Clinical correlations of antiganglioside GMl antibodies are important because high titers of these antibodies may have therapeutic significance. To further evaluate this significance, we reviewed our experience with 78 patients who had the following diagnoses: amyotrophic lateral sclerosis (ALS), ALS syndromes in patients with gammopathy or thyroid abnormalities, cervical spondylosis simulating ALS, motor neuropathies, and chronic inflammatory demyelinating polyneuropathies (CIDP). Antiganglioside antibody titers were measured “blind” by ELlSA assay at the neuromuscular clinical laboratory, Johns Hopkins School of Medicine. We conclude that anti-GM1 antibodies are found in a wide variety of neuromuscular conditions. Patients with classical ALS had a mean anti-GM1 antibody titer significantly lower than patients with CIDP or motor neuropathy. Patients with ALS associated with gammopathy or thyroid disorders had higher anti-GM1 titers than seen in classical ALS. The highest mean titer occurred in patients with CIDP, a treatable neuropathy. Key words: GM1 ganglioside autoimmune amyotrophic lateral sclerosis neuropathy cervical spondylosis MUSCLE & NERVE 14:1021-1027 1991
CLINICAL CORRELATIONS OF ANTImGMI ANTIBODIES IN AMYOTROPHIC LATERAL SCLEROSIS AND NEUROPATHIES NANCY L. LAMB, MD, and BERNARD M. PATTEN, MD, FACP
Antibodies to GM1 and other gangliosides have been described in a variety of neurologic and autoimmune conditions. In 1984, Endo and associates reported a frequent occurrence of antibodies to GMl and asailo-GM1 in the sera of patients with multiple sclerosis, systemic lupus erythematosus, and even ischemic brain damage.4 In 1986, Freddo et al. reported a patient with motor neuron disease and IgM M-protein which bound to GM1, GDlb, and asailo-GM1.6 In 1988, 4 more patients were described with motor neuropathy or lower motor neuron disease and IgM M- rotein with activity against GM1 and GDlb.9,12,1? M~~~
From the Department of Neurology, Baylor College of Medicine, Houston, Texas. Acknowledgments: This work was supported by a gift from George Lindler and by some good friends. We thank Drs. Alan Pestronk and Andreas Steck for their reviews of the manuscript and helpful suggestions, and Pamela Louis for preparing the manuscript for print. Presented in part at the Annual Meeting of the American Neurological Association, New Orleans, LA, 1989 Address reprint requests to Bernard M. Patten, MD, Department of Neurology, Baylor College of Medicine, 6501 Fannin. Houston, TX 77030. Accepted for publication August 30, 1990 CCC 0148-639X/91/01001021-07 0 1991 John Wiley & Sons, Inc.
$04.00
Clinical Correlations of Anti-GM1 Antibodies
recently, others have reported GM 1 autoantibodies in patients with lower motor neuropathies, without associated g a m m ~ p a t h y . ’ ~A* ~f ew ~ , of ~~ these patients showed improvements in strength following immunosuppressive Pestronk and associates found polyclonal IgM anti-GM1 antibodies in the sera of more than 50% of patients with ALS. Similar antibodies at a titer above 40 were seen in only 8% of normal controls, and not seen in any patient with diabetic or alcohol-related neuropathy. l8 Pestronks data showed that patients with only lower motor neuron signs had the highest occurrence of anti-GM1 antibodies (85%). Patients with non-neural immune diseases also had a high frequency of anti-GM1 antibodies, whereas those with acute and chronic inflammatory polyneuropathies had a lower incidence.” In a subsequent study, Pestronk found high titer anti-GM1 antibodies were frequent in lower motor neuron syndromes associated with multifocal conduction blocks; 21 of 25 of these patients had a titer above 130. Patients with lower motor neuron syndrome, and a predominantly distal weakness, but with no conduction block, had elevated anti-GM1 antibodies in 18 of 28 cases. Patients with IgM monoclonal paraproteinemias
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showed high anti-GM1 antibody titers in 6 of 6 cases. T o further investigate the prevalence of antiGM1 antibodies, we reviewed our experience with 78 patients sent to us for evaluation of acquired motor nerve and motor neuron disease. We found that high titer anti-GM1 antibodies are more frequent in lower motor neuron syndromes than in classical ALS, a finding of possible significance in relation to recent theories about the pathogenesis of ALS3 In addition, high titers of serum IgM anti-GM 1 antibodies were frequent in chronic inflammatory polyneuropathy, a treatable neuropathy. METHODS
The series consisted of 78 patients between the ages of 29 and 79, all referred for evaluation of severe progressive neuromuscular disease. A majority of the patients had a referral diagnosis of either “ALS” or “rule out ALS.” Each patient was studied with a complete history and physical examination, neurological examinations, blood and urine tests (included SMA-20, thyroid function tests, antithyroglobulin and antimicrosoma1 antibodies, parathyroid hormone level, blood lead, mercury and aluminum, rheumatoid factor, antinuclear antibody, C3, C4, serum protein electrophoresis with high resolution, CPK, RAJI assay for circulating immune complexes, hexoseaminidase A and B levels, and antiganglioside GM1 antibody), electromyographic and nerve conduction studies, spinal tap with CSF electrophoresis, and MRI scan of the brain and cervical spinal cord. We biopsied muscle and sural nerves in 64 of 78 patients. In addition, a myelogram was done whenever spinal cord pathology was suspected, and salivary gland biopsy performed whenever Sjogren’s syndrome was suspected. This set of studies was meant to detect and to differentiate those conditions that may be associated with motor nerve or motor neuron disorder^.'^' 1 9 16 ,1 7 Following evaluation, we divided patients into 7 diagnostic groups. Group assignment was made independent of and without knowledge of the anti-GM 1 antibody titer. Patients.
