Acta Med Scand 206: 131-135, 1979
My asthenia Grav is and Werl hof' s Disease W. A. Veenhoven. H . J. Oosterhuis and G. S. van der Schans From t h e Division c?f'Hematology,Department o j Medicine and the Department o j Neurology, University of Groningen, Groningen, The Netherlands
ABSTRACT. A case of Werlhof's disease (immune thrombocytopenia)associated with myasthenia gravis is described. The two disorders developed within a few months of each other. The immunological and practical aspects of the association are discussed. K e y words: myasthenia gravis, Werlhof s disease. Acta Med Scand 206: 131, 1979.
thrombocytopenia,
are more common in myasthenic women than can be expected. Pure red cell aplasia has some preference for myasthenic patients because of its association with a thymoma ( I 1). A number of associations of Werlhof s disease and other autoimmune disorders have been described. Immune thrombocytopenia may occur in the course of systemic lupus erythematosus (2) or in association with autoimmune hemolytic anemia (Evans' syndrome) (2). An association with Hashimoto's disease has been described (3). Three cases of MG associated with ITP have been reported recently (14, 15, 19). In these cases the disorders did not arise simultaneously; MG developed many years after the ITP (14, 19) or the reverse (15). The present paper reports on a case of MG and Werlhof s disease occurring at about the same time.
In Werlhof s disease, thrombocytopenia has been shown to be due to accelerated destruction of platelets by an immune mechanism (9). Several forms of the disease are recognized, e.g. idiopathic thrombocytopenia (ITP), when no exogenous factor is apparent, and drug-induced or symptomatic thrombocytopenia, in the course of certain other disorders (2). A humoral mechanism is considered responsible for platelet destruction. A cell-mediated mechanism has not been demonstrated convincingCASE REPORT ly (9). A 19-year-old man was in good health until Feb. 1976, Myasthenia gravis (MG) is a disorder of when he noticed a stiffness in his face and a strange way of neuromuscular transmission, which is probably due laughing. In May 1976, swallowing and articulation beto an autoimmune attack, reducing the available came difficult and he experienced diplopia. Proximal weakness in arms and legs supervened. His symptoms acetylcholine receptors of the postsynaptic memincreased after exercise and were more prominent at branes of skeletal muscle. This reduction has been night. demonstrated biochemically and histologically and The diagnosis of MG was made after a positive edroseems to have a direct relation with the circulating phonium chloride test and was confirmed by typical antibodies reacting with acetylcholine-receptor- decremental response of the muscle action potentials after supramaximal stimulation of the nerve at a rate of 3 protein (4). Immune complexes at the motor end- per second. Treatment with prostigmine bromide and plates (MEP) have been demonstrated (5). Thymic pyridostigmine bromide was started in June and amabnormalities are observed as thymomas in 10-15 % benonium chloride was added in August. Nevertheless of the patients and follicular hyperplasia in 5 0 4 0 % his symptoms increased and he was brought to our hospiof the thymuses removed by operation. An authoritative review is given by Drachman (4). Abbreviations: ITP = idiopathic thrombocytopenia, MG = The association between MG and other auto- myasthenia gravis, MEP = motor endplates. immune diseases has been reported frequently, Reprint requesrs to: W . A. Veenhoven, Division of although epidemiologic studies are scarce. At least Hematology, Department of Medicine, University of rheumatoid arthritis (12) and thyroid disorders (16) Groningen, Oostersingel59, Groningen, The Netherlands. A c ~ t iMrd
Sccmd 206
132
W . A . Veenkoven et al.
platelet count x 10~11
800
500
400
300
200
100
I
June
July
Aug.
Scpt.
Oct.
Nov.
1976
Dec.
Jan.
Febr.
