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Myasthenia gravis on the Dutch antilles: an epidemiological study
Clinical Neurology and Neurosurgery 102 (2000) 195 – 198 www.elsevier.com/locate/clineuro
Myasthenia gravis on the Dutch antilles: an epidemiological study H. Holtsema a, J. Mourik b, R.E. Rico b, J.R. Falconi c, J.B.M. Kuks a, H.J.G.H. Oosterhuis a,* a
Department of Neurology, Uni6ersity Hospital Groningen, Groningen, The Netherlands b Elisabeth Hospital, Curac¸ao, Dutch Antilles, The Netherlands c H. Oracio Oduber Hospital, Aruba, Dutch Antilles, The Netherlands
Received 9 August 1999; received in revised form 14 August 2000; accepted 14 August 2000
Abstract We carried out an epidemiological study on the prevalence and annual incidence of myasthenia gravis on tropical islands Curac¸ao and Aruba in the period 1980–1995. Twenty-one patients (seven men and 14 women) were identified. The point prevalence increased from 29 per million in 1980 to about 70 per million in 1990 – 1995; the annual incidence over the total period was 4.7 per million. The female:male ratio was 2:1; purely ocular cases (2/21) comprised 9.5% and thymomas (4/21), 19%. These data are in accordance with most other epidemiological studies in non-tropical areas. No other studies on myasthenia gravis in tropical areas have been reported. © 2000 Elsevier Science B.V. All rights reserved.
1. Introduction Myasthenia gravis (MG) is an acquired antibody mediated autoimmune disease, causing a functional shortage of the acetylcholine receptors (AChR) at the muscular endplates. The result is a fluctuating weakness of voluntary muscles, with a predominance of the extraocular and bulbar muscles. Epidemiological studies of MG in the past concerned mostly populations in Western Europe, Northern America and Asia (Table 1) [1 – 12]. We present an epidemiological study of MG on the two tropical islands — Curac¸ao and Aruba. They are located in front of the coast of Venezuela (position 12°N, 69°W) and are a part of The Netherlands. The medical care on these islands corresponds to Western standards and most physicians have had their professional training in The Netherlands.
2. Patients and methods All the patients known at the neurological practices at the St. Elisabeth Hospital on Curac¸ao and of the H. * Corresponding author. Present address: P.O. Box 30.001, 9700 RB Gronigen, the Netherlands. Tel./fax: + 31-50-3611707.
Oracio Oduber Hospital on Aruba between 1 January 1980 and 1 January 1997 were evaluated. Inclusion criteria were: unequivocal clinical symptoms, a positive reaction to anticholinesterases and/or the presence of antibodies to acetylcholine receptors (AchR) and/or a decrement of the compound muscle action potential to B 85% at supramaximal nerve stimulation. Twenty-one patients (Curac¸ao 13, Aruba 8) met these criteria. Data were collected by a review of the local medical records and of the records of the Academic Hospital Groningen, where some of the patients were treated. Recent information on actual clinical condition and treatment was collected by interview and examination in nine patients and by telephonic interview in six other patients. The prevalence was defined on 1 January 1980, 1 January 1985, 1 January 1990, 1 January 1995. The first symptoms were those present at any time of the first 3 months of the disease. The maximal severity was indicated on a six points global disability scale (0 =remission, 5= respiratory crisis) as was earlier described [13]. Remission was defined as lack of specific MG complains or signs. Much impro6ed as a change of two on the global disability scale. Impro6ed as a change of one point on the global disability scale. Antibodies against AChR were measured in 20 patients with the immunoprecipitation test [14].
0303-8467/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 0 ) 0 0 1 0 3 - 7
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
196
3. Results
3.2. Onset
3.1. Epidemiology
The age at onset ranged from 5 to 75 years (mean 33 years, median 31 years). The presenting signs were ocular in nine (48%), bulbar in five (23%), oculobulbar in two (10%), in the extremities in two (10%) and generalized in three (14%) patients. In only two of the nine patients with initial ocular symptoms, the MG remained purely ocular. Most patients (n= 16) were diagnosed within 1 year after onset, four patients after 1–5 years.
The follow-up in our study ranged from 1 to 25 years (mean 11, median 9 years). Twenty-one patients (14 women and seven men) met the criteria. An overview of demographic and clinical data is given in Fig. 1. None of the patients had a family member with MG. Table 2 shows the point prevalence and annual incidence of MG per million inhabitants in our population.
Table 1 Reported incidence and prevalence of myasthenia gravis Country
Study period
Annual incidencea
Prevalence (per million)a
Reference
Norway Finland
1951–1981 1974
4.0 –
90 (81–100) 52 (45–59)
[1] [2]
Japan Kumamoto
1982
–
67 (52–85)
[3]
The Netherlands Amsterdam
1926–1965
4.0
56 (46–81)
[4]
Italy Sardinia Bologna Ferrara Emilia Romana
1958–1986 1987–1988 1987–1988 1993–1994
2.5 – – 14.7b
45 49 (36–66) 97 (64–128)
[5] [6] [6] [7]
Denmark Eastern Viborg Western
1970–1987 1973–1987c 1975–1989
4.4 9.8 5.0
77 (67–90) 125 (84–180) 78
[8] [9] [10]
Hong Kong
1975–1987
4.0
54
[11]
USA Virginia
1970–1984
9.1
142 (112–178)
[12]
UK Cambridgeshire
1965–1995
11
150 (120–180)
[16]
a
( ) 95% confidence interval. Prospective study. c Two neonatal cases excluded. b
Table 2 Point prevalence and annual incidence of MG per million inhabitants Population of Curac¸ao and Arubaa
1 January 1980
208.000
6
28.8
1 January 1985
215.830
9
41.6
1 January 1990
208.455
18
86.5
1 January 1995 1980–1995
229.800
15
65.2
a b
Source: census. Per million.
Number of patients present
Prevalenceb
Date
Newly diagnosed patients
Annual incidence
3
2.8
8
7.5
4
3.6
15
4.7
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
197
years and deteriorated shortly, thereafter. Another man (age 34) had a severe course with repeating crises and died 1 year after onset and thymomectomy in a septic shock. Fourteen patients without thymoma underwent thymectomy 1–15 years (ten within 3 years), after onset, three came in a remission, five were much improved and took only a small dosage of anticholinesterases, six were not improved and were treated with prednisone. Six patients had a myasthenic crisis and two of these died, probably due to inadequate medication. Three further patients from our group died, one patient (W 28 years, see above) succumbed to a sepsis; two patients (M 45 years and W 60 years) died from a prostate and an ovary carcinoma, respectively, when their MG was in remission.
4. Discussion
Fig. 1. Demographic and clinical data.
3.3. Antibodies against AChR Thirteen out of twenty patients had a positive antiAChR-ab test (] 2 nmol/l), two patients had values 1 – 2 nmol/l; in the two ocular and in three generalized patients, the test was negative (Fig. 1).
3.4. Other auto-immune diseases Three patients with concomitant autoimmune disease were found in our group. A female patient (onset 19 years) underwent a cervical thymectomy 1 year after onset, but did not improve and was treated with prednisone and azathioprine with much improvement. She developed a necrotic vasculitis and died at the age of 28 due to a sinus thrombosis and multiple internal organ abscesses (no thymic remnants were found at autopsy). A man with a thymoma (onset 32 years) developed an alopecia totalis at the age of 45 years. A woman with purely ocular MG at age had undergone a thyroidectomy 4 years before, because of hyperthyroidism.