Diagnostic Groups
Group 1 . ALS: Sixteen patients were diagnosed as having strictly defined ALS. All had evidence of both upper (Babinski sign or hyperreflexia) and diffuse lower motor neuron (atrophy, weakness, fasciculations) involvement with a pro-
1022
Clinical Correlations of Anti-GM1 Antibodies
gressive course not accompanied by sensory findings or unexplained bowel or bladder dysfunction. Significant bulbar muscle involvement was present in 13 of 16 patients. The presence of lower motor neuron disorders without sensory changes was supported by electrophysiologic testing with fibrillations and fasciculations of multiple muscles of upper and lower extremities and normal motor and sensory nerve conduction velocities. No patients included in group 1 had a gammopathy or a history of thyroid abnormality or high antithyroid antibodies. Other exclusionary criteria included current evidence or history of cervical cord compression or myelopathy, a history of trauma with major involvement of the central nervous system, and history, or laboratory evidence, of lead or mercury intoxication. There were 7 men and 9 women. T h e mean age was 54 years (range 35 to 77). Thus, this group consisted of only patients with classic ALS, with upper and lower motor neuron signs, and no clinical or laboratory evidence to suggest autoimmunity or any other known cause of the ALS syndrome. Group 2. ALS with gammopathy (6 patients) or thyroid disease (4 patients): Ten patients were diagnosed as having AIS associated with gammopathy or thyroid dysfunction. They met the criteria for ALS as defined above, but, in addition, had either a monoclonal gammopathy on high-resolution serum electrophoresis (6 patients), or had evidence for thyroid disease (4 patients). In each case, the diffuse lower motor neuron disease was confirmed by electrophysiologic testing showing fibrillations and fasciculations and normal motor and sensory nerve conductions in upper and lower extremities. Of the 6 with gammopathy (3 men, 3 women), each had confirmed monoclonal by immunoelectrophoresis. Of the 4 patients with thyroid disease (2 men, 2 women), 3 were hypothyroid ( 1 with thyroiditis), and one was euthyroid with high titers of antithyroid antibodies. Progressive bulbar palsy was present in 3 of 6 with gammopathy, and in all of those with thyroid abnormalities. T h e mean ages were 50 years for gammopathy (range 33 to 74) and 45 years (range 34 to 59) for the patients with thyroid disease. Thus, this group consisted of patients with ALS with upper and lower motor neuron signs who also had evidence for monoclonal gammopathy or thyroid disease. We felt it necessary to separate this group from the pure ALS of group 1, because we believe gammopathy or thyroid disease might be immunological markers that sepa-
MUSCLE & NERVE
October 1991
rate the ALS syndrome, and suggest the ossible existence of ALS of autoimmune rigi in.^,' Group 3. Cervical spondylosis with neuromuscular disease simulating ALS: Twelve patients (9 men, 3 women) had current or past cervical spondylosis with associated spinal cord compression. Most (8 of 12) of these patients had both motor and sensory findings, but motor impairment in all cases was more marked than were the sensory findings. Nine of the 12 had both upper and lower motor neuron signs. Bulbar muscle involvement was seen in 2 of 12. The cervical spine problems included: severe spondylosis with cord compression (8 of 12 patients), recent cervical laminectomy (3 of 12), and severe scoliosis and spondylosis (1 of 12). T h e mean age was 60 years (range 44 to 78). Thus, these patients referred with the diagnosis of ALS were grouped separately because they differed from groups 1 and 2 in having cervical cord compression. What relation, if any, the cord compression had to the associated neuromuscular disease simulating atypical ALS, we d o not know, but we needed a separate group for those patients whose cases did not conform to the rigidly defined groups 1 and 2. Group 4. Motor neuropathy or neuronopathy: Nine patients with lower motor neuron signs without evidence of upper motor neuron or sensory involvement were classified in group 4. These patients had symptoms of progressive weakness which was more ronounced in distal than in proximal muscles?'One patient had findings consistent with multifocal motor neuropathy (MMN), with selective motor conduction blocks on nerve conduction studies,*l but his titers of anti-GM 1 were average for this group, not high. Evidence of immunological abnormalities other than anti-GM 1 antibodies was seen in 4 of 9 patients in this group: 2 men, 1 with increased CSF IgG production and 1 with circulating immune complexes by RAG1 assay; and 2 women, 1 with Sjogren's syndrome clinically and by biopsy, and 1 with thyroiditis. The other 5 patients were male and without evidence of other significant laboratory abnormalities. Bulbar muscle involvement was present in 2 of 9 patients; onset of symptoms was less than 3 years prior to drawing anti-GM1 titers in most (7 of 9) patients. T h e mean age was 47 years (range 29 to 65). Thus, this group consisted of patients with evidence of lower motor neuron dysfunction without upper motor neuron or sensory involvement. We felt it necessary to separate this group from ALS
B
Clinical Correlations of Anti-GM1 Antibodies
because these patients in general have a slower course, and this group is the one Pestronk found had the highest incidence of the highest titers of anti-GM1 antibodies and the best chance of responding to treatment. ''-'' Group 5A. CIDP, motor more than sensory: Thirteen patients had chronic inflammatory demyelinating polyneuropathy with a greater degree of motor than sensory impairment by clinical examination and by electrophysiologic testing. Although the motor findings were predominant, these patients had definite sensory findings by both neurologic examination and sensory nerve conduction studies. Clinical impression, in all cases, was supported by sural nerve biopsy showing chronic endoneurial inflammation. Additional laboratory abnormalities of interest were seen in 6 of 13 and included monoclonal gammopathies in 3 patients, a biclonal gammopathy, past history of autoimmune hyperthyroid thyroiditis, and elevated ANA and RF (1 each). Eight of the 13 were within 3 years of onset of symptoms at the time the anti-GM1 antibody titer was taken. Five were men and 8 were women; the mean age was 48 years (range 24 to 72). Thus, this group consisted of patients with clear-cut peripheral neuropathy and would not be mistaken for ALS or lower motor neuron disease. T h e idea of establishing this subgroup was to see if this group differed from the ALS groups 1, 2, or 3 in incidence or titer of anti-GM1 antibodies. Group 5B. CIDP, motor about the same or less than sensory: Eighteen patients had chronic inflammatory polyneuropathy with sensory findings, by examination and by electrophysiologic testing, which were greater than o r equal to motor nerve findings. All 18 had chronic endoneurial inflammation on sural nerve biopsy. Additional diagnoses of interest were present in 7 of 18 patients and included monoclonal gammopathies in 3, elevated ANA titer in 2, and common variable hypogammaglobulinemia and Sjogren's syndrome (1 each). The onset of symptoms was within 3 years in 6 patients, between 3 to 5 years prior to this study in 5 , and over 5 years in 7. There were 10 men and 8 women; mean age was 59 (range 38 to 79). This group had clear-cut peripheral sensory-motor neuropathy and was established to see if having a large sensory component in the clinical picture made any difference in regard to incidence or titer of anti-GM1 antibodies. Group I : pure ALS; group 2: ALS plus gammopathy or thyroid
Summary of the Clinical Groups.