March
April
May
June
1977
Fig. I . Clinical course. P=prednisone (60=60 mg daily,
60/0=60 mg on alternate days), Spl=splenectomy, Thy =thymectomy.
tal in Oct. 1976 because of attacks of respiratory insuficiency. On admission he was in general good health with the typical picture of a generalized MG. His vital capacity at rest was reduced to 80% of the normal value. A chest X-ray revealed no evidence of a thymoma and antimuscle antibodies were not detected. Thymectomy seemed indicated. Thrombocytopenia was detected at the routine laboratory examinations. There was no history of purpura or other bleeding manifestations. The family history was unremarkable and no bleeding disorders, myasthenia or thyroid diseases were known. The spleen was not palpable and no lymphadenopathy, goitre or bleeding manifestations were found. The platelet count in an electronic particle counter, confirmed by phase contrast microscopy, ranged from 46000 to 55 000/mm3. WBC was 7800/mm3, with a normal differential count. Serum electrophoresis and tests for renal hepatic functions revealed normal findings. Cultures of urine and sputum were negative. Examination of a bone marrow smear revealed an increased number of megakaryocytes with a normal appearance. Survival of 5~chromium-labelleddonor plateles was markedly shortened to 72 hours. Coagulation tests yielded normal results, serum thyroxine level was within the normal range, 8.7 pg/lOO ml. Tests for rheumatoid factor,
antinuclear and antithyroid antibodies gave negative results. The patient's blood group was B Rhesus D-positive, HLA typing A,, A,, B,, B,. Cytotoxic antileucocyte antibodies were not found. The complement C,, level was normal. The diagnosis of Werlhof s disease (immune thrombocytopenia) was made. None of the drugs taken by the patient have been reported to provoke an immune thrombocytopenia. Ambenonium chloride-the only drug that had been added recently-was withheld. In the next three weeks the platelet count did not increase and ranged from 16000 to 4OW/mm3. Subsequently, treatment with prednisone, in a dose increasing from 30 to 60 mg daily, was given. In the next six weeks the platelet count rose somewhat but did not exceed 65000/mm3. The bleeding time (Ivy) was 7-9 min. The myasthenia improved only partially. Prednisone treatment was continued on an alternate day dose scheme. Splenectomy was considered because thymectomy was contraindicated by the persistent thrombocytopenia. Splenectomy was performed in Jan. 1977. It was followed by a prompt and sustained remission of the ITP: the platelet count remained above 300000/mm3. Thymectomy was performed two months later. Following both operations, a short period of ventilatory assistance was neces-
Myustheniu gruvis und Werlhof’s disease
133
Table I. Irnr?iir~iologiculclatu on the putient Phase of disease ...
Thrombocytopenia Remission of thrombocytopenia 1 week
6 months
Treatment ...
Untreated
IgM platelet antibodies IgG platelet antibodies
-
-
-
Platelet-bound IgM Platelet-bound IgG IgG antibodies to skeletal muscle
Weak
-
-
-
-
IgG antibodies to MEP
+ ++
Prednisone, Thymectomy splenectomy
+
+ -
+ (1:4)
(1 : 10)
- (1 : 10)
Dubious
+
sary. Histological examination of the spleen revealed no abnormalities. A few germinal follicles were found in the thymus and there was no thymoma. Following the thymectomy, the myasthenic symptoms decreased and the prednisone dosage could be reduced gradually but could not be discontinued. The clinical course is summarized in Fig. I . A recent respiratory tract infection was followed by a short exacerbation of the myasthenia. The immune thrombocytopenia remained in remission throughout. Immunological studies were performed on several occa$ions in the course of the disease. Antibodies to skeletal muscle were detected by an indirect immunofluorescence technique described by Feltkamp et al. (7). Only fluorescent anti-IgG sera were used. Antibodies to MEP were detected by an indirect immunofluorescence technique using fluorescent anti-IgG sera, as recently described by Sontag-Tschroots et al. (20).
Platelet-bound immunoglobulins were detected by direct immunofluorescence on gel-filtered platelets as previously described (17). Platelet antibodies were detected in sera by an indirect immunofluorescence technique previously described (18). Patient serum and platelet-rich plasma prepared from EDTA-anticoagulated blood were incubated, washed by gel filtration and stained with fluorescent rabbit antihuman IgG and IgM. The results of the immunological studies are given in Table I. In a control study, no platelet antibodies were found in the sera of 12 patients with active MG and no skeletal muscle antibodies were detected in the sera of 12 patients with Werlhof s disease.
