFEMG was most sensitive, being positive in 92% of cases. The RNS test was positive in 77%)of cases, while the AChR-ab assay was positive in 7370 of cases (Table 1). All three tests were more sensitive in generalized MG than in ocular MG. However, the difference in the diagnostic sensitivity between ocular and generalized MC; was almost negligible for the AChR-ab assay, but was significant ( P = 0.0002) for the RNS test. The RNS test and the SFEMG became more sensitive with increasing severity of
MG. However, for the AChR-ab assay, there was no such clear relationship. T h e least-sensitive test for ocular MG was the RNS test but, for generalized MG, the AChR-ab assay was least sensitive. In any form of MG, the SFEMG was most sensitive. In mild MG (I and IIA), the SFEMG was abnormal in 89% of cases, the AChR-ab assay and the RNS test each in 69% (Table 2). In severe MG (IIB and IIC), the SFEMG was abnormal in all cases, while the RNS test was abnormal in 97% of cases, arid the AChR-ab assay in 88%. In 32 patients with negative AChR-ab assay, the SFEMG was most sensitive in diagnosis of MG, being positive in 97% of cases, in contrast to 66% for the RNS test (Table 2). It should be noted that 88% of patients in this group had mild MG. In 28 patients with a negative RNS test, the SFEMG was positive in 89% of cases, in contrast to 61% for the AChR-ab assay. All patients in this group had mild MG and about 31% of patients with mild MG had negative RNS tests. Of 10 patients with negative SFEMG, the AChR-ab assay positive in 80% and the KNS test in 60%. All of these patients had mild MG. In 1 1 patients with negative AChR-ab assay and RNS test, the SFEMG was abnormal in all cases. All of these patients had mild MG. In 1 case with a negative AChR-ab and SFEMG assay, the RNS test was abnormal. This case had ocular MG. In 4 patients with negative RNS and SFEMG test, the AChR-ab assay with positive. All of these patients had mild MG. DISCUSSION
Our study showed that one of the three tests is abnormal in all patients with symptomatic MG. Conversely, it can be said that, if none of these tests
Table 1. Diagnostic sensitivity of three laboratory tests in MG according to severity. Number of cases
Subgroup
AChR-ab assay
RNS test Proximal
Distal
SFEMG
9 (4q$ 83 (83)$
7 (35) 66 (66) 37(552) 24 (85 7) 5 (100) 74 (61 6)
16 (80j-t 94 (94) 61 (91) 28 (100) 5 (100) 110 (91 7)
~
Ocular (I) Generalized ( 1 1 ) Mild (IIA) Moderate (IlB) Severe (IIC) Total
20 100 67 28
5 120
14 (70)* 74 (74) 46(687) 25 (89 2) 4 (80) 88 (73 3)
51 (761) 27 (96 4) 5 (100) 92 (76 6)
*Number of cases (%/ t o n e patient bad abnormal SFEMG ln the orbicularis ocuh muscle whde SFEMG was normal in the EDC muscle #Difference between these two hgure IS stafistically s i g n h x n t (P = 0 0002)
Diagnostic Tests in MG
MUSCLE & NERVE
June 1992
721
~
~
~~
Table 2. Diagnostic sensitivity of the laboratory tests in MG subgroups Subqroups Mild MG (I and HA) AChR-ab assay (-)* RNS test ( - ) SFEMG (-) AChR-abISFEMG (-) AChR-ab/RNS test (-) RNS test/SFEMG (-)
Number of cases
AChR-ab assay
87
60 (68 9%)
32t 28$
10
17 (607%) 8 (80%)
1 11 4
4 (100%)
RNS test
SFEMG
60 (68 9%) 21 (659%)
77 (88 5%) 31 (96.9%) 25 (89 3%)
6 (60%) 1 (100%) 11 (100%)
‘Negative fTwenty-nine cases had mild MG (/ and / / A ) #Twenty-seven cases had mdd MG
are abnormal, the diagnosis of MG should be doubted even in the presence of objective weakness. We have observed one asymptomatic MG patient who showed negative results on all three tests, but this rule has heen held true in all symptomatic MG patients so far in o u r experience. O u r study showed that the SFEMG is the most sensitive of the three tests, followed by the KNS test and the AChR-ab assay in that order. O u r results are different from two previous studies which showed that the AChK-ab assay was su >e rior to the RNS test in diagnostic sensitivity.’ , I x O u r study is also unique in that we performed all three laboratory tests in all of our patients, whereas, in two previous studies, the AChK-ab assay was tested in only one third, and the KNS in only one third to one half of patients in whom the SFEMG was tested.’’.” T h e reason for the selection of a specific test was not given. However, it seems apparent that the SFEMG was heavily used for confirmation of diagnosis of MG in these studies and, therefore, it is possible that these results may not represent a genuine comparison. O u r study showed that all three tests are more sensitive in generalized MG than in ocular M G and also with increasing severity of disease. ‘ i h e difference in sensitivity between ocular and generalized MG is least in the AChK-ab assay and greatest in the KNS test, indicating that the f’ormer is relatively uniform in diagnostic sensitivity regardless of severity of MG, while the KNS test is least helpful in the diagnosis of ocular MG. Similar observations were made by St%lbergand Sanders.Ix O u r study f o u n d that the SFEMG was the crucial objective test in the 11 (9%) MG patients in whom the AChK-ab assay and KNS test were both negative, thus the SFEMG was the only test confirming diagnosis of M G in this group. O u r study also identified groups o f MG pa-
8-
722
Diagnostic Tests in MG
tients in whom the SFEMG is most helpful in confirmation of diagnosis: (1) patient with negative AChR-ab assay; (2) patients with negative RNS test; and ( 3 ) patients with mild MG ( I and IIA). In these groups, the SFEMG was the most sensitivie test, being abnormal in more than 89% of cases, indicating the great usefulriess of SFEMG in the diagnosis of MG. Traditionally, clinicians have had the greatest diagnostic difficulty in the mild MG group, because the majority of patients in this group have either a negative AChK-ab assay or normal RNS test. In Stilberg’s series, the SFEMG was abnormal in all of 17 MG patients who had a negative AChK-ab assay.” In our series, the SFEMG was abnormal in 97% of patients with negative AChR-ah assay. In 58 patients with mild MG in Kelly’s series, in whom the RNS test was normal, the SFEMG was abnormal in 92% of cases and the AChR-ab assay was positive in 80% of cases.4 In the present study, in 27 patients with mild MG, in whom the KNS test was normal, the SFEMG was abnormal in 89% of cases and the AChR-ab assay was positive in 59%. In recent years, the AChK-ab assay has been the single most useful clinical test in MG because of its relative specificity. ’Though this test is easily available, the test results may not be available for days o r weeks. ‘The most commonly available AChK-ab assay is one using purified human AChR. This test is positive in 70% to 87%) of patients with MG. 1 .:
