taglandins on the cellular immune response is the underlying cause of the chronic inflammatory reaction in MS. Supported in part by Grants 1 PO1 CA 22507, CA 08748, CA 19267, CA 17404, and R 0 1 EY 01616, from the US Public Health Service, National Institutes of Health. During the course of this study, Dr Willoughby was recipient of an Overseas Research Fellowship from the Medical Research Council of New Zealand and a grant from the J. M. Foundation, New York. Expert technical assistance was provided by Mrs M. Modi. We thank Dr J. E. Pike of the Upjohn Company for his generous gift of PGE, and PGE,.
References 1. Bourne NR, Lichtenstein LM, Melmon KL, et al: Modulation
2.
3.
4. 5.
6.
7.
8.
9.
of inflammation and immunity by cyclic AMP. Science 184:19-28, 1974 Bray MA, Gordon D, Morley J: Role of prostaglandins in reactions of cellular immunity. Br J Pharmacol 52:453P, 1974 Goodwin JS, Messner RP: Prostaglandin E inhibition of mitogen stimulation in patients with multiple sclerosis. Prostaglandlns 15:281-286, 1978 Gordon D, Bray MA, Morley J: Control of lymphokine secretion by prostaglandins. Nature 262:401-403. 1976 Kirby PJ, Morley J, Ponsford JR, et al: Defective PGE reactivity in leucocytes of multiple sclerosis patients. Prostaglandins 11:62 1-630, 1976 Offner H , Clausen J: Inhibition of lymphocyte response to stimulants induced by unsaturated fatty acids and prostaglandins. Lancet 2:400-401, 1974 Offner H, Clausen J: Inhibition of lymphocyte response to stimulants induced by unsaturated fatty acids and prostaglandins in multiple sclerosis. Lancet 2:1204-1205, 1974 Smith JW, Steiner AL, Parker CW: Human lymphocyte metabolism: effects of cyclic and non-cyclic nucleotides on stimulation by phytohemagglutinin. J Clin Invest 50:442-448, 197 1 Willoughby EW, Dupont B, Hansen J, et al: The indirect assay for leucocyte migration inhibitory factor (LIFjstandardization and the effect of pH. J lmmunol Methods 22:99-110, 1978
Dermatomyositis and Toxoplasmosis G. F. M . Hendrickx, MD, J. Verhage, MD, F. G. I. Jennekens, MD, and F. van Knapen, DVM
In a patient with childhood dermatomyositis, high toxoplasrna antibodies were found at the time of diagnosis. A direct imrnunofluorescence technique demonstrated active toxoplasmosis in the muscle biopsy. The response to treatment and follow-up in this patient suggest that toxoplasmosis could have caused the dermatomyositis. H e n d r i c k x GFM, Verhage J, Jennekens FGI, e t al: Dermatomyositis and toxoplasmosis. A n n N e u r o l 5:393-395, 1979
A relationship between polymyositisldermatomyositis and toxoplasmosis has been suggested on the basis of sequential antibody studies [ 4 , 5, 71. However, no parasite was seen in the biopsies of these patients. In a case of childhood dermatomyositis with high toxoplasma antibodies, we had the opportunity to study this relationship in more detail. T h e eyelids o f a previously healthy 8-year-old boy became swollen and red o v e r o n e week. D u r i n g t h e next nine months, similar skin anomalies developed o n t h e hands, elbows, a n d knees. His face became edematous. He developed fatigue and muscle weakness, and ultimately was unable t o walk. Physical examination disclosed a heliotrope erythema, most pronounced o n t h e eyelids, elbows, dorsal surfaces of t h e hands, and t h e knees. I n s o m e of these places t h e skin was flaky. Foci of vasculitis could be s e e n around t h e nail matrices. T h e l o n g muscles of t h e back and extremities w e r e weak; hypotonia was most pronounced in t h e proximal muscle g r o u p s of t h e shoulder and t h e pelvic girdle. The general laboratory findings w e r e normal. Slightly elevated values w e r e obtained for creatine phosphokinase ( 6 1 U p e r liter, range 5 t o 45), and lactic dehydrogenase ( 4 8 7 U p e r liter, range 35 t o 189). T h e total hemolytic c o m p l e m e n t (CH,,) and t h e s e r u m concentration of IgA, I g G , and IgM w e r e normal. B y indirect immunofluorescence, s m o o t h and striated muscle autoantibodies and antinuclear antibodies w e r e n o t demonstrable. H i g h toxoplasma antibodies w e r e f o u n d in t h e s e r u m with both t h e
From t h e University Children’s Hospital Het Wilhelmina Kinderziekenhuis, Utrecht, and the Pathology Laboratory, Department of Parasitology, National Institute of Public Health, Bilthoven. The Netherlands. Accepted for publication, Sept 11, 1978. Address reprint requests to Dr Hendrickx, Department of Pediatrics, Diaconessenhuis, Theodor Fliednerstraat 1, 5600 PD Eindhoven. The Netherlands.