DISCUSSION The association of MG and ITP has been reported in three cases in the past two years. Segal and Weintraub (19) described a patient with ITP who had a remission after splenectomy and developed
Hashimoto’s disease and MG ten years later. Pinals et al. (14) described a patient with Graves’ disease followed by ITP and 12 years later by MG. Remuzzi et al. (15) described a patient with MG who developed ITP ten years later. All these patients were females. Platelet antibodies were found in the first case by a platelet factor 3 release assay and in the last case by a serotonin release test. The antibodies were not characterized. HLA typing did not show a definite association between HLA type and disease. HLA-B,2 was found in the former two cases and HLA-B8 in the latter case. MG has a prevalence of 2.4 and 8.6 per 100000, respectively, for men and women (10). The prevalence of Werlhof s disease is not exactly known but is estimated from clinical admission data to be about 4 per 100000. The female: male ratio in Werlhof s disease is about 3 : 1. Thus, the chance of coincidence of MG and Werlhofs disease is extremely small, especially with respect to males. In a series of 400 consecutive patients with MG observed by one of us (H.J.O.), only one patient was seen who probably had suffered from Werlhof s disease in the past: a young woman suffering from MG from the age of 27 who underwent splenectomy at the age of 22. Our present patient is a young man who developed MG and ITP within a few months of each other. The thrombocytopenia was discovered on a routine examination after intake of anticholinergic drugs for several months. Withdrawal of ambenonium chloride did not change the platelet count notably, the other drugs could not be withheld without endangering the patient, but they are not known to have elicited an immune Actir
M r d Srund 206
134
W.A. Veenhoven et a / .
thrombocytopenia. Remission of the ITP was not achieved on prednisone treatment, but splenectomy was followed by a persistently normal platelet count. On admission, IgG platelet antibodies were found in the patient’s serum and IgG as well as small quantities of IgM on his platelets. The serum antibodies persisted throughout the course but the platelet IgM disappeared in a few weeks, the IgG several weeks later when remission was reached. The rapidly disappearing IgM is consistent with the recent onset of immune thrombocytopenia. After splenectomy, IgG antibodies were still present in the serum. Because a platelet transfusion had been given for survival studies, the presence of isoantibodies at that time cannot be ruled out. Platelet-bound antibodies were not detected six months after splenectomy. IgG antibodies to skeletal muscle were not found initially, when a 1 : 10 diluted serum was tested. They were detected, however, when a dilution of 1 : 4 was used, Thus, they were found in a very low titer. IgG antibodies to MEP were detected most clearly in a later phase of the disease when thymectomy had been performed and the patient was still on prednisone. IgG antibodies to skeletal muscle are found in 22% (7) and antibodies to acetylcholine receptor substance in 87% (4) of MG cases. Serum platelet antibodies belonging to the IgG class are found in about 60-70% of patients with ITP (9). Platelet antibodies were not found in the sera of our 12 control patients with MG and skeletal muscle antibodies were not detected in 12 control patients with Werlhofs disease. Platelet antibodies are supposed to be produced largely in the spleen, but also in other parts of the reticuloendothelial system (9). Production of acetylcholine receptor antibodies by thymic lymphocytes has been reported recently (22). In our patient, antibodies to MEP were, however, still present after thymectomy. Whether the platelet and MEP IgG antibodies are cross-reacting or independent cannot be determined from our data. A modest association between MG and HLA-B8 has been described by several authors (7). Goebel et al. (8) reported an association between ITP and HLA-B, and HLA-BI2.In a recent study we could, however, not find associations of any significance (21). Neither B, nor BIZare present in the patient presented here.