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ANTIBODY VS CLINICAL DISORDER
disease subgrouped into ALS plus gammopathy, and ALS plus thyroid disease; group 3: cervical spondylosis with neuromuscular disease resembling ALS; group 4: lower motor neuron disorders with no evidence of upper motor neuron involvement; and group 5: chronic inflammatory demyelinating polyneuropathy subgrouped into CIDP, with motor signs more than sensory, and CIDP with motor signs less than or equal to sensory signs. Serum from all patients was assayed “blind” for circulating antibodies to GM 1 using thin-layer chromatography and enzymelinked immunosorbent assay methods in the neuromuscular clinical laboratory at Johns Hopkins School of Medicine. The methodology is described in recent publications by Pestronk and co-workers.14,18-20 A positive titer was considered 3 SD above the mean, i.e., >50. A high titer was considered greater than 600.
0
Antibody Assay.
Statistical analysis was by SPSSPC+ on an IBM-AT computer. Results were expressed as mean +- SD. The significance of differences between groups was tested using the nonparametric Mann- Whitney U test. The significance of correlations between variables was evaluated using 2-tailed probability from Pearson product-moment correlations. In all cases, P < 0.05 was considered significant.
f(3 . L
w
2
600
-
350.
:
Statistical Analysis.
RESULTS
Frequency of Anti-GM 1 Antibodies and Mean Titers. The incidence of anti-GM1 antibodies varied among the groups and subgroups from 44% to 100%. The lowest incidence, 44%, was in group 1 patients with strictly defined ALS. The highest incidence was in group 2, with all patients having positive titers. The overall incidence of positive titers was 68% (Table 1). The mean titers of anti-GM 1 antibodies varied among the groups and subgroups from 57, the lowest in group 1, to 616, the highest in CIDP with motor signs more than sensory. The mean titer for all patients was 316. T h e second highest mean titer was in group 4, the lower motor neuron group (Table 1). The 1 patient with multifocal blocks on EMG did not have a high titer. The decreased incidence and lower mean titer in the group 1 ALS patients was statistically different (P < 0.05) from the incidence and titers of each of the other groups. Very high titers (>600)
1024
Clinical Correlations of Anti-GM1 Antibodies
mm
mm
ALS
LS
tG
WN
I IDP I>S
FIGURE 1. IgM antiganglioside GM1 antibody titer in amyotrophic lateral sclerosis (ALS), ALS with monoclonal gammopa thy (ALS + G), ALS with thyroid abnormalities (ALS + thyroid), cervical spondylosis (CSp), lower motor neuron syndromes (MN), chronic inflammatory demyelinating polyneuropathy with motor greater than sensory involvement (CIDP M > S), and CIDP with sensory findings comparable with or greater than motor involvement (CIDP [Lz]S). High anti-GM1 antibody titers occurred most frequently in CIDP with M > S and in MN, but were also seen in ClDP with M [Lz] S. Anti-GM1 titers above 600 were not seen in ALS.
were associated with cervical spondylosis (l),lower motor neuron disease (2), CIDP (lo), and not just with lower motor neuron disease as reported.’’ No patient in ALS groups 1 or 2 had a titer greater than 600. Correlations of Anti-GY1 Antibody Titer With Other Variables. The mean anti-GM1 titer from 34 of
78 patients with immunologic laboratory abnormalities (positive for gammopathy, ANA, RF, antithyroid antibodies, RAJI, Sjogren’s syndrome, high CSF IgG, or hypogammaglobulinemia) was above the mean titer for patients without additional abnormal immune laboratory findings, but the difference was not statistically significant. On
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*
Table 1. IgM anti-GM1 antibody titer. Diagnostic group
Frequency of positive (>50) Anti-GM1 antibodies
Mean IgM anti-GM1 titer
Standard deviation
7116, 44% 616, 100% 414, 100% 7/12, 58% 719, 78% 10113, 77% 12/18, 67% 53178, 68%
57 246 292 244 556 616 283 316
103 95 194 31 7 599 562 405 423
ALS ALS and garnrnopathy ALS and thyroid abnormalities Cervical spondylosis Motor neuropathy CIDP, motor > sensory CIDP, motor 5 sensory All cases
Note Mean lgM anti-GM7 antibody titer in ALS. ALS with gammopathy and with thyroid hormone abnormalities, cervical spondylosis, lower motor neuron, and chronic inflammatory demyebnating polyneuropathies (CIDP) with predominance of motor findings and with sensory and motor findings of comparable severity The mean serum lgM anti-GM1 antibody titer was lowest in ALS and highest in ClDP with a predominance of motor neuropathy. when compared with the other groups
CIDP, the mean titer from the 13 of 31 patients with immunologic laboratory abnormalities was only slightly above the mean titer for the entire CIDP group. There were no significant correlations between anti-GM 1 titer and the following variables: age, sex, presence of bulbar muscle involvement, presence or absence of inflammation or demyelination on sural nerve biopsy, and onset of symptoms longer or shorter than 3 years prior to obtaining the anti-GM1 titer. Thirteen of 78 patients had monoclonal gammopathy, including 6 of 26 ALS patients (groups 1 and 2), and 6 from the CIDP group. One patient with CIDP had a biclonal gammopathy. Monoclonal Gammopathies.