3.5. Course of the disease
Eighteen of the 21 patients underwent thymectomy. Four patients (21%) had a thymoma. None of these improved after the operation. On the contrary, MG, rather, worsened after thymomectomy, in spite of complete removal of the tumour. One patient (M 35) was operated after a period of mild MG during 12
The prevalence and annual incidence of MG on Curac¸ao and Aruba in the period 1985–1997 fell in the range of the values reported for non-tropical areas (Table 1). Also, other parameters such as the female:male ratio (2:1), the fraction of pure ocular cases and of thymomas is in accordance with other reports [8,15]. The increasing prevalence and incidence in the last decades which seems to become apparent in the data from Table 1 in a study of the published populations [17] might also be present in this population between 1985 and 1995 but the small number of patients, makes this uncertain. The annual incidences and the prevalences in our study did not change appreciably over the various 5 year periods and are more or less comparable with the data of other populations. In the most recent studies [7,16] the annual incidence as well as the prevalence is increased as compared with the older ones, although also somewhat older reviews [9,12] have relatively high incidences. Improved diagnostic facilities (anti-AChR test since 1978–1983), single fibre EMG since 1985 and a greater diagnostic suspicion may have been important, especially in the diagnosis of purely ocular cases [17]. The increased prevalence will also be explained by a longer life span in general and by the specific treatment. It is difficult to know which factors have played a decisive role in this population. In fact, all patients with generalized MG under the age of 50 and all the patients with thymomas underwent thymectomy, as is generally advised. Although the number of patients in this study is small, we can conclude that the epidemiological results found in this study of a population in a tropical area do not differ from the results found in studies done in other parts of the world. The same is true for age at onset, clinical course and response to thymectomy [15].
198
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
References [1] Storm Mathisen A. Epidemiology of myasthenia gravis in Norway. Acta Neurol Scand 1984;707:274–82. [2] Pirskanen R. Genetic aspects in myasthenia gravis, a family study of 264 Finnish patients. Acta Neurol Scand 1977;56:365 – 88. [3] Arak S, Uchino M, Kumasmoto T. Prevalence studies of multiple sclerosis, myasthenia gravis and myopathies in Kumamoto district, Japan. Neuroepidemiology 1987;6:120–9. [4] Oosterhuis HJGH. The natural course of myasthenia gravis: a longterm follow-up study. J Neurol Neurosurg Psychiatry 1989;52:1121 – 7. [5] Giagheddu M, Puggioni G, Sanna G, Tamburini G, Marrosu F, Rachele MG, Murgia B, Rosati G. Epidemiological study of myasthenia gravis in Sardinia, Italy. Acta Neurol Scand 1989;79:326 – 33. [6] D’Allessandro R, Granieri E, Benassi G, Tola MR, Casmiro M, Mazzanti B, Gamberini G, Caniatti L. Comparative study on the prevalence of myasthenia gravis in the provinces of Bologna and Ferrara, Italy. Acta Neurol Scand 1991;83:83–8. [7] Tola M.R., Emilia Romagna Study Group on Clinical and Epidemiological Problems in Neurology. Incidence of myasthenia gravis in the Emilia Romagna region: a prospective multicentre study. Neurology 1998;51:255–8. [8] Somnier FE, Keiding N, Paulson OB. Epidemiology of myasthe-
.
[9] [10]
[11] [12]
[13] [14]
[15]
[16]
[17]
nia gravis in Denmark: a longitudinal and comprehensive population survey. Arch Neurol 1991;481:733 – 9. Sorensen TTI, Holm EB. Myasthenia gravis in the county of Viborg, Denmark. Eur Neurol 1989;29:177 – 9. Christensen PB, Jensen TS, Tsiropoulos I, et al. Incidence and prevalence of myasthenia gravis in Western Denmark 1975– 1989. Neurology 1993;43:1779 – 83. Yu YI, Hawkins BR, Wong V, Woo E. Myasthenia gravis in the Hong Kong Chinese. Acta Neurol Scand 1992;86:113 –9. Phillips LH, Torner JC, Anderson MS, Cox GM. The epidemiology of myasthenia gravis in central and western Virginia. Neurology 1992;42:1888 – 93. Oosterhuis HJGH. Myasthenia Gravis. Edinburgh: Churchill Livingstone, 1984:84. Limburg PC, The TH, Hummel-Tappel E, Oosterhuis HJGH. Anti-acetylcholine receptor antibodies in myasthenia gravis: their relation to the clinical state and the effect of therapy. J Neurol Sci 1983;58:357 – 70. Beekman R, Kuks JBM, Oosterhuis HJGH. Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients. J Neurol Sci 1997;244:112 – 8. Robertson NP, Deans J, Compston DAS. Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 1998;65:492 – 6. Phillips LH, II, Torner HJ. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology 1996;47:1233 – 8.