The practical consequence of the association of autoimmune disorders is to carefully search for the others when one of them has been found. This is especially important when an operation, e.g. splenectomy, thymectomy or thyroidectomy, is considered. Serious complications-such as bleeding due to thrombocytopenia, respiratory insufficiency in myasthenia or thyrotoxic crises-may be prevented by adequate preoperative treatment. REFERENCES I . Bach, F. H. & van Rood, J . J.: The major histocompatibility complex. N Engl J Med 295: 927, 1976. 2. Baldini, M.: Idiopathic thrombocytopenic purpura. N Engl J Med 271: 1245, 1301, 1360, 1966. 3. Crabtree, G. R., Lee, J. C. & Cornwell, G. G.: Autoimmune thrombocytopenic purpura and Hashimoto’s thyroiditis. Ann Intern Med 83: 371, 1975. 4. Drachman, D. B.: Myasthenia gravis. N Engl J Med 298: 136, 186, 1978. 5. Engel, A. G., Lambert, E. H. & Howard, F. M.: Immune complexes (IgG and C,) at the motor endplate in myasthenia gravis. Mayo Clin Proc 52: 267, 1977. 6. Engel, A. G., Lindstrom, J. M., Lambert, E. H. & Lennon, V. A.: Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and its experimental autoimmune model. Neurology 27: 307, 1977. 7. Feltkamp, T. E. W., van den Berg-Loonen, P. M., Nijenhuis, L. E., Engelfriet, C. P., van Rossum, A. L., van Loghem, J. J. & Oosterhuis, H. J. G. H.: Myasthenia gravis, autoantibodies and HLA antigens. Br Med J 1: 131, 1974. 8. Goebel, K. M., Hahn, E. & Havemann, K.: HLA matching in autoimmune thrombocytopenic purpura. Br J Haematol 35: 341, 1977. 9. McMillan, R.: The pathogenesis of immune thrombocytic purpura. CRC Crit Rev Clin Lab Sci 8: 303, 1977. 10. Oosterhuis, H. J. G. H.: Epidemiologie der Myasthenie in Amsterdam. In: Myasthenia gravis (ed. G. Hertel u. A.), pp. 103-108. Thieme Verlag, Stuttgart 1977. 11. Oosterhuis, H. J. G. H., Feltkamp, T. E. W., van Rossum, A. L., van den Berg-Loonen, D. M. & Nijenhuis, L. E.: HLA antigens, auto-antibody production and associated diseases in patients with thymoma, with and without myasthenia gravis. Ann NY Acad Sci 274: 468, 1976. 12. Oosterhuis, H. J. G. H. & De Haas, W. H. D.: Rheumatic diseases in patients with myasthenia gravis. Acta Neurol Scand 44: 219, 1968. 3 . Oosterhuis, H. J. G. H., Sluyter, A. H. C., Feltkamp, T. E. W. & van der Geld, H.: Myasthenia gravis, combined with thymoma and aplastic anaemia. Ned Tijdschr Geneeskd 109: 308, 1965. 4. Pinals, R. S., Russell, H. T., Haas, D. C. & Farah, F.:
Myustlieniu gravis and Werlhof’s disease
15.
16.
17.
18.
Graves disease, myasthenia gravis and purpura. Ann Intern Med 87: 250, 1977. Remuzzi, G., Livio, M., Donati, M. B. & de Gaetano, G.: Myasthenia gravis, thrombocytopenia and HLA antigens. Ann Intern Med 87: 250, 1977. Rof-Carbullo, J.: Myasthenia gravis and hyperthyroidism in neurology. Proceedings X Int. Congress Neurology. Excerpta Medica Congress Series 3 19: 446, 1975. van der Schans, G. S. , Veenhoven, W. A., MettingScherphuis, H. E. & Nieweg, H. 0.: Demonstration of platelet membrane associated immunoglobulins and complement in some blood disorders by direct membrane immunofluorescence (abstr.). Br J Haematol35: 679, 1977. van der Schans, G. S., Veenhoven, W. A., Snijder, J. A . M. & Nieweg, H. 0.: The detection of platelet
19.
20.
21. 22.