DISCUSSION
Our data show a high frequency of serum antibodies reacting with the GM1 ganglioside in patients in groups 4 and 5. T h e lowest frequency of significant antiganglioside antibodies, as well as the lowest mean titer, occurred in group 1, i.e., ALS which was not accompanied by a thyroid abnormality or a monoclonal gammopathy. ALS patients with gammopathy o r thyroid disease (group 2) had titers higher than patients with strictly defined ALS in group 1. The occurrence of higher anti-GM 1 antibody titers in ALS patients with thyropathic findings, compared with other ALS patients, has not previously been explored in detail and the significance of this finding is not known. This could, but not
Clinical Correlations of Anti-GM1 Antibodies
necessarily, reflect abnormal immune activity in a subset of ALS In contrast to reports by Pestronk and associates,18’*’ we observed anti-GM1 antibodies to be frequent in patients with motor and sensory neuropathy. The differences in findings may reflect differences in criteria used for classification of chronic inflammatory polyneuropathy, a heterogeneous syndrome with few established or standardized clinical subclassifications, and differences in patient population for CIDP in our referral practice(s). We included 13 patients in our CIDP groups with additional immunologic findings; however, these 13 patients had similar anti-GM1 antibody titers to the other patients with CIDP without abnormal immunologic laboratory findings and, therefore, it is unlikely that inclusion of such patients explains the observed difference. Twenty-one of 30 (70%) of our patients with CIDP had elevated titers of anti-GM1 antibodies, with 12 of 30 of these patients having high titers above 350. In comparison, all of a group of 24 CIDP patients assayed in the same laboratory were found to have anti-GM 1 antibody titers below 350.” Patients in this series, with recent or current evidence of cervical spinal cord pathology secondary to severe cervical spondylosis (group 3), showed moderate to high titers of anti-GM1 antibodies; this is a heterogeneous group of patients. Two patients in this group with bulbar findings may have had ALS, and others may have had peripheral motor neuropathies or CIDP in addition to, and unrelated to, their diagnosis of significant cervical spondylosis. It is, however, prudent to ei-
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ther subdivide or to exclude these patients from other diagnostic groups because the possibility of an etiologic relationship between significant CNS insults and a subset of ALS, and also of motor neuropathy, has not been ruled out.5*7*871031s,23 In addition, since traumatic and ischemic brain damage may affect antiganglioside antibody a ~ t i v i t y , ~ ongoing spinal cord insult resulting from spondylosis could have a similar effect. Whether antiganglioside GM 1 antibodies are primarily or secondarily related to neural tissue damage, or whether they represent nonpathogenic indicators of autoimmune reactivity, is not yet known. The association observed between gammopathies and n e u r ~ p a t h y , ~I7~ ~and ~ ' ~the association observed between multifocal motor neuropathy and high titer anti-GM 1 antibodies with improvement in some patients following immunosuppression*l V z 5raised the question of a possible primary relationship between these autoantibodies and nerve damage. Alternatively, the high frequency of anti-GM 1 antibodies in patients with spondylosis and associated spinal cord pathology seen in this study, and the frequent occurrence of anti-GM 1 antibodies in patients following ischemic and traumatic CNS damage,4 suggests that these autoantibodies may form secondarily, following exposure of the immune system to damaged neural tissue. If these autoantibodies form as a secondary response to neural tissue damage, it is possible that, once present, they contribute to further neural tissue injury. The GM1 ganglioside represents a likely target
for autoimmune attack because it is a constituent of cell membranes and is found in particularly high concentrations in the membranes of neural tissue. GMl, along with 4 other gangliosides, (GDla, GDlb, GTla, and GTlb) constitute about 80% to 90% of the total gangliosides in most mammalian brains," and GMl has been found to be the most abundant ganglioside in human CNS myelin. l3 Fine specificities to antibodies reacting with GM1 ganglioside have been studied by Baba et a1.' They found GM1 was the only common ganglioside that reacted with antibodies in all of 3 patients studied with multifocal motor neuropathy; this suggested that GM1 could be a princi a1 target antigen in multifocal motor neuropathy. In a larger sense, our analysis emphasizes the variety and complexity of clinical and laboratory findings in patients with ALS, motor neuron and motor nerve syndromes, and CIDP. We agree with reports by others that there appears to be an association between high titers of anti-GM1 antibodies and lower motor nerve and neuron synd r o m e ~ however ~~; anti-GM1 antibodies of comparable titers may also be seen in CIDP. In addition, there may be a relationship between spinal cord insult from severe cervical spondylosis and Occurrence of anti-GM1 antibodies, but the reason for this relationship is unclear. When the nature of these antiglycolipid antibodies and the autoimmune mechanism associated with them is more clearly elucidated, measurement of antiganglioside antibodies may prove to be a useful adjunct to the evaluation of these patients.
P
REFERENCES 1. Appel S, Stockton-Appel V, Stewart S, Kerman RH: Amyotrophic lateral sclerosis. Associated clinical disorders and immunological evaluations. Arch Neurol 1986;43:234- 238. 2. Baba H, Daune GC, Ilyas AA, Pestronk A, Cornblath DR, Chaudhry V, Griffin JW, Quarles Rh: Anti-GM1 ganglioside antibodies with differing fine specificities in patients with multifocal motor neuropathy. J Neurozmmunol 1989;25:143- 149. 3. Drachman DB, Kuncl W: Amyotrophic lateral sclerosis: An unconventional autoimmune disease? Ann Neurol 1989;26:269-274. 4. Endo T, Scott DD, Stewart SS, Kundu SK, Marcus DM: Antibodies to glycosphingolipids in patients with multiple sclerosis and SLE. J Immunol 1984;132:1793- 1797. 5. Felmus MT, Patten BM, Swanke L: Antecedent events in amyotrophic lateral sclerosis. Neurology 1976;26: 167- 172. 6. Freddo L: Gangliosides GMl and GDlb are antigens for IgM M-protein in a patient with motor neuron disease. Neurology 1986;36:454-458. 7. Gallagher JP, Sanders M: Trauma and amyotrophic lateral sclerosis: a report of 78 patients. Acta Neurol Scand 1987;75:145- 150. 8. Gresham LS, Molgaard CA, Golbeck AL, Smith R: Amyo-
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Clinical Correlations of Anti-GM1 Antibodies
trophic lateral sclerosis and history of skeletal fracture: a case-control study. Neurology 1987;37:717- 719. 9. Ito H, Latov N: Monoclonal IgM in two patients with motor neuron disease bind to the carbohydrate antigens Gal(B1-3)GalNAc and Gal(B1-3)GlcNAc. J Neuroimmunol 1988;19:245-253. 10. Juergens SM, Kurland LT, Okazaki H, Mulder DW: ALS in Rochester, Minnesota, 1925- 1977. Neurology 1980;30:464-470. 11. Kasdon DL: Cervical spondylitic myelopathy with reversible fasciculations in the lower extremities. Arch Neurol 1977;34:774-776. 12. Latov N, Hays AP, Donofrio PD, Liap J , Ito H, McGinnis S, et al: Monoclonal IgM with unique specificity to gangliosides GMl and GDlb and to lacto-N-tetraose associated with human motor neuron disease. Neurology 1988;38:763-768. 13. Leeden RW, Cochran FB, Yu RK, et al: Gangliosides of the CNS myelin membrane. Adv Exp Med Eiol 1980;125:167- 176. 14. Marcus DM, Latov N, Hsi BP, Gillard BK: Measurement and significance of antibodies against GM 1 ganglioside. J Neuroimmunol 1989;25: 255- 259.