0364-5134/79/040393-03$01.25 0 1978 by G. F. M. H e n d r i c k x 393
reciprocal IF titres
16000 8192
-
2043 4096
1024
-
512
-
256
-
128
-
0----0
IF CF
0, ‘0,
,o‘
reciprocal CF titres
3, \
\
‘0
-
_ _ _ _ _ _o
-
- 32 - 16 - 8
- 4 - 2 ,
,
1
,
,
1
,
,
indirect immunofluorescent antibody (IF) test and the comF i g I . Time-sequence study, i n relation to medication, of plement fixation test (Fig 1). No specific IgM antibodies toxoplasma antibodies-complement-fixation (CF) and imwere demonstrated. Inoculation of muscle material and munojuorescence (IF) tests--in the serum of a patient with liquor in mice did not reveal isolation of toxoplasma. T h e childhood dermatomyositis. electromyogram showed fibrillation potentials and positive sharp waves. All motor unit potentials were polyphasic. T h e interference pattern showed a slight reduction under clinical recurrence developed, accompanied by contracmaximal volitional effort. tures of the hip. Once daily, 2.5 mg of methotrexate was The muscle biopsy showed enlargement of the perimyadded for a short period to the prednisolone, but it was sial spaces, which contained copious and often perivascusubsequently withdrawn because of ulcers in the mouth lady localized cellular infiltrates. Inflammatory cells were and skin lesions o n the face. About ten months after treatpresent in the walls of some of the small vessels. In some ment was started, improvement occurred. From this time places infiltrates composed of many lymphocytes, some on, calcifications were radiographically visible in the soft plasma cells, and large active histiocytes had spread betissues. During the administration of prednisolone alone o r tween the muscle fibers in the fasciculi. Muscle fiber atin combination with methotrexate, the toxoplasma antirophy and changes such as loss of striation, vacuolization, body titers rose again. and phagocytosis were present in a predominantly perifascicular distribution. Free tachyzoites were seen in cryostat Discussion sections from the muscle biopsy by a direct IF technique using fluoresceinated high-titer rabbit antibody to ~ O X O - T h e p a t i e n t suffered from active toxoplasmosis as inplasma* [8](Fig 2). dicated by the high antitoxoplasma titers, the decline The diagnosis of dermatomyositis was made and the of t h e s e titers under the influence of medication, and child was treated with 2 mg per kilogram of prednisolone, the p r e s e n c e of tachyzoites i n the muscle biopsy. I n and with 25 mg of pyrimethamine once daily and 750 mg of patients with a primary infection, I g M antibodies can sulfadiazine four times daily to combat the toxoplasmosis. be found in the blood over an initial period of several Because thrombopenia developed, pyrimethamine and months. T h e a b s e n c e of such antibodies in o u r pasulfadiazine were withheld after three weeks. Four weeks tient suggests e i t h e r that t h e toxoplasmosis had b e e n later the number of platelets was normal and the drugs p r e s e n t for some t i m e or that reactivation had ocwere reinstated. Recurrence of thrombopenia led to a seccurred. Histological examination of t h e muscle biond cessation. These treatment procedures resulted in a sharp reduction of antibody titers (see Fig 1). The compleopsy d i d n o t lead to identification of parasites, b u t ment fixation test became negative, and the IF test t h e direct immunofluorescence study with anshowed a residual titer of 1:512 in the spring of 1976. titoxoplasma antiserum was successful in this respect. The prednisolone was gradually reduced after two and a The latter technique appears more sensitive. half months. Four months after treatment was started a The recent literature has suggested a relationship between toxoplasmosis a n d polymyositis/derma+Commercially available from Wellcome, Beckenham, UK. tomyositis [4, 5 , 71. In a c u t e toxoplasmosis, (focal)
394 Annals of Neurology
Vol 5 N o 4
April 1979
F i g 2 . Direct immunofluorescent staining of free toxoplasma tachyzoites (arrows) in a cryostat section from the muscle biopsy. The parasites are situated in loose connective tissue. ( ~ 8 0before 0 25 % reduction.)
tent toxoplasmosis seems to require concurrent or previous treatment with antitoxoplasma agents.