Myasthenia gravis on the Dutch antilles: an epidemiological study H. Holtsema a, J. Mourik b, R.E. Rico b, J.R. Falconi c, J.B.M. Kuks a, H.J.G.H. Oosterhuis a,* a
Department of Neurology, Uni6ersity Hospital Groningen, Groningen, The Netherlands b Elisabeth Hospital, Curac¸ao, Dutch Antilles, The Netherlands c H. Oracio Oduber Hospital, Aruba, Dutch Antilles, The Netherlands
Received 9 August 1999; received in revised form 14 August 2000; accepted 14 August 2000
Abstract We carried out an epidemiological study on the prevalence and annual incidence of myasthenia gravis on tropical islands Curac¸ao and Aruba in the period 1980–1995. Twenty-one patients (seven men and 14 women) were identified. The point prevalence increased from 29 per million in 1980 to about 70 per million in 1990 – 1995; the annual incidence over the total period was 4.7 per million. The female:male ratio was 2:1; purely ocular cases (2/21) comprised 9.5% and thymomas (4/21), 19%. These data are in accordance with most other epidemiological studies in non-tropical areas. No other studies on myasthenia gravis in tropical areas have been reported. © 2000 Elsevier Science B.V. All rights reserved.
1. Introduction Myasthenia gravis (MG) is an acquired antibody mediated autoimmune disease, causing a functional shortage of the acetylcholine receptors (AChR) at the muscular endplates. The result is a fluctuating weakness of voluntary muscles, with a predominance of the extraocular and bulbar muscles. Epidemiological studies of MG in the past concerned mostly populations in Western Europe, Northern America and Asia (Table 1) [1 – 12]. We present an epidemiological study of MG on the two tropical islands — Curac¸ao and Aruba. They are located in front of the coast of Venezuela (position 12°N, 69°W) and are a part of The Netherlands. The medical care on these islands corresponds to Western standards and most physicians have had their professional training in The Netherlands.
2. Patients and methods All the patients known at the neurological practices at the St. Elisabeth Hospital on Curac¸ao and of the H. * Corresponding author. Present address: P.O. Box 30.001, 9700 RB Gronigen, the Netherlands. Tel./fax: + 31-50-3611707.
Oracio Oduber Hospital on Aruba between 1 January 1980 and 1 January 1997 were evaluated. Inclusion criteria were: unequivocal clinical symptoms, a positive reaction to anticholinesterases and/or the presence of antibodies to acetylcholine receptors (AchR) and/or a decrement of the compound muscle action potential to B 85% at supramaximal nerve stimulation. Twenty-one patients (Curac¸ao 13, Aruba 8) met these criteria. Data were collected by a review of the local medical records and of the records of the Academic Hospital Groningen, where some of the patients were treated. Recent information on actual clinical condition and treatment was collected by interview and examination in nine patients and by telephonic interview in six other patients. The prevalence was defined on 1 January 1980, 1 January 1985, 1 January 1990, 1 January 1995. The first symptoms were those present at any time of the first 3 months of the disease. The maximal severity was indicated on a six points global disability scale (0 =remission, 5= respiratory crisis) as was earlier described [13]. Remission was defined as lack of specific MG complains or signs. Much impro6ed as a change of two on the global disability scale. Impro6ed as a change of one point on the global disability scale. Antibodies against AChR were measured in 20 patients with the immunoprecipitation test [14].
0303-8467/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved. PII: S 0 3 0 3 - 8 4 6 7 ( 0 0 ) 0 0 1 0 3 - 7
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
196
3. Results
3.2. Onset
3.1. Epidemiology
The age at onset ranged from 5 to 75 years (mean 33 years, median 31 years). The presenting signs were ocular in nine (48%), bulbar in five (23%), oculobulbar in two (10%), in the extremities in two (10%) and generalized in three (14%) patients. In only two of the nine patients with initial ocular symptoms, the MG remained purely ocular. Most patients (n= 16) were diagnosed within 1 year after onset, four patients after 1–5 years.
The follow-up in our study ranged from 1 to 25 years (mean 11, median 9 years). Twenty-one patients (14 women and seven men) met the criteria. An overview of demographic and clinical data is given in Fig. 1. None of the patients had a family member with MG. Table 2 shows the point prevalence and annual incidence of MG per million inhabitants in our population.