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15. Nardelli E, Steck AJ, Barkas T, Schleup M, Jerusalem F: Motor neuron syndrome and monoclonal IgM with antibody activity against gangliosides GMl and GDlb. Ann Neural 1988;23:524-528. 16. Patten BM: The syndromic nature of amyotrophic lateral sclerosis. Adv Exp Med Biol 1987;209:99- 107. 17. Patten BM: Neuropathy and motor neuron syndromes associated with plasma cell disease. Acta Neural Scand 1984;70:47-61. 18. Pestronk A, Adams RN, Clawson L, Cornblath D, Kunel RW, Griffen D, Drachman DB: Serum antibodies to GMI ganglioside in amyotrophic lateral sclerosis. Neurology 1988;38:1457- 1461. 19. Pestronk A, Adams RN, Cornblath D, Kuncl RW, Drachman DB, Clawson L: Patterns of serum IgM antibodies to GM 1 and GDla gangliosides in amyotrophic lateral sclerosis. Ann Neural 1989;25:98- 102. 20. Pestronk A, Chaudhry V, Feldman EL, Griffin JW, Cornblath DR, Denys EH, Glasberg M, Kuncl RW, Olney RK, Yee WC: Lower motor neuron syndrome defined by patterns of weakness, nerve conduction abnormalities, and
Clinical Correlations of Anti-GM1 Antibodies
21.
22.
23.
24.
25.
high titers of antiglycolipid antibodies. Ann Neural 1990;27:316-326. Pestronk A, Cornblath DR, Ilyas AA, Baba H, Quarles RH, Griffin JW, Alderson K, Adams RN: A treatable multifocal motor neuropathy with antibodies to GM 1 ganglioside. Ann Neurol 1988;24:73-78. Rapport MM, Donnenfeld H , Brunner W, Hungund B, Bartfeld H: Ganglioside patterns in amyotrophic lateral sclerosisamyotrophic lateral sclerosis brain regions. Ann Neural 1985; 18:60- 67. Riggs JE: Trauma and amyotrophic lateral sclerosis. Arch Neurol 1985;42:205. Shy ME, Evans VA, Lublin FD, Knobler RL, HeimanPatterson T, Tahmoush AJ, Parry G: Anti-GM1 antibodies in motor neuron disease patients without plasma cell dyscrasia. Ann Neurol 1987;22:167. Shy ME, Heiman-Patterson T, Parry GJ, Tahmoush AJ, Evans VA, Schick PK: Motor neuropathy in a patient with autoantibodies against ganglioside GMl and GDlb: lmNeurapathj provement following immunotherapy. 1988;38:252.
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CLINICAL CORRELATIONS OF ANTImGMI ANTIBODIES IN AMYOTROPHIC LATERAL SCLEROSIS AND NEUROPATHIES NANCY L. LAMB, MD, and BERNARD M. PATTEN, MD, FACP
Antibodies to GM1 and other gangliosides have been described in a variety of neurologic and autoimmune conditions. In 1984, Endo and associates reported a frequent occurrence of antibodies to GMl and asailo-GM1 in the sera of patients with multiple sclerosis, systemic lupus erythematosus, and even ischemic brain damage.4 In 1986, Freddo et al. reported a patient with motor neuron disease and IgM M-protein which bound to GM1, GDlb, and asailo-GM1.6 In 1988, 4 more patients were described with motor neuropathy or lower motor neuron disease and IgM M- rotein with activity against GM1 and GDlb.9,12,1? M~~~
From the Department of Neurology, Baylor College of Medicine, Houston, Texas. Acknowledgments: This work was supported by a gift from George Lindler and by some good friends. We thank Drs. Alan Pestronk and Andreas Steck for their reviews of the manuscript and helpful suggestions, and Pamela Louis for preparing the manuscript for print. Presented in part at the Annual Meeting of the American Neurological Association, New Orleans, LA, 1989 Address reprint requests to Bernard M. Patten, MD, Department of Neurology, Baylor College of Medicine, 6501 Fannin. Houston, TX 77030. Accepted for publication August 30, 1990 CCC 0148-639X/91/01001021-07 0 1991 John Wiley & Sons, Inc.
$04.00
Clinical Correlations of Anti-GM1 Antibodies
recently, others have reported GM 1 autoantibodies in patients with lower motor neuropathies, without associated g a m m ~ p a t h y . ’ ~A* ~f ew ~ , of ~~ these patients showed improvements in strength following immunosuppressive Pestronk and associates found polyclonal IgM anti-GM1 antibodies in the sera of more than 50% of patients with ALS. Similar antibodies at a titer above 40 were seen in only 8% of normal controls, and not seen in any patient with diabetic or alcohol-related neuropathy. l8 Pestronks data showed that patients with only lower motor neuron signs had the highest occurrence of anti-GM1 antibodies (85%). Patients with non-neural immune diseases also had a high frequency of anti-GM1 antibodies, whereas those with acute and chronic inflammatory polyneuropathies had a lower incidence.” In a subsequent study, Pestronk found high titer anti-GM1 antibodies were frequent in lower motor neuron syndromes associated with multifocal conduction blocks; 21 of 25 of these patients had a titer above 130. Patients with lower motor neuron syndrome, and a predominantly distal weakness, but with no conduction block, had elevated anti-GM1 antibodies in 18 of 28 cases. Patients with IgM monoclonal paraproteinemias
MUSCLE & NERVE
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1021
showed high anti-GM1 antibody titers in 6 of 6 cases. T o further investigate the prevalence of antiGM1 antibodies, we reviewed our experience with 78 patients sent to us for evaluation of acquired motor nerve and motor neuron disease. We found that high titer anti-GM1 antibodies are more frequent in lower motor neuron syndromes than in classical ALS, a finding of possible significance in relation to recent theories about the pathogenesis of ALS3 In addition, high titers of serum IgM anti-GM 1 antibodies were frequent in chronic inflammatory polyneuropathy, a treatable neuropathy. METHODS
The series consisted of 78 patients between the ages of 29 and 79, all referred for evaluation of severe progressive neuromuscular disease. A majority of the patients had a referral diagnosis of either “ALS” or “rule out ALS.” Each patient was studied with a complete history and physical examination, neurological examinations, blood and urine tests (included SMA-20, thyroid function tests, antithyroglobulin and antimicrosoma1 antibodies, parathyroid hormone level, blood lead, mercury and aluminum, rheumatoid factor, antinuclear antibody, C3, C4, serum protein electrophoresis with high resolution, CPK, RAJI assay for circulating immune complexes, hexoseaminidase A and B levels, and antiganglioside GM1 antibody), electromyographic and nerve conduction studies, spinal tap with CSF electrophoresis, and MRI scan of the brain and cervical spinal cord. We biopsied muscle and sural nerves in 64 of 78 patients. In addition, a myelogram was done whenever spinal cord pathology was suspected, and salivary gland biopsy performed whenever Sjogren’s syndrome was suspected. This set of studies was meant to detect and to differentiate those conditions that may be associated with motor nerve or motor neuron disorder^.'^' 1 9 16 ,1 7 Following evaluation, we divided patients into 7 diagnostic groups. Group assignment was made independent of and without knowledge of the anti-GM 1 antibody titer. Patients.