References 1. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl
myositis is described, but only rarely have parasites been seen in the muscle biopsies [6]. In our case, coincidence between the simultaneous occurrence of toxoplasmosis and dermatomyositis cannot be ruled out entirely. Etiology is always difficult to demonstrate. There is only one previous description of a case of polymyositis (with concurrent neurological abnormalities) in which the muscle biopsy showed toxoplasma cysts without other changes [ 3 ] . With respect to Kagen’s 141 hypothesis that patients with myositis might be predisposed, either by the disease or by the therapy, to complications associated with toxoplasmosis, we can add that in our patient the muscle biopsy showed tachyzoites before therapy. The possibility that myositis can reactivate latent toxoplasmosis cannot be excluded. O n the basis of our findings, it appears advisable to make a thorough search for active toxoplasmosis in all patients with polymyositis/dermatomyositis. Investigation of muscle tissue for the parasite seems to be important both in the choice of treatment and in discovery of the pathogenesis of the diseases. If Toxoplasma gondii plays a role in the genesis of these diseases, the current primary treatment with corticosteroids may have to be modified [l, 21. In the present state of our knowledge, high-dose prednisone (prednisolone) in the presence of either active or la-
J Med 292:344-347, 403-407, 1975 2. Carpenter S, Karpati G, Rothman S, e t al: T h e childhood type of dermatomyositis. Neurology (Minneap) 26952-962, 1976 3. Greenlee JE, Johnson WD Jr, Campa JF, e t al: Adult toxoplasmosis presenting as polymyositis and cerebellar ataxia. Ann Intern Med 82:367-371, 1975 4. Kagen LJ, Kimball AC, Christian CL: Serologic evidence of toxoplasmosis among patients with polymyositis. Am J Med 56:186-191, 1974 5. McNicholl B, Underhill D: Toxoplasmic polymyositis. Ir J Med Sci 3:525-527, 1970 6 . Remington JS, Cavanaugh EN: Isolation of the encysted form of Tnxnplasnza gondif from human skeletal muscle and brain. N Engl J Med 273:1308-1310, 1965 7. Samuels BS, Rietschel RL: Polymyositis and toxoplasmosis. JAMA 235:60-61, 1976 8. Van Knapen F, Panmabean SO: Identification of toxoplasma infections in man and animal by a direct immunofluorescent technique (in Dutch). Medikon 5:33-35, 1976
Case Report: Hendrickx et al: Dermatomyositis and Toxoplasmosis
395
References 1. Bourne NR, Lichtenstein LM, Melmon KL, et al: Modulation
2.
3.
4. 5.
6.
7.
8.
9.
of inflammation and immunity by cyclic AMP. Science 184:19-28, 1974 Bray MA, Gordon D, Morley J: Role of prostaglandins in reactions of cellular immunity. Br J Pharmacol 52:453P, 1974 Goodwin JS, Messner RP: Prostaglandin E inhibition of mitogen stimulation in patients with multiple sclerosis. Prostaglandlns 15:281-286, 1978 Gordon D, Bray MA, Morley J: Control of lymphokine secretion by prostaglandins. Nature 262:401-403. 1976 Kirby PJ, Morley J, Ponsford JR, et al: Defective PGE reactivity in leucocytes of multiple sclerosis patients. Prostaglandins 11:62 1-630, 1976 Offner H , Clausen J: Inhibition of lymphocyte response to stimulants induced by unsaturated fatty acids and prostaglandins. Lancet 2:400-401, 1974 Offner H, Clausen J: Inhibition of lymphocyte response to stimulants induced by unsaturated fatty acids and prostaglandins in multiple sclerosis. Lancet 2:1204-1205, 1974 Smith JW, Steiner AL, Parker CW: Human lymphocyte metabolism: effects of cyclic and non-cyclic nucleotides on stimulation by phytohemagglutinin. J Clin Invest 50:442-448, 197 1 Willoughby EW, Dupont B, Hansen J, et al: The indirect assay for leucocyte migration inhibitory factor (LIFjstandardization and the effect of pH. J lmmunol Methods 22:99-110, 1978
Dermatomyositis and Toxoplasmosis G. F. M . Hendrickx, MD, J. Verhage, MD, F. G. I. Jennekens, MD, and F. van Knapen, DVM
In a patient with childhood dermatomyositis, high toxoplasrna antibodies were found at the time of diagnosis. A direct imrnunofluorescence technique demonstrated active toxoplasmosis in the muscle biopsy. The response to treatment and follow-up in this patient suggest that toxoplasmosis could have caused the dermatomyositis. H e n d r i c k x GFM, Verhage J, Jennekens FGI, e t al: Dermatomyositis and toxoplasmosis. A n n N e u r o l 5:393-395, 1979
