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Cerebral infarction after caesarean section due to heterozygosity for homocystinuria; a case report
European Journal of Obstetrics & Gynecology and Reproductive Biology, 40 (1991) 241-243
241
0 1991 Elsevier Science Publishers B.V. 0028-2243/91/$03.50 EUROBS 01126
Cerebral infarction after caesarean section due to heterozygosity for homocystinuria; a case report A.G. Minkhorst ‘, P.W.J. van Dongen’, G.H.J. Boers 3 and P.H.M. de Wit * Departments of ’ Obstetrics and Gynaecology ’ Neurology, and 3 Endocrinology, University Hospital Nijmegen, P. 0. Box 9101, 6500 HB Nijmegen, The Netherlands
Accepted for publication 11 October 1990
Eleven days after a caesarean section cerebral infarction was diagnosed. The underlying cause appeared to be a heterozygous form of homocystinuria. This inborn error in methionine metabolism increases the risk of premature arteriosclerosis, even in heterozygotes. The biochemical abnormalities can be prevented in most of the patients by treatment with vitamin B6 (pyridoxine). Pregnancy; Cerebral infarction; Heterozygosity; Homocystinuria;
Introduction
Homozygous homocystinuria leads to complications such as arteriosclerosis and thromboembolic events. It is known that heterozygosity for homocystinuria also predisposes to the development of premature occlusive arterial disease causing intermittent claudication, renovascular hypertension and ischemic cerebrovascular disease [l-3]. In the normal population the frequency of heterozygous homocystinuria is 1: 70 to 1: 200 [l]. Case report
A 32-year-old woman, G6 P2 (three abortions), was admitted to our hospital with premature rup-
Correspondence: Dr P.W.J. van Dongen, Department of Obstetrics and Gynaecology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Pyridoxine
ture of membranes. This sixth pregnancy was complicated by first trimester vaginal blood loss due to a vanishing twin. At 30 weeks’ gestation the membranes ruptured spontaneously with little vaginal blood loss. Intravenous tocolysis was started. After 1 day of admission an emergency caesarean section was performed because of prolapse of the umbilical cord. A healthy boy of 1650 g was born. During the operation, 1 g cefalotine was given. The circumvallate placenta weighed 400 g. The patient received dextran infusions postoperatively for 48 h, and was mobilized on the first postoperative day to prevent thrombosis. No heparin was administered during this emergency procedure because the preventive effect of heparin on thrombosis is present only if given before the operation and not during. On the second day she developed fever (37.5-39.5 o C). Antibiotics were started (cefalexine and metronidazol). The fever normalized. On the seventh day a wound abscess developed with E. coli bacteria resistent to
242
cefalexine. There were no signs of bacteremia. Except for dextran in the two first days and mobilization no extra anticoagulation therapy was given. Because of the wound abscess she remained hospitalized. On the 11th day postoperatively she developed headache, motor aphasia and paresis of the right hand. A computer tomogram showed a minor hypodense area around the medial cerebral artery which intensified dramatically after an angiography performed to elucidate the source of the probable occlusion. After this procedure total aphasia and right paralysis developed. Anticoagulation therapy was started (heparin i.v.) and the time-consuming period of revalidation begun. Breast feeding was discontinued. Further investigations showed normal blood morphology; normal biochemical parameters (liver- and renal functions); negative Rose-, Latex-, antinuclear factor (ANF) and anticardiolipine tests; no clotting disorders; normal ECG; no abnormality of ultrasound cardiography, chest Xray and Doppler haematotachogram (HTG). The possibility of a vasoconstriction due to contrast used for the angiography which worsened the infarction could not be excluded. A standardized oral methionine loading test was performed 6 weeks after birth to exclude heterozygosity for homocystinuria as the underlying cause for this cerebral infarction at young age [l-3]. The level of free homocysteine increased to 19.8 pmol/l (normal maximal value in premenopausal women after loading: 6.8 * 1.2 SD pmol/l) which indicated heterozygosity for homocystinuria [4]. Measurement of very low activity of cystathionine synthase activity in cultured fibroblasts from a skin biopsy (1.09 pmol/h per mg protein; normal range: 3.6-25.7) confirmed the heterozygosity [4]. Treatment with vitamin B6 (pyridoxine) in a dose of 250 mg daily was started. After 6 weeks of treatment with vitamin B6 a repeated methionine loading test showed a nearly normalisation of the methionine tolerance (rise of free homocysteine to 11.0 pmol/l). Until now, 2 years after her cerebral infarction, with continuous treatment of vitamin B6 the patient is well and no further vascular events happened.
Discussion
Homocystinuria is an autosomal inherited inborn error of the essential ammo acid methionine. Until recently it was thought to be expressed phenotypically only in homozygous form. The most common features of the homozygous form are : ectopia lentis, early arteriosclerosis and thrombo-embolic events, marfanoid characteristics, scoliosis, seizures, behavioural psychiatric disorders, stillbirth and spontaneous abortions [3-121. The clinical expression is very heterogeneous. The deficient activity of the enzyme cystathionine synthase in homozygous cases results in an accumulation of homocysteine and methionine in both plasma and tissues and of excessive urinary excretion of these amino acids (Fig. 1). To detect this disease, the so-called cyanid-test may be used. However, it may be false-negative in homozygotes in 50% [14]. Amino acid analysis in serum or plasma is preferable to identify homozygotes. Nowadays there is evidence that the heterozygous form can also cause illness by increasing the risk of premature arteriosclerosis, resulting in symptoms like intermittent claudication, renovascular hypertension and ischaemic cerebrovascular disease [l-3,13]. Heterozygosity is characterized only by decreased methionine tolerance measured as a pathological rise of homocysteine in the blood after methionine loading [4]. Definite proof of homocystinuria by cystathionine synthase deficiency in homo- or heterozygous form is made
MethYlGroup
Donor
CoenzYme Apoenzyme
NS-methyltetrahydm~late 812 NSmethYltetrahydrofolate
Weof Mock I” Hcmoqstinuru ApoenzYme
.CY?.tath~onme
svnthase
Fig. 1. Schematic summary of the metabolic pathway of methionine. (Permission for reproduction by Ritchie [6] and Blackwell Scientific Publications.)
243
by measuring the enzyme activity in cultured fibroblasts. Homocystinuria may lead to premature occlusive disease due to vascular damage. Animal and in vitro studies have given support to the hypothesis that excess of homocysteine induces endothelial cell injury and thereby initiates the process of premature arteriosclerosis [15]. Several reports mention the clinical benefits of homocysteine-lowering therapy such as vitamin B6 (pyridoxin), folic acid and vitamin B12 [14,16] in homozygous patients (Fig. 1). The number of initial and recurrent thrombo-embolic events may be reduced significantly after an early start of such treatment. Those homozygotes who did not respond to vitamin B6 or folic acid, had positive effects with methionine restriction if they started early in life with this diet [16]. The clinical effects of homocysteine-lowering treatment in heterozygous patients who suffered from vascular complications before the start of therapy are subject of further study [4]. Our patient developed a cerebral infarction on the 11th day of the puerperium. This thrombotic event may have been caused by the thrombotic tendency of both pregnancy and puerperium, the operation itself, the insufficient anticoagulant prevention and the fever due to the wound abscess. In normal pregnant women the irreversible metabolism of homocysteine to cysteine is more efficient than in non-pregnant women. As a result, lower plasma total homocysteine levels are found in pregnant women than in nonpregnant women [17]. However, the increasing fetal demands towards term for folic acid and the cofactors vitamin B6 and B12 may result in a deficiency of the vitamins mentioned [lo]. The lower levels of the hydrofolate, pyridoxin (vitamin B6) and B12 may reduce the efficiency of the remethylation of homocysteine to methionine and the cystathionine P-synthase activity, resulting in increased levels of homocysteine (Fig. 1) [lo]. Lower folate levels might have been an additional cause for the exacerbation of hyperhomocysteinemia in our patient with her already impaired homocysteine metabolism. Therefore, in our opinion, the cerebral infarction was induced mainly by her heterozygosity for homocystinuria. Probably the angiography aggra-
vated the infarction due duced by the contrast.