Diagnostic Groups
Group 1 . ALS: Sixteen patients were diagnosed as having strictly defined ALS. All had evidence of both upper (Babinski sign or hyperreflexia) and diffuse lower motor neuron (atrophy, weakness, fasciculations) involvement with a pro-
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Clinical Correlations of Anti-GM1 Antibodies
gressive course not accompanied by sensory findings or unexplained bowel or bladder dysfunction. Significant bulbar muscle involvement was present in 13 of 16 patients. The presence of lower motor neuron disorders without sensory changes was supported by electrophysiologic testing with fibrillations and fasciculations of multiple muscles of upper and lower extremities and normal motor and sensory nerve conduction velocities. No patients included in group 1 had a gammopathy or a history of thyroid abnormality or high antithyroid antibodies. Other exclusionary criteria included current evidence or history of cervical cord compression or myelopathy, a history of trauma with major involvement of the central nervous system, and history, or laboratory evidence, of lead or mercury intoxication. There were 7 men and 9 women. T h e mean age was 54 years (range 35 to 77). Thus, this group consisted of only patients with classic ALS, with upper and lower motor neuron signs, and no clinical or laboratory evidence to suggest autoimmunity or any other known cause of the ALS syndrome. Group 2. ALS with gammopathy (6 patients) or thyroid disease (4 patients): Ten patients were diagnosed as having AIS associated with gammopathy or thyroid dysfunction. They met the criteria for ALS as defined above, but, in addition, had either a monoclonal gammopathy on high-resolution serum electrophoresis (6 patients), or had evidence for thyroid disease (4 patients). In each case, the diffuse lower motor neuron disease was confirmed by electrophysiologic testing showing fibrillations and fasciculations and normal motor and sensory nerve conductions in upper and lower extremities. Of the 6 with gammopathy (3 men, 3 women), each had confirmed monoclonal by immunoelectrophoresis. Of the 4 patients with thyroid disease (2 men, 2 women), 3 were hypothyroid ( 1 with thyroiditis), and one was euthyroid with high titers of antithyroid antibodies. Progressive bulbar palsy was present in 3 of 6 with gammopathy, and in all of those with thyroid abnormalities. T h e mean ages were 50 years for gammopathy (range 33 to 74) and 45 years (range 34 to 59) for the patients with thyroid disease. Thus, this group consisted of patients with ALS with upper and lower motor neuron signs who also had evidence for monoclonal gammopathy or thyroid disease. We felt it necessary to separate this group from the pure ALS of group 1, because we believe gammopathy or thyroid disease might be immunological markers that sepa-
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rate the ALS syndrome, and suggest the ossible existence of ALS of autoimmune rigi in.^,' Group 3. Cervical spondylosis with neuromuscular disease simulating ALS: Twelve patients (9 men, 3 women) had current or past cervical spondylosis with associated spinal cord compression. Most (8 of 12) of these patients had both motor and sensory findings, but motor impairment in all cases was more marked than were the sensory findings. Nine of the 12 had both upper and lower motor neuron signs. Bulbar muscle involvement was seen in 2 of 12. The cervical spine problems included: severe spondylosis with cord compression (8 of 12 patients), recent cervical laminectomy (3 of 12), and severe scoliosis and spondylosis (1 of 12). T h e mean age was 60 years (range 44 to 78). Thus, these patients referred with the diagnosis of ALS were grouped separately because they differed from groups 1 and 2 in having cervical cord compression. What relation, if any, the cord compression had to the associated neuromuscular disease simulating atypical ALS, we d o not know, but we needed a separate group for those patients whose cases did not conform to the rigidly defined groups 1 and 2. Group 4. Motor neuropathy or neuronopathy: Nine patients with lower motor neuron signs without evidence of upper motor neuron or sensory involvement were classified in group 4. These patients had symptoms of progressive weakness which was more ronounced in distal than in proximal muscles?'One patient had findings consistent with multifocal motor neuropathy (MMN), with selective motor conduction blocks on nerve conduction studies,*l but his titers of anti-GM 1 were average for this group, not high. Evidence of immunological abnormalities other than anti-GM 1 antibodies was seen in 4 of 9 patients in this group: 2 men, 1 with increased CSF IgG production and 1 with circulating immune complexes by RAG1 assay; and 2 women, 1 with Sjogren's syndrome clinically and by biopsy, and 1 with thyroiditis. The other 5 patients were male and without evidence of other significant laboratory abnormalities. Bulbar muscle involvement was present in 2 of 9 patients; onset of symptoms was less than 3 years prior to drawing anti-GM1 titers in most (7 of 9) patients. T h e mean age was 47 years (range 29 to 65). Thus, this group consisted of patients with evidence of lower motor neuron dysfunction without upper motor neuron or sensory involvement. We felt it necessary to separate this group from ALS
B
Clinical Correlations of Anti-GM1 Antibodies
because these patients in general have a slower course, and this group is the one Pestronk found had the highest incidence of the highest titers of anti-GM1 antibodies and the best chance of responding to treatment. ''-'' Group 5A. CIDP, motor more than sensory: Thirteen patients had chronic inflammatory demyelinating polyneuropathy with a greater degree of motor than sensory impairment by clinical examination and by electrophysiologic testing. Although the motor findings were predominant, these patients had definite sensory findings by both neurologic examination and sensory nerve conduction studies. Clinical impression, in all cases, was supported by sural nerve biopsy showing chronic endoneurial inflammation. Additional laboratory abnormalities of interest were seen in 6 of 13 and included monoclonal gammopathies in 3 patients, a biclonal gammopathy, past history of autoimmune hyperthyroid thyroiditis, and elevated ANA and RF (1 each). Eight of the 13 were within 3 years of onset of symptoms at the time the anti-GM1 antibody titer was taken. Five were men and 8 were women; the mean age was 48 years (range 24 to 72). Thus, this group consisted of patients with clear-cut peripheral neuropathy and would not be mistaken for ALS or lower motor neuron disease. T h e idea of establishing this subgroup was to see if this group differed from the ALS groups 1, 2, or 3 in incidence or titer of anti-GM1 antibodies. Group 5B. CIDP, motor about the same or less than sensory: Eighteen patients had chronic inflammatory polyneuropathy with sensory findings, by examination and by electrophysiologic testing, which were greater than o r equal to motor nerve findings. All 18 had chronic endoneurial inflammation on sural nerve biopsy. Additional diagnoses of interest were present in 7 of 18 patients and included monoclonal gammopathies in 3, elevated ANA titer in 2, and common variable hypogammaglobulinemia and Sjogren's syndrome (1 each). The onset of symptoms was within 3 years in 6 patients, between 3 to 5 years prior to this study in 5 , and over 5 years in 7. There were 10 men and 8 women; mean age was 59 (range 38 to 79). This group had clear-cut peripheral sensory-motor neuropathy and was established to see if having a large sensory component in the clinical picture made any difference in regard to incidence or titer of anti-GM1 antibodies. Group I : pure ALS; group 2: ALS plus gammopathy or thyroid
Summary of the Clinical Groups.