A relationship between polymyositisldermatomyositis and toxoplasmosis has been suggested on the basis of sequential antibody studies [ 4 , 5, 71. However, no parasite was seen in the biopsies of these patients. In a case of childhood dermatomyositis with high toxoplasma antibodies, we had the opportunity to study this relationship in more detail. T h e eyelids o f a previously healthy 8-year-old boy became swollen and red o v e r o n e week. D u r i n g t h e next nine months, similar skin anomalies developed o n t h e hands, elbows, a n d knees. His face became edematous. He developed fatigue and muscle weakness, and ultimately was unable t o walk. Physical examination disclosed a heliotrope erythema, most pronounced o n t h e eyelids, elbows, dorsal surfaces of t h e hands, and t h e knees. I n s o m e of these places t h e skin was flaky. Foci of vasculitis could be s e e n around t h e nail matrices. T h e l o n g muscles of t h e back and extremities w e r e weak; hypotonia was most pronounced in t h e proximal muscle g r o u p s of t h e shoulder and t h e pelvic girdle. The general laboratory findings w e r e normal. Slightly elevated values w e r e obtained for creatine phosphokinase ( 6 1 U p e r liter, range 5 t o 45), and lactic dehydrogenase ( 4 8 7 U p e r liter, range 35 t o 189). T h e total hemolytic c o m p l e m e n t (CH,,) and t h e s e r u m concentration of IgA, I g G , and IgM w e r e normal. B y indirect immunofluorescence, s m o o t h and striated muscle autoantibodies and antinuclear antibodies w e r e n o t demonstrable. H i g h toxoplasma antibodies w e r e f o u n d in t h e s e r u m with both t h e
From t h e University Children’s Hospital Het Wilhelmina Kinderziekenhuis, Utrecht, and the Pathology Laboratory, Department of Parasitology, National Institute of Public Health, Bilthoven. The Netherlands. Accepted for publication, Sept 11, 1978. Address reprint requests to Dr Hendrickx, Department of Pediatrics, Diaconessenhuis, Theodor Fliednerstraat 1, 5600 PD Eindhoven. The Netherlands.
0364-5134/79/040393-03$01.25 0 1978 by G. F. M. H e n d r i c k x 393
reciprocal IF titres
16000 8192
-
2043 4096
1024
-
512
-
256
-
128
-
0----0
IF CF
0, ‘0,
,o‘
reciprocal CF titres
3, \
\
‘0
-
_ _ _ _ _ _o
-
- 32 - 16 - 8
- 4 - 2 ,
,
1
,
,
1
,
,
indirect immunofluorescent antibody (IF) test and the comF i g I . Time-sequence study, i n relation to medication, of plement fixation test (Fig 1). No specific IgM antibodies toxoplasma antibodies-complement-fixation (CF) and imwere demonstrated. Inoculation of muscle material and munojuorescence (IF) tests--in the serum of a patient with liquor in mice did not reveal isolation of toxoplasma. T h e childhood dermatomyositis. electromyogram showed fibrillation potentials and positive sharp waves. All motor unit potentials were polyphasic. T h e interference pattern showed a slight reduction under clinical recurrence developed, accompanied by contracmaximal volitional effort. tures of the hip. Once daily, 2.5 mg of methotrexate was The muscle biopsy showed enlargement of the perimyadded for a short period to the prednisolone, but it was sial spaces, which contained copious and often perivascusubsequently withdrawn because of ulcers in the mouth lady localized cellular infiltrates. Inflammatory cells were and skin lesions o n the face. About ten months after treatpresent in the walls of some of the small vessels. In some ment was started, improvement occurred. From this time places infiltrates composed of many lymphocytes, some on, calcifications were radiographically visible in the soft plasma cells, and large active histiocytes had spread betissues. During the administration of prednisolone alone o r tween the muscle fibers in the fasciculi. Muscle fiber atin combination with methotrexate, the toxoplasma antirophy and changes such as loss of striation, vacuolization, body titers rose again. and phagocytosis were present in a predominantly perifascicular distribution. Free tachyzoites were seen in cryostat Discussion sections from the muscle biopsy by a direct IF technique using fluoresceinated high-titer rabbit antibody to ~ O X O - T h e p a t i e n t suffered from active toxoplasmosis as inplasma* [8](Fig 2). dicated by the high antitoxoplasma titers, the decline The diagnosis of dermatomyositis was made and the of t h e s e titers under the influence