135
iso-antibodies by membrane fluorescence. J Clin Lab Med 90:4, 1977. Segal, B. M. & Weintraub, M. 1.: Hashimoto’s thyroiditis, myasthenia gravis, idiopathic thrombocytopenic purpura. Ann Intern Med 85: 761, 1976. Sontag-Tschroots, I. R. J. M., Schulz-Raateland, R. C. M., van Walbeek, H. K. & Feltkamp, T. E. W.: Antibodies to motor endplates demonstrated with the immunofluorescence technique. Clin Exp Immunol. In press 1979. Veenhoven, W. A., Kaars Sijpesteijn, .I. A. & van der Schans, G. S.: HLA antigens in idiopathic thrombocytopenic purpura. Acta Haematol. In press 1979. Vincent, A., Thomas, H. C., Scadding, G. K. & Newsom-Davis, J.: In vitro synthesis of antiacetylcholine-receptor antibody by thymic lymphocytes in myasthenia gravis. Lancet 1: 305, 1978.
Actci
Med Sccind 206
My asthenia Grav is and Werl hof' s Disease W. A. Veenhoven. H . J. Oosterhuis and G. S. van der Schans From t h e Division c?f'Hematology,Department o j Medicine and the Department o j Neurology, University of Groningen, Groningen, The Netherlands
ABSTRACT. A case of Werlhof's disease (immune thrombocytopenia)associated with myasthenia gravis is described. The two disorders developed within a few months of each other. The immunological and practical aspects of the association are discussed. K e y words: myasthenia gravis, Werlhof s disease. Acta Med Scand 206: 131, 1979.
thrombocytopenia,
are more common in myasthenic women than can be expected. Pure red cell aplasia has some preference for myasthenic patients because of its association with a thymoma ( I 1). A number of associations of Werlhof s disease and other autoimmune disorders have been described. Immune thrombocytopenia may occur in the course of systemic lupus erythematosus (2) or in association with autoimmune hemolytic anemia (Evans' syndrome) (2). An association with Hashimoto's disease has been described (3). Three cases of MG associated with ITP have been reported recently (14, 15, 19). In these cases the disorders did not arise simultaneously; MG developed many years after the ITP (14, 19) or the reverse (15). The present paper reports on a case of MG and Werlhof s disease occurring at about the same time.
In Werlhof s disease, thrombocytopenia has been shown to be due to accelerated destruction of platelets by an immune mechanism (9). Several forms of the disease are recognized, e.g. idiopathic thrombocytopenia (ITP), when no exogenous factor is apparent, and drug-induced or symptomatic thrombocytopenia, in the course of certain other disorders (2). A humoral mechanism is considered responsible for platelet destruction. A cell-mediated mechanism has not been demonstrated convincingCASE REPORT ly (9). A 19-year-old man was in good health until Feb. 1976, Myasthenia gravis (MG) is a disorder of when he noticed a stiffness in his face and a strange way of neuromuscular transmission, which is probably due laughing. In May 1976, swallowing and articulation beto an autoimmune attack, reducing the available came difficult and he experienced diplopia. Proximal weakness in arms and legs supervened. His symptoms acetylcholine receptors of the postsynaptic memincreased after exercise and were more prominent at branes of skeletal muscle. This reduction has been night. demonstrated biochemically and histologically and The diagnosis of MG was made after a positive edroseems to have a direct relation with the circulating phonium chloride test and was confirmed by typical antibodies reacting with acetylcholine-receptor- decremental response of the muscle action potentials after supramaximal stimulation of the nerve at a rate of 3 protein (4). Immune complexes at the motor end- per second. Treatment with prostigmine bromide and plates (MEP) have been demonstrated (5). Thymic pyridostigmine bromide was started in June and amabnormalities are observed as thymomas in 10-15 % benonium chloride was added in August. Nevertheless of the patients and follicular hyperplasia in 5 0 4 0 % his symptoms increased and he was brought to our hospiof the thymuses removed by operation. An authoritative review is given by Drachman (4). Abbreviations: ITP = idiopathic thrombocytopenia, MG = The association between MG and other auto- myasthenia gravis, MEP = motor endplates. immune diseases has been reported frequently, Reprint requesrs to: W . A. Veenhoven, Division of although epidemiologic studies are scarce. At least Hematology, Department of Medicine, University of rheumatoid arthritis (12) and thyroid disorders (16) Groningen, Oostersingel59, Groningen, The Netherlands. A c ~ t iMrd
Sccmd 206
132
W . A . Veenkoven et al.
platelet count x 10~11
800
500
400
300
200
100
I
June
July
Aug.