Table 1 Reported incidence and prevalence of myasthenia gravis Country
Study period
Annual incidencea
Prevalence (per million)a
Reference
Norway Finland
1951–1981 1974
4.0 –
90 (81–100) 52 (45–59)
[1] [2]
Japan Kumamoto
1982
–
67 (52–85)
[3]
The Netherlands Amsterdam
1926–1965
4.0
56 (46–81)
[4]
Italy Sardinia Bologna Ferrara Emilia Romana
1958–1986 1987–1988 1987–1988 1993–1994
2.5 – – 14.7b
45 49 (36–66) 97 (64–128)
[5] [6] [6] [7]
Denmark Eastern Viborg Western
1970–1987 1973–1987c 1975–1989
4.4 9.8 5.0
77 (67–90) 125 (84–180) 78
[8] [9] [10]
Hong Kong
1975–1987
4.0
54
[11]
USA Virginia
1970–1984
9.1
142 (112–178)
[12]
UK Cambridgeshire
1965–1995
11
150 (120–180)
[16]
a
( ) 95% confidence interval. Prospective study. c Two neonatal cases excluded. b
Table 2 Point prevalence and annual incidence of MG per million inhabitants Population of Curac¸ao and Arubaa
1 January 1980
208.000
6
28.8
1 January 1985
215.830
9
41.6
1 January 1990
208.455
18
86.5
1 January 1995 1980–1995
229.800
15
65.2
a b
Source: census. Per million.
Number of patients present
Prevalenceb
Date
Newly diagnosed patients
Annual incidence
3
2.8
8
7.5
4
3.6
15
4.7
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
197
years and deteriorated shortly, thereafter. Another man (age 34) had a severe course with repeating crises and died 1 year after onset and thymomectomy in a septic shock. Fourteen patients without thymoma underwent thymectomy 1–15 years (ten within 3 years), after onset, three came in a remission, five were much improved and took only a small dosage of anticholinesterases, six were not improved and were treated with prednisone. Six patients had a myasthenic crisis and two of these died, probably due to inadequate medication. Three further patients from our group died, one patient (W 28 years, see above) succumbed to a sepsis; two patients (M 45 years and W 60 years) died from a prostate and an ovary carcinoma, respectively, when their MG was in remission.
4. Discussion
Fig. 1. Demographic and clinical data.
3.3. Antibodies against AChR Thirteen out of twenty patients had a positive antiAChR-ab test (] 2 nmol/l), two patients had values 1 – 2 nmol/l; in the two ocular and in three generalized patients, the test was negative (Fig. 1).
3.4. Other auto-immune diseases Three patients with concomitant autoimmune disease were found in our group. A female patient (onset 19 years) underwent a cervical thymectomy 1 year after onset, but did not improve and was treated with prednisone and azathioprine with much improvement. She developed a necrotic vasculitis and died at the age of 28 due to a sinus thrombosis and multiple internal organ abscesses (no thymic remnants were found at autopsy). A man with a thymoma (onset 32 years) developed an alopecia totalis at the age of 45 years. A woman with purely ocular MG at age had undergone a thyroidectomy 4 years before, because of hyperthyroidism.