of medication, and child was treated with 2 mg per kilogram of prednisolone, the p r e s e n c e of tachyzoites i n the muscle biopsy. I n and with 25 mg of pyrimethamine once daily and 750 mg of patients with a primary infection, I g M antibodies can sulfadiazine four times daily to combat the toxoplasmosis. be found in the blood over an initial period of several Because thrombopenia developed, pyrimethamine and months. T h e a b s e n c e of such antibodies in o u r pasulfadiazine were withheld after three weeks. Four weeks tient suggests e i t h e r that t h e toxoplasmosis had b e e n later the number of platelets was normal and the drugs p r e s e n t for some t i m e or that reactivation had ocwere reinstated. Recurrence of thrombopenia led to a seccurred. Histological examination of t h e muscle biond cessation. These treatment procedures resulted in a sharp reduction of antibody titers (see Fig 1). The compleopsy d i d n o t lead to identification of parasites, b u t ment fixation test became negative, and the IF test t h e direct immunofluorescence study with anshowed a residual titer of 1:512 in the spring of 1976. titoxoplasma antiserum was successful in this respect. The prednisolone was gradually reduced after two and a The latter technique appears more sensitive. half months. Four months after treatment was started a The recent literature has suggested a relationship between toxoplasmosis a n d polymyositis/derma+Commercially available from Wellcome, Beckenham, UK. tomyositis [4, 5 , 71. In a c u t e toxoplasmosis, (focal)
394 Annals of Neurology
Vol 5 N o 4
April 1979
F i g 2 . Direct immunofluorescent staining of free toxoplasma tachyzoites (arrows) in a cryostat section from the muscle biopsy. The parasites are situated in loose connective tissue. ( ~ 8 0before 0 25 % reduction.)
tent toxoplasmosis seems to require concurrent or previous treatment with antitoxoplasma agents.
References 1. Bohan A, Peter JB: Polymyositis and dermatomyositis. N Engl
myositis is described, but only rarely have parasites been seen in the muscle biopsies [6]. In our case, coincidence between the simultaneous occurrence of toxoplasmosis and dermatomyositis cannot be ruled out entirely. Etiology is always difficult to demonstrate. There is only one previous description of a case of polymyositis (with concurrent neurological abnormalities) in which the muscle biopsy showed toxoplasma cysts without other changes [ 3 ] . With respect to Kagen’s 141 hypothesis that patients with myositis might be predisposed, either by the disease or by the therapy, to complications associated with toxoplasmosis, we can add that in our patient the muscle biopsy showed tachyzoites before therapy. The possibility that myositis can reactivate latent toxoplasmosis cannot be excluded. O n the basis of our findings, it appears advisable to make a thorough search for active toxoplasmosis in all patients with polymyositis/dermatomyositis. Investigation of muscle tissue for the parasite seems to be important both in the choice of treatment and in discovery of the pathogenesis of the diseases. If Toxoplasma gondii plays a role in the genesis of these diseases, the current primary treatment with corticosteroids may have to be modified [l, 21. In the present state of our knowledge, high-dose prednisone (prednisolone) in the presence of either active or la-
J Med 292:344-347, 403-407, 1975 2. Carpenter S, Karpati G, Rothman S, e t al: T h e childhood type of dermatomyositis. Neurology (Minneap) 26952-962, 1976 3. Greenlee JE, Johnson WD Jr, Campa JF, e t al: Adult toxoplasmosis presenting as polymyositis and cerebellar ataxia. Ann Intern Med 82:367-371, 1975 4. Kagen LJ, Kimball AC, Christian CL: Serologic evidence of toxoplasmosis among patients with polymyositis. Am J Med 56:186-191, 1974 5. McNicholl B, Underhill D: Toxoplasmic polymyositis. Ir J Med Sci 3:525-527, 1970 6 . Remington JS, Cavanaugh EN: Isolation of the encysted form of Tnxnplasnza gondif from human skeletal muscle and brain. N Engl J Med 273:1308-1310, 1965 7. Samuels BS, Rietschel RL: Polymyositis and toxoplasmosis. JAMA 235:60-61, 1976 8. Van Knapen F, Panmabean SO: Identification of toxoplasma infections in man and animal by a direct immunofluorescent technique (in Dutch). Medikon 5:33-35, 1976
Case Report: Hendrickx et al: Dermatomyositis and Toxoplasmosis
395