Scpt.
Oct.
Nov.
1976
Dec.
Jan.
Febr.
March
April
May
June
1977
Fig. I . Clinical course. P=prednisone (60=60 mg daily,
60/0=60 mg on alternate days), Spl=splenectomy, Thy =thymectomy.
tal in Oct. 1976 because of attacks of respiratory insuficiency. On admission he was in general good health with the typical picture of a generalized MG. His vital capacity at rest was reduced to 80% of the normal value. A chest X-ray revealed no evidence of a thymoma and antimuscle antibodies were not detected. Thymectomy seemed indicated. Thrombocytopenia was detected at the routine laboratory examinations. There was no history of purpura or other bleeding manifestations. The family history was unremarkable and no bleeding disorders, myasthenia or thyroid diseases were known. The spleen was not palpable and no lymphadenopathy, goitre or bleeding manifestations were found. The platelet count in an electronic particle counter, confirmed by phase contrast microscopy, ranged from 46000 to 55 000/mm3. WBC was 7800/mm3, with a normal differential count. Serum electrophoresis and tests for renal hepatic functions revealed normal findings. Cultures of urine and sputum were negative. Examination of a bone marrow smear revealed an increased number of megakaryocytes with a normal appearance. Survival of 5~chromium-labelleddonor plateles was markedly shortened to 72 hours. Coagulation tests yielded normal results, serum thyroxine level was within the normal range, 8.7 pg/lOO ml. Tests for rheumatoid factor,
antinuclear and antithyroid antibodies gave negative results. The patient's blood group was B Rhesus D-positive, HLA typing A,, A,, B,, B,. Cytotoxic antileucocyte antibodies were not found. The complement C,, level was normal. The diagnosis of Werlhof s disease (immune thrombocytopenia) was made. None of the drugs taken by the patient have been reported to provoke an immune thrombocytopenia. Ambenonium chloride-the only drug that had been added recently-was withheld. In the next three weeks the platelet count did not increase and ranged from 16000 to 4OW/mm3. Subsequently, treatment with prednisone, in a dose increasing from 30 to 60 mg daily, was given. In the next six weeks the platelet count rose somewhat but did not exceed 65000/mm3. The bleeding time (Ivy) was 7-9 min. The myasthenia improved only partially. Prednisone treatment was continued on an alternate day dose scheme. Splenectomy was considered because thymectomy was contraindicated by the persistent thrombocytopenia. Splenectomy was performed in Jan. 1977. It was followed by a prompt and sustained remission of the ITP: the platelet count remained above 300000/mm3. Thymectomy was performed two months later. Following both operations, a short period of ventilatory assistance was neces-
Myustheniu gruvis und Werlhof’s disease
133
Table I. Irnr?iir~iologiculclatu on the putient Phase of disease ...
Thrombocytopenia Remission of thrombocytopenia 1 week
6 months
Treatment ...