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ANTIBODY VS CLINICAL DISORDER
disease subgrouped into ALS plus gammopathy, and ALS plus thyroid disease; group 3: cervical spondylosis with neuromuscular disease resembling ALS; group 4: lower motor neuron disorders with no evidence of upper motor neuron involvement; and group 5: chronic inflammatory demyelinating polyneuropathy subgrouped into CIDP, with motor signs more than sensory, and CIDP with motor signs less than or equal to sensory signs. Serum from all patients was assayed “blind” for circulating antibodies to GM 1 using thin-layer chromatography and enzymelinked immunosorbent assay methods in the neuromuscular clinical laboratory at Johns Hopkins School of Medicine. The methodology is described in recent publications by Pestronk and co-workers.14,18-20 A positive titer was considered 3 SD above the mean, i.e., >50. A high titer was considered greater than 600.
0
Antibody Assay.
Statistical analysis was by SPSSPC+ on an IBM-AT computer. Results were expressed as mean +- SD. The significance of differences between groups was tested using the nonparametric Mann- Whitney U test. The significance of correlations between variables was evaluated using 2-tailed probability from Pearson product-moment correlations. In all cases, P < 0.05 was considered significant.
f(3 . L
w
2
600
-
350.
:
Statistical Analysis.
RESULTS
Frequency of Anti-GM 1 Antibodies and Mean Titers. The incidence of anti-GM1 antibodies varied among the groups and subgroups from 44% to 100%. The lowest incidence, 44%, was in group 1 patients with strictly defined ALS. The highest incidence was in group 2, with all patients having positive titers. The overall incidence of positive titers was 68% (Table 1). The mean titers of anti-GM 1 antibodies varied among the groups and subgroups from 57, the lowest in group 1, to 616, the highest in CIDP with motor signs more than sensory. The mean titer for all patients was 316. T h e second highest mean titer was in group 4, the lower motor neuron group (Table 1). The 1 patient with multifocal blocks on EMG did not have a high titer. The decreased incidence and lower mean titer in the group 1 ALS patients was statistically different (P < 0.05) from the incidence and titers of each of the other groups. Very high titers (>600)
1024
Clinical Correlations of Anti-GM1 Antibodies
mm
mm
ALS
LS
tG
WN
I IDP I>S
FIGURE 1. IgM antiganglioside GM1 antibody titer in amyotrophic lateral sclerosis (ALS), ALS with monoclonal gammopa thy (ALS + G), ALS with thyroid abnormalities (ALS + thyroid), cervical spondylosis (CSp), lower motor neuron syndromes (MN), chronic inflammatory demyelinating polyneuropathy with motor greater than sensory involvement (CIDP M > S), and CIDP with sensory findings comparable with or greater than motor involvement (CIDP [Lz]S). High anti-GM1 antibody titers occurred most frequently in CIDP with M > S and in MN, but were also seen in ClDP with M [Lz] S. Anti-GM1 titers above 600 were not seen in ALS.
were associated with cervical spondylosis (l),lower motor neuron disease (2), CIDP (lo), and not just with lower motor neuron disease as reported.’’ No patient in ALS groups 1 or 2 had a titer greater than 600. Correlations of Anti-GY1 Antibody Titer With Other Variables. The mean anti-GM1 titer from 34 of
78 patients with immunologic laboratory abnormalities (positive for gammopathy, ANA, RF, antithyroid antibodies, RAJI, Sjogren’s syndrome, high CSF IgG, or hypogammaglobulinemia) was above the mean titer for patients without additional abnormal immune laboratory findings, but the difference was not statistically significant. On
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*
Table 1. IgM anti-GM1 antibody titer. Diagnostic group
Frequency of positive (>50) Anti-GM1 antibodies
Mean IgM anti-GM1 titer
Standard deviation
7116, 44% 616, 100% 414, 100% 7/12, 58% 719, 78% 10113, 77% 12/18, 67% 53178, 68%
57 246 292 244 556 616 283 316
103 95 194 31 7 599 562 405 423
ALS ALS and garnrnopathy ALS and thyroid abnormalities Cervical spondylosis Motor neuropathy CIDP, motor > sensory CIDP, motor 5 sensory All cases
Note Mean lgM anti-GM7 antibody titer in ALS. ALS with gammopathy and with thyroid hormone abnormalities, cervical spondylosis, lower motor neuron, and chronic inflammatory demyebnating polyneuropathies (CIDP) with predominance of motor findings and with sensory and motor findings of comparable severity The mean serum lgM anti-GM1 antibody titer was lowest in ALS and highest in ClDP with a predominance of motor neuropathy. when compared with the other groups
CIDP, the mean titer from the 13 of 31 patients with immunologic laboratory abnormalities was only slightly above the mean titer for the entire CIDP group. There were no significant correlations between anti-GM 1 titer and the following variables: age, sex, presence of bulbar muscle involvement, presence or absence of inflammation or demyelination on sural nerve biopsy, and onset of symptoms longer or shorter than 3 years prior to obtaining the anti-GM1 titer. Thirteen of 78 patients had monoclonal gammopathy, including 6 of 26 ALS patients (groups 1 and 2), and 6 from the CIDP group. One patient with CIDP had a biclonal gammopathy. Monoclonal Gammopathies.