to vasoconstriction
in-
References 1 Boers GHJ, Smals AGH, Trijbels FJM et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709-715. 2 Malinow MR, Kang SS, Taylor LM et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989;79:1180-1188. 3 Brattstriim L, Israelsson B, Norrving B et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Atherosclerosis 1990;81: 51-60. 4 Boers GHJ, Fowler B, Smals AGH et al. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 1985;69:164-169. 5 Mudd SH, Levy HL, Skovby F. In: Striver ChR, Beaudet AL, Sly WS and Valle D (eds.) The metabolic basis of inherited disease, 6 edn., New York; McGraw-Hill, Inc., 1989;693-735. 6 Ritchie JWK, Carson NAJ. Pregnancy and homocystinuria. J Obstet Gynaecol Br Commonw 1973;80:664-669. 7 Brenton DP, Cusworth DC, Biddle SA et al. Pregnancy and homocystinuria. Ann Clin Biochem 1977;14:161-162. 8 Drayer JIM, Cleophas AJM, Trijbels JMF et al. Symptoms, diagnostic pitfalls and treatment of homocystinuria in seven adult patients. Neth J Med 1980;23:89-94. 9 Kurczynski TW, Muir WA, Fleisher LD et al. Maternal homocystinuria: studies of an untreated mother and fetus. Arch Dis Child 1980;55:721-723, presenting as 10 Newman G, Mitchell JRA. Homocystinuria multiple arterial occlusions. Quart J Med, New Series L 111 1984;210:251-258. EG. Homocystinuria: 11 Kelly TE, Wilson WG, Squillaro need for early diagnosis and therapy. Virg Med 1982;109:392-394. of 12 Hilden M, Brandt NJ, Nilsson IM et al. Investigations coagulation and fibrinolysis in homocystinuria. Acta Med Stand 1974;195:533-535. 13 Brattstriim LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia, a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 1984;15:1012-1016. 14 Boers GHJ. Homocystinuria, a risk factor of premature vascular disease. Clinical Research Series No. 3. Dordrecht-Holland/ Riverton-USA; Foris Publications, 1986. 15 Wall RT, Harlan JM, Harker LA et al. Homocysteine induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1985;18:113-121. 16 Mudd SH, Skovby F, Levy HL et al. The natural history of homocystinuria due to cystathionine /3-synthase deficiency. Am J Hum Gen 1985;37:1-31. 17 Kang SS, Wong PWK, Zhou J et al. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism 1986;35:889-891.
241
0 1991 Elsevier Science Publishers B.V. 0028-2243/91/$03.50 EUROBS 01126
Cerebral infarction after caesarean section due to heterozygosity for homocystinuria; a case report A.G. Minkhorst ‘, P.W.J. van Dongen’, G.H.J. Boers 3 and P.H.M. de Wit * Departments of ’ Obstetrics and Gynaecology ’ Neurology, and 3 Endocrinology, University Hospital Nijmegen, P. 0. Box 9101, 6500 HB Nijmegen, The Netherlands
Accepted for publication 11 October 1990
Eleven days after a caesarean section cerebral infarction was diagnosed. The underlying cause appeared to be a heterozygous form of homocystinuria. This inborn error in methionine metabolism increases the risk of premature arteriosclerosis, even in heterozygotes. The biochemical abnormalities can be prevented in most of the patients by treatment with vitamin B6 (pyridoxine). Pregnancy; Cerebral infarction; Heterozygosity; Homocystinuria;
Introduction
Homozygous homocystinuria leads to complications such as arteriosclerosis and thromboembolic events. It is known that heterozygosity for homocystinuria also predisposes to the development of premature occlusive arterial disease causing intermittent claudication, renovascular hypertension and ischemic cerebrovascular disease [l-3]. In the normal population the frequency of heterozygous homocystinuria is 1: 70 to 1: 200 [l]. Case report
A 32-year-old woman, G6 P2 (three abortions), was admitted to our hospital with premature rup-
Correspondence: Dr P.W.J. van Dongen, Department of Obstetrics and Gynaecology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Pyridoxine
ture of membranes. This sixth pregnancy was complicated by first trimester vaginal blood loss due to a vanishing twin. At 30 weeks’ gestation the membranes ruptured spontaneously with little vaginal blood loss. Intravenous tocolysis was started. After 1 day of admission an emergency caesarean section was performed because of prolapse of the umbilical cord. A healthy boy of 1650 g was born. During the operation, 1 g cefalotine was given. The circumvallate placenta weighed 400 g. The patient received dextran infusions postoperatively for 48 h, and was mobilized on the first postoperative day to prevent thrombosis. No heparin was administered during this emergency procedure because the preventive effect of heparin on thrombosis is present only if given before the operation and not during. On the second day she developed fever (37.5-39.5 o C). Antibiotics were started (cefalexine and metronidazol). The fever normalized. On the seventh day a wound abscess developed with E. coli bacteria resistent to