Untreated
IgM platelet antibodies IgG platelet antibodies
-
-
-
Platelet-bound IgM Platelet-bound IgG IgG antibodies to skeletal muscle
Weak
-
-
-
-
IgG antibodies to MEP
+ ++
Prednisone, Thymectomy splenectomy
+
+ -
+ (1:4)
(1 : 10)
- (1 : 10)
Dubious
+
sary. Histological examination of the spleen revealed no abnormalities. A few germinal follicles were found in the thymus and there was no thymoma. Following the thymectomy, the myasthenic symptoms decreased and the prednisone dosage could be reduced gradually but could not be discontinued. The clinical course is summarized in Fig. I . A recent respiratory tract infection was followed by a short exacerbation of the myasthenia. The immune thrombocytopenia remained in remission throughout. Immunological studies were performed on several occa$ions in the course of the disease. Antibodies to skeletal muscle were detected by an indirect immunofluorescence technique described by Feltkamp et al. (7). Only fluorescent anti-IgG sera were used. Antibodies to MEP were detected by an indirect immunofluorescence technique using fluorescent anti-IgG sera, as recently described by Sontag-Tschroots et al. (20).
Platelet-bound immunoglobulins were detected by direct immunofluorescence on gel-filtered platelets as previously described (17). Platelet antibodies were detected in sera by an indirect immunofluorescence technique previously described (18). Patient serum and platelet-rich plasma prepared from EDTA-anticoagulated blood were incubated, washed by gel filtration and stained with fluorescent rabbit antihuman IgG and IgM. The results of the immunological studies are given in Table I. In a control study, no platelet antibodies were found in the sera of 12 patients with active MG and no skeletal muscle antibodies were detected in the sera of 12 patients with Werlhof s disease.
DISCUSSION The association of MG and ITP has been reported in three cases in the past two years. Segal and Weintraub (19) described a patient with ITP who had a remission after splenectomy and developed
Hashimoto’s disease and MG ten years later. Pinals et al. (14) described a patient with Graves’ disease followed by ITP and 12 years later by MG. Remuzzi et al. (15) described a patient with MG who developed ITP ten years later. All these patients were females. Platelet antibodies were found in the first case by a platelet factor 3 release assay and in the last case by a serotonin release test. The antibodies were not characterized. HLA typing did not show a definite association between HLA type and disease. HLA-B,2 was found in the former two cases and HLA-B8 in the latter case. MG has a prevalence of 2.4 and 8.6 per 100000, respectively, for men and women (10). The prevalence of Werlhof s disease is not exactly known but is estimated from clinical admission data to be about 4 per 100000. The female: male ratio in Werlhof s disease is about 3 : 1. Thus, the chance of coincidence of MG and Werlhofs disease is extremely small, especially with respect to males. In a series of 400 consecutive patients with MG observed by one of us (H.J.O.), only one patient was seen who probably had suffered from Werlhof s disease in the past: a young woman suffering from MG from the age of 27 who underwent splenectomy at the age of 22. Our present patient is a young man who developed MG and ITP within a few months of each other. The thrombocytopenia was discovered on a routine examination after intake of anticholinergic drugs for several months. Withdrawal of ambenonium chloride did not change the platelet count notably, the other drugs could not be withheld without endangering the patient, but they are not known to have elicited an immune Actir
M r d Srund 206
134
W.A. Veenhoven et a / .
thrombocytopenia. Remission of the ITP was not achieved on prednisone treatment, but splenectomy was followed by a persistently normal platelet count. On admission, IgG platelet antibodies were found in the patient’s serum and IgG as well as small quantities of IgM on his platelets. The serum antibodies persisted throughout the course but the platelet IgM disappeared in a few weeks, the IgG several weeks later when remission was reached. The rapidly disappearing IgM is consistent with the recent onset of immune thrombocytopenia. After splenectomy, IgG antibodies were still present in the serum. Because a platelet transfusion had been given for survival studies, the presence of isoantibodies at that time cannot be ruled out. Platelet-bound antibodies were not detected six months after splenectomy. IgG antibodies to skeletal muscle were not found initially, when a 1 : 10 diluted serum was tested. They were detected, however, when a dilution of 1 : 4 was used, Thus, they were found in a very low titer. IgG antibodies to MEP were detected most clearly in a later phase of the disease when thymectomy had been performed and the patient was still on prednisone. IgG antibodies to skeletal muscle are found in 22% (7) and antibodies to acetylcholine receptor substance in 87% (4) of MG cases. Serum platelet antibodies belonging to the IgG class are found in about 60-70% of patients with ITP (9). Platelet antibodies were not found in the sera of our 12 control patients with MG and skeletal muscle antibodies were not detected in 12 control patients with Werlhofs disease. Platelet antibodies are supposed to be produced largely in the spleen, but also in other parts of the reticuloendothelial system (9). Production of acetylcholine receptor antibodies by thymic lymphocytes has been reported recently (22). In our patient, antibodies to MEP were, however, still present after thymectomy. Whether the platelet and MEP IgG antibodies are cross-reacting or independent cannot be determined from our data. A modest association between MG and HLA-B8 has been described by several authors (7). Goebel et al. (8) reported an association between ITP and HLA-B, and HLA-BI2.In a recent study we could, however, not find associations of any significance (21). Neither B, nor BIZare present in the patient presented here.