DISCUSSION
Our data show a high frequency of serum antibodies reacting with the GM1 ganglioside in patients in groups 4 and 5. T h e lowest frequency of significant antiganglioside antibodies, as well as the lowest mean titer, occurred in group 1, i.e., ALS which was not accompanied by a thyroid abnormality or a monoclonal gammopathy. ALS patients with gammopathy o r thyroid disease (group 2) had titers higher than patients with strictly defined ALS in group 1. The occurrence of higher anti-GM 1 antibody titers in ALS patients with thyropathic findings, compared with other ALS patients, has not previously been explored in detail and the significance of this finding is not known. This could, but not
Clinical Correlations of Anti-GM1 Antibodies
necessarily, reflect abnormal immune activity in a subset of ALS In contrast to reports by Pestronk and associates,18’*’ we observed anti-GM1 antibodies to be frequent in patients with motor and sensory neuropathy. The differences in findings may reflect differences in criteria used for classification of chronic inflammatory polyneuropathy, a heterogeneous syndrome with few established or standardized clinical subclassifications, and differences in patient population for CIDP in our referral practice(s). We included 13 patients in our CIDP groups with additional immunologic findings; however, these 13 patients had similar anti-GM1 antibody titers to the other patients with CIDP without abnormal immunologic laboratory findings and, therefore, it is unlikely that inclusion of such patients explains the observed difference. Twenty-one of 30 (70%) of our patients with CIDP had elevated titers of anti-GM1 antibodies, with 12 of 30 of these patients having high titers above 350. In comparison, all of a group of 24 CIDP patients assayed in the same laboratory were found to have anti-GM 1 antibody titers below 350.” Patients in this series, with recent or current evidence of cervical spinal cord pathology secondary to severe cervical spondylosis (group 3), showed moderate to high titers of anti-GM1 antibodies; this is a heterogeneous group of patients. Two patients in this group with bulbar findings may have had ALS, and others may have had peripheral motor neuropathies or CIDP in addition to, and unrelated to, their diagnosis of significant cervical spondylosis. It is, however, prudent to ei-
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1025
ther subdivide or to exclude these patients from other diagnostic groups because the possibility of an etiologic relationship between significant CNS insults and a subset of ALS, and also of motor neuropathy, has not been ruled out.5*7*871031s,23 In addition, since traumatic and ischemic brain damage may affect antiganglioside antibody a ~ t i v i t y , ~ ongoing spinal cord insult resulting from spondylosis could have a similar effect. Whether antiganglioside GM 1 antibodies are primarily or secondarily related to neural tissue damage, or whether they represent nonpathogenic indicators of autoimmune reactivity, is not yet known. The association observed between gammopathies and n e u r ~ p a t h y , ~I7~ ~and ~ ' ~the association observed between multifocal motor neuropathy and high titer anti-GM 1 antibodies with improvement in some patients following immunosuppression*l V z 5raised the question of a possible primary relationship between these autoantibodies and nerve damage. Alternatively, the high frequency of anti-GM 1 antibodies in patients with spondylosis and associated spinal cord pathology seen in this study, and the frequent occurrence of anti-GM 1 antibodies in patients following ischemic and traumatic CNS damage,4 suggests that these autoantibodies may form secondarily, following exposure of the immune system to damaged neural tissue. If these autoantibodies form as a secondary response to neural tissue damage, it is possible that, once present, they contribute to further neural tissue injury. The GM1 ganglioside represents a likely target
for autoimmune attack because it is a constituent of cell membranes and is found in particularly high concentrations in the membranes of neural tissue. GMl, along with 4 other gangliosides, (GDla, GDlb, GTla, and GTlb) constitute about 80% to 90% of the total gangliosides in most mammalian brains," and GMl has been found to be the most abundant ganglioside in human CNS myelin. l3 Fine specificities to antibodies reacting with GM1 ganglioside have been studied by Baba et a1.' They found GM1 was the only common ganglioside that reacted with antibodies in all of 3 patients studied with multifocal motor neuropathy; this suggested that GM1 could be a princi a1 target antigen in multifocal motor neuropathy. In a larger sense, our analysis emphasizes the variety and complexity of clinical and laboratory findings in patients with ALS, motor neuron and motor nerve syndromes, and CIDP. We agree with reports by others that there appears to be an association between high titers of anti-GM1 antibodies and lower motor nerve and neuron synd r o m e ~ however ~~; anti-GM1 antibodies of comparable titers may also be seen in CIDP. In addition, there may be a relationship between spinal cord insult from severe cervical spondylosis and Occurrence of anti-GM1 antibodies, but the reason for this relationship is unclear. When the nature of these antiglycolipid antibodies and the autoimmune mechanism associated with them is more clearly elucidated, measurement of antiganglioside antibodies may prove to be a useful adjunct to the evaluation of these patients.
P
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15. Nardelli E, Steck AJ, Barkas T, Schleup M, Jerusalem F: Motor neuron syndrome and monoclonal IgM with antibody activity against gangliosides GMl and GDlb. Ann Neural 1988;23:524-528. 16. Patten BM: The syndromic nature of amyotrophic lateral sclerosis. Adv Exp Med Biol 1987;209:99- 107. 17. Patten BM: Neuropathy and motor neuron syndromes associated with plasma cell disease. Acta Neural Scand 1984;70:47-61. 18. Pestronk A, Adams RN, Clawson L, Cornblath D, Kunel RW, Griffen D, Drachman DB: Serum antibodies to GMI ganglioside in amyotrophic lateral sclerosis. Neurology 1988;38:1457- 1461. 19. Pestronk A, Adams RN, Cornblath D, Kuncl RW, Drachman DB, Clawson L: Patterns of serum IgM antibodies to GM 1 and GDla gangliosides in amyotrophic lateral sclerosis. Ann Neural 1989;25:98- 102. 20. Pestronk A, Chaudhry V, Feldman EL, Griffin JW, Cornblath DR, Denys EH, Glasberg M, Kuncl RW, Olney RK, Yee WC: Lower motor neuron syndrome defined by patterns of weakness, nerve conduction abnormalities, and
Clinical Correlations of Anti-GM1 Antibodies
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