242
cefalexine. There were no signs of bacteremia. Except for dextran in the two first days and mobilization no extra anticoagulation therapy was given. Because of the wound abscess she remained hospitalized. On the 11th day postoperatively she developed headache, motor aphasia and paresis of the right hand. A computer tomogram showed a minor hypodense area around the medial cerebral artery which intensified dramatically after an angiography performed to elucidate the source of the probable occlusion. After this procedure total aphasia and right paralysis developed. Anticoagulation therapy was started (heparin i.v.) and the time-consuming period of revalidation begun. Breast feeding was discontinued. Further investigations showed normal blood morphology; normal biochemical parameters (liver- and renal functions); negative Rose-, Latex-, antinuclear factor (ANF) and anticardiolipine tests; no clotting disorders; normal ECG; no abnormality of ultrasound cardiography, chest Xray and Doppler haematotachogram (HTG). The possibility of a vasoconstriction due to contrast used for the angiography which worsened the infarction could not be excluded. A standardized oral methionine loading test was performed 6 weeks after birth to exclude heterozygosity for homocystinuria as the underlying cause for this cerebral infarction at young age [l-3]. The level of free homocysteine increased to 19.8 pmol/l (normal maximal value in premenopausal women after loading: 6.8 * 1.2 SD pmol/l) which indicated heterozygosity for homocystinuria [4]. Measurement of very low activity of cystathionine synthase activity in cultured fibroblasts from a skin biopsy (1.09 pmol/h per mg protein; normal range: 3.6-25.7) confirmed the heterozygosity [4]. Treatment with vitamin B6 (pyridoxine) in a dose of 250 mg daily was started. After 6 weeks of treatment with vitamin B6 a repeated methionine loading test showed a nearly normalisation of the methionine tolerance (rise of free homocysteine to 11.0 pmol/l). Until now, 2 years after her cerebral infarction, with continuous treatment of vitamin B6 the patient is well and no further vascular events happened.
Discussion
Homocystinuria is an autosomal inherited inborn error of the essential ammo acid methionine. Until recently it was thought to be expressed phenotypically only in homozygous form. The most common features of the homozygous form are : ectopia lentis, early arteriosclerosis and thrombo-embolic events, marfanoid characteristics, scoliosis, seizures, behavioural psychiatric disorders, stillbirth and spontaneous abortions [3-121. The clinical expression is very heterogeneous. The deficient activity of the enzyme cystathionine synthase in homozygous cases results in an accumulation of homocysteine and methionine in both plasma and tissues and of excessive urinary excretion of these amino acids (Fig. 1). To detect this disease, the so-called cyanid-test may be used. However, it may be false-negative in homozygotes in 50% [14]. Amino acid analysis in serum or plasma is preferable to identify homozygotes. Nowadays there is evidence that the heterozygous form can also cause illness by increasing the risk of premature arteriosclerosis, resulting in symptoms like intermittent claudication, renovascular hypertension and ischaemic cerebrovascular disease [l-3,13]. Heterozygosity is characterized only by decreased methionine tolerance measured as a pathological rise of homocysteine in the blood after methionine loading [4]. Definite proof of homocystinuria by cystathionine synthase deficiency in homo- or heterozygous form is made
MethYlGroup
Donor
CoenzYme Apoenzyme
NS-methyltetrahydm~late 812 NSmethYltetrahydrofolate
Weof Mock I” Hcmoqstinuru ApoenzYme
.CY?.tath~onme
svnthase
Fig. 1. Schematic summary of the metabolic pathway of methionine. (Permission for reproduction by Ritchie [6] and Blackwell Scientific Publications.)