The practical consequence of the association of autoimmune disorders is to carefully search for the others when one of them has been found. This is especially important when an operation, e.g. splenectomy, thymectomy or thyroidectomy, is considered. Serious complications-such as bleeding due to thrombocytopenia, respiratory insufficiency in myasthenia or thyrotoxic crises-may be prevented by adequate preoperative treatment. REFERENCES I . Bach, F. H. & van Rood, J . J.: The major histocompatibility complex. N Engl J Med 295: 927, 1976. 2. Baldini, M.: Idiopathic thrombocytopenic purpura. N Engl J Med 271: 1245, 1301, 1360, 1966. 3. Crabtree, G. R., Lee, J. C. & Cornwell, G. G.: Autoimmune thrombocytopenic purpura and Hashimoto’s thyroiditis. Ann Intern Med 83: 371, 1975. 4. Drachman, D. B.: Myasthenia gravis. N Engl J Med 298: 136, 186, 1978. 5. Engel, A. G., Lambert, E. H. & Howard, F. M.: Immune complexes (IgG and C,) at the motor endplate in myasthenia gravis. Mayo Clin Proc 52: 267, 1977. 6. Engel, A. G., Lindstrom, J. M., Lambert, E. H. & Lennon, V. A.: Ultrastructural localization of the acetylcholine receptor in myasthenia gravis and its experimental autoimmune model. Neurology 27: 307, 1977. 7. Feltkamp, T. E. W., van den Berg-Loonen, P. M., Nijenhuis, L. E., Engelfriet, C. P., van Rossum, A. L., van Loghem, J. J. & Oosterhuis, H. J. G. H.: Myasthenia gravis, autoantibodies and HLA antigens. Br Med J 1: 131, 1974. 8. Goebel, K. M., Hahn, E. & Havemann, K.: HLA matching in autoimmune thrombocytopenic purpura. Br J Haematol 35: 341, 1977. 9. McMillan, R.: The pathogenesis of immune thrombocytic purpura. CRC Crit Rev Clin Lab Sci 8: 303, 1977. 10. Oosterhuis, H. J. G. H.: Epidemiologie der Myasthenie in Amsterdam. In: Myasthenia gravis (ed. G. Hertel u. A.), pp. 103-108. Thieme Verlag, Stuttgart 1977. 11. Oosterhuis, H. J. G. H., Feltkamp, T. E. W., van Rossum, A. L., van den Berg-Loonen, D. M. & Nijenhuis, L. E.: HLA antigens, auto-antibody production and associated diseases in patients with thymoma, with and without myasthenia gravis. Ann NY Acad Sci 274: 468, 1976. 12. Oosterhuis, H. J. G. H. & De Haas, W. H. D.: Rheumatic diseases in patients with myasthenia gravis. Acta Neurol Scand 44: 219, 1968. 3 . Oosterhuis, H. J. G. H., Sluyter, A. H. C., Feltkamp, T. E. W. & van der Geld, H.: Myasthenia gravis, combined with thymoma and aplastic anaemia. Ned Tijdschr Geneeskd 109: 308, 1965. 4. Pinals, R. S., Russell, H. T., Haas, D. C. & Farah, F.:
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