3.5. Course of the disease
Eighteen of the 21 patients underwent thymectomy. Four patients (21%) had a thymoma. None of these improved after the operation. On the contrary, MG, rather, worsened after thymomectomy, in spite of complete removal of the tumour. One patient (M 35) was operated after a period of mild MG during 12
The prevalence and annual incidence of MG on Curac¸ao and Aruba in the period 1985–1997 fell in the range of the values reported for non-tropical areas (Table 1). Also, other parameters such as the female:male ratio (2:1), the fraction of pure ocular cases and of thymomas is in accordance with other reports [8,15]. The increasing prevalence and incidence in the last decades which seems to become apparent in the data from Table 1 in a study of the published populations [17] might also be present in this population between 1985 and 1995 but the small number of patients, makes this uncertain. The annual incidences and the prevalences in our study did not change appreciably over the various 5 year periods and are more or less comparable with the data of other populations. In the most recent studies [7,16] the annual incidence as well as the prevalence is increased as compared with the older ones, although also somewhat older reviews [9,12] have relatively high incidences. Improved diagnostic facilities (anti-AChR test since 1978–1983), single fibre EMG since 1985 and a greater diagnostic suspicion may have been important, especially in the diagnosis of purely ocular cases [17]. The increased prevalence will also be explained by a longer life span in general and by the specific treatment. It is difficult to know which factors have played a decisive role in this population. In fact, all patients with generalized MG under the age of 50 and all the patients with thymomas underwent thymectomy, as is generally advised. Although the number of patients in this study is small, we can conclude that the epidemiological results found in this study of a population in a tropical area do not differ from the results found in studies done in other parts of the world. The same is true for age at onset, clinical course and response to thymectomy [15].
198
H. Holtsema et al. / Clinical Neurology and Neurosurgery 102 (2000) 195–198
References [1] Storm Mathisen A. Epidemiology of myasthenia gravis in Norway. Acta Neurol Scand 1984;707:274–82. [2] Pirskanen R. Genetic aspects in myasthenia gravis, a family study of 264 Finnish patients. Acta Neurol Scand 1977;56:365 – 88. [3] Arak S, Uchino M, Kumasmoto T. Prevalence studies of multiple sclerosis, myasthenia gravis and myopathies in Kumamoto district, Japan. Neuroepidemiology 1987;6:120–9. [4] Oosterhuis HJGH. The natural course of myasthenia gravis: a longterm follow-up study. J Neurol Neurosurg Psychiatry 1989;52:1121 – 7. [5] Giagheddu M, Puggioni G, Sanna G, Tamburini G, Marrosu F, Rachele MG, Murgia B, Rosati G. Epidemiological study of myasthenia gravis in Sardinia, Italy. Acta Neurol Scand 1989;79:326 – 33. [6] D’Allessandro R, Granieri E, Benassi G, Tola MR, Casmiro M, Mazzanti B, Gamberini G, Caniatti L. Comparative study on the prevalence of myasthenia gravis in the provinces of Bologna and Ferrara, Italy. Acta Neurol Scand 1991;83:83–8. [7] Tola M.R., Emilia Romagna Study Group on Clinical and Epidemiological Problems in Neurology. Incidence of myasthenia gravis in the Emilia Romagna region: a prospective multicentre study. Neurology 1998;51:255–8. [8] Somnier FE, Keiding N, Paulson OB. Epidemiology of myasthe-
.
[9] [10]
[11] [12]
[13] [14]
[15]
[16]
[17]
nia gravis in Denmark: a longitudinal and comprehensive population survey. Arch Neurol 1991;481:733 – 9. Sorensen TTI, Holm EB. Myasthenia gravis in the county of Viborg, Denmark. Eur Neurol 1989;29:177 – 9. Christensen PB, Jensen TS, Tsiropoulos I, et al. Incidence and prevalence of myasthenia gravis in Western Denmark 1975– 1989. Neurology 1993;43:1779 – 83. Yu YI, Hawkins BR, Wong V, Woo E. Myasthenia gravis in the Hong Kong Chinese. Acta Neurol Scand 1992;86:113 –9. Phillips LH, Torner JC, Anderson MS, Cox GM. The epidemiology of myasthenia gravis in central and western Virginia. Neurology 1992;42:1888 – 93. Oosterhuis HJGH. Myasthenia Gravis. Edinburgh: Churchill Livingstone, 1984:84. Limburg PC, The TH, Hummel-Tappel E, Oosterhuis HJGH. Anti-acetylcholine receptor antibodies in myasthenia gravis: their relation to the clinical state and the effect of therapy. J Neurol Sci 1983;58:357 – 70. Beekman R, Kuks JBM, Oosterhuis HJGH. Myasthenia gravis: diagnosis and follow-up of 100 consecutive patients. J Neurol Sci 1997;244:112 – 8. Robertson NP, Deans J, Compston DAS. Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 1998;65:492 – 6. Phillips LH, II, Torner HJ. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology 1996;47:1233 – 8.