243
by measuring the enzyme activity in cultured fibroblasts. Homocystinuria may lead to premature occlusive disease due to vascular damage. Animal and in vitro studies have given support to the hypothesis that excess of homocysteine induces endothelial cell injury and thereby initiates the process of premature arteriosclerosis [15]. Several reports mention the clinical benefits of homocysteine-lowering therapy such as vitamin B6 (pyridoxin), folic acid and vitamin B12 [14,16] in homozygous patients (Fig. 1). The number of initial and recurrent thrombo-embolic events may be reduced significantly after an early start of such treatment. Those homozygotes who did not respond to vitamin B6 or folic acid, had positive effects with methionine restriction if they started early in life with this diet [16]. The clinical effects of homocysteine-lowering treatment in heterozygous patients who suffered from vascular complications before the start of therapy are subject of further study [4]. Our patient developed a cerebral infarction on the 11th day of the puerperium. This thrombotic event may have been caused by the thrombotic tendency of both pregnancy and puerperium, the operation itself, the insufficient anticoagulant prevention and the fever due to the wound abscess. In normal pregnant women the irreversible metabolism of homocysteine to cysteine is more efficient than in non-pregnant women. As a result, lower plasma total homocysteine levels are found in pregnant women than in nonpregnant women [17]. However, the increasing fetal demands towards term for folic acid and the cofactors vitamin B6 and B12 may result in a deficiency of the vitamins mentioned [lo]. The lower levels of the hydrofolate, pyridoxin (vitamin B6) and B12 may reduce the efficiency of the remethylation of homocysteine to methionine and the cystathionine P-synthase activity, resulting in increased levels of homocysteine (Fig. 1) [lo]. Lower folate levels might have been an additional cause for the exacerbation of hyperhomocysteinemia in our patient with her already impaired homocysteine metabolism. Therefore, in our opinion, the cerebral infarction was induced mainly by her heterozygosity for homocystinuria. Probably the angiography aggra-
vated the infarction due duced by the contrast.
to vasoconstriction
in-
References 1 Boers GHJ, Smals AGH, Trijbels FJM et al. Heterozygosity for homocystinuria in premature peripheral and cerebral occlusive arterial disease. N Engl J Med 1985;313:709-715. 2 Malinow MR, Kang SS, Taylor LM et al. Prevalence of hyperhomocyst(e)inemia in patients with peripheral arterial occlusive disease. Circulation 1989;79:1180-1188. 3 Brattstriim L, Israelsson B, Norrving B et al. Impaired homocysteine metabolism in early-onset cerebral and peripheral occlusive arterial disease. Atherosclerosis 1990;81: 51-60. 4 Boers GHJ, Fowler B, Smals AGH et al. Improved identification of heterozygotes for homocystinuria due to cystathionine synthase deficiency by the combination of methionine loading and enzyme determination in cultured fibroblasts. Hum Genet 1985;69:164-169. 5 Mudd SH, Levy HL, Skovby F. In: Striver ChR, Beaudet AL, Sly WS and Valle D (eds.) The metabolic basis of inherited disease, 6 edn., New York; McGraw-Hill, Inc., 1989;693-735. 6 Ritchie JWK, Carson NAJ. Pregnancy and homocystinuria. J Obstet Gynaecol Br Commonw 1973;80:664-669. 7 Brenton DP, Cusworth DC, Biddle SA et al. Pregnancy and homocystinuria. Ann Clin Biochem 1977;14:161-162. 8 Drayer JIM, Cleophas AJM, Trijbels JMF et al. Symptoms, diagnostic pitfalls and treatment of homocystinuria in seven adult patients. Neth J Med 1980;23:89-94. 9 Kurczynski TW, Muir WA, Fleisher LD et al. Maternal homocystinuria: studies of an untreated mother and fetus. Arch Dis Child 1980;55:721-723, presenting as 10 Newman G, Mitchell JRA. Homocystinuria multiple arterial occlusions. Quart J Med, New Series L 111 1984;210:251-258. EG. Homocystinuria: 11 Kelly TE, Wilson WG, Squillaro need for early diagnosis and therapy. Virg Med 1982;109:392-394. of 12 Hilden M, Brandt NJ, Nilsson IM et al. Investigations coagulation and fibrinolysis in homocystinuria. Acta Med Stand 1974;195:533-535. 13 Brattstriim LE, Hardebo JE, Hultberg BL. Moderate homocysteinemia, a possible risk factor for arteriosclerotic cerebrovascular disease. Stroke 1984;15:1012-1016. 14 Boers GHJ. Homocystinuria, a risk factor of premature vascular disease. Clinical Research Series No. 3. Dordrecht-Holland/ Riverton-USA; Foris Publications, 1986. 15 Wall RT, Harlan JM, Harker LA et al. Homocysteine induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1985;18:113-121. 16 Mudd SH, Skovby F, Levy HL et al. The natural history of homocystinuria due to cystathionine /3-synthase deficiency. Am J Hum Gen 1985;37:1-31. 17 Kang SS, Wong PWK, Zhou J et al. Total homocyst(e)ine in plasma and amniotic fluid of pregnant women. Metabolism 1986;35:889-891.