- Email: [email protected]
AGE, VITAMIN D, AND SOLAR ULTRAVIOLET
distribution of targeted literature and the beginning of health-care professional, educational, and workplace initiatives. This is very much the future of the campaign, and it is important your readers understand what is going on. Commission of the European Communities, Jean Monnet House, 8 Storey’s Gate, London SW1P 3AT
JOHN DREW, United
Kingdom Offices
PRENATAL DIAGNOSIS
SIR,-Your note (Sept 16, p 695) on the Royal College of Physicians’ report Prenatal diagnosis and genetic screening failed to mention one important part of that report. Chapter 6, entitled Evaluation of Pre-natal Diagnosis, contains charts and diagrams setting out the cost benefits of screening and abortion of affected babies. It concludes that "screening and prenatal diagnosis offer major financial advantages. The investment required is relatively modest and will conserve NHS resources for other uses". The National Health Service was set up to cater for the needs of the weakest and most vulnerable in society. The idea was that treatment should be given according to need and not according to ability to pay. Now the Royal College of Physicians seems to be suggesting that those most in need of treatment should be not just abandoned to their fate, but also actively sought out and destroyed by abortion, to release facilities for others judged more worthy of care.
Speaking as one with a detectable, abortable condition (I was spina bifida) I find this form of eugenic, fatal apartheid insulting, distressing, and unworthy of the profession to which I
bom with owe
my life.
35 Stileham Bank, Milborne St Andrew, Blandford Forum, Dorset DT1 1 0LE
ALISON DAVIS
MYOPATHY AS POSSIBLE SIDE-EFFECT OF
CYCLOSPORIN
SIR,-Dr Goy and colleagues (June 24, p 1446) describe three of possible cyclosporin-related myopathy, severe in one case, moderate in the second, and without clinical symptoms in the third. The patients had all been on steroids, but apparently not recently; two were on enalapril; all three received azathioprine. In the patient with severe signs, the muscular signs improved after cyclosporin (and perhaps enalapril, though this is not mentioned) withdrawal. We feel uneasy about their conclusion as to the possible myotoxicity cases
of cyclosporin. The results of the muscle biopsies are quite different from one patient to another, and non-specific. In one patient, the muscular alterations had no clinical consequences. Our first question is, what is the muscle status in patients after transplantation? Could these alterations, at least in the patient without clinical signs, be
commonplace after heart transplant, and not related to cyclosporin? Our second is, what are the long-term alterations in muscle structure induced by steroids (including high doses [not given precisely] for graft rejection)? Until these questions are answered, we believe patient three has no real evidence of muscular toxicity of cyclosporin. We are thus left with two cases of myopathy, occurring with multiple treatments, including cyclosporin and enalapril (in addition to steroids and azathioprine, whose responsibility seems to have been excluded). Causality assessment of the data provided makes the responsibility of enalapril at least as plausible as that of cyclosporin: in patient one it is not stated clearly that enalapril was stopped, but Goy and colleagues say the patient improved on azathioprine and steroids alone, so presumably enalapril was stopped. In patient two no information is provided about a possible dechallenge. Thus the case against enalapril is as strong as against cyclosporin, especially since severe myopathy with enalapril alone has been described.1 We feel the situation is not quite as clear-cut as Goy and colleagues suggest. Although myopathy could indeed be a side-
effect of cyclosporin-and certainly physicians should be alerted to that possibility-the evidence is not strong enough to indict the drug as sole cause for these myopathies. In all cases so far, cyclosporin was associated with other drugs known to cause myopathy: more than any single drug, the association could be responsible for the muscular symptoms. PHILIPPE CHASSAGNE OTHMAN MEJJAD Service of Rheumatology, and NICHOLAS MOORE Regional Centre of Pharmacovigilance, XAVIER LELOËT Hôpital de Boisguillaume, PIERRE DESHAYES BP 100, 76233 Boisguillaume Cedex, France X, Moore N, Deshayes P. Pseudopolymyalgia with enalapril. Br Med J 1989; 298: 325.
1. Leloet
rheumatica
during
treatment
AGE, VITAMIN D, AND SOLAR ULTRAVIOLET SIR,-During exposure to sunlight solar radiation converts skin stores of 7-dehydrocholesterol (provitamin D3) to previtamin D3, which then slowly converts to vitamin D,. Ageing significantly decreases the capacity of skin to produce provitamin D3,’ and this reduction cannot be explained by the decrease in total mass of epidermis. Exposure of human skin to simulated sunlight in vitro also demonstrated that ageing decreased previtamin D3 production.’ To determine the effect of the age-related reduction in concentrations of provitamin D3 in skin, volunteers were exposed to simulated sunlight and circulating vitamin D was measured. Six healthy white subjects aged 20-30 and six older white subjects aged 62-80 with skin type III received whole body exposure to "sunlight" (32 mJ/em2) in a National Biologic light box emitting energy between 260 and 360 nm.2 Serum concentrations of vitamin D were measured2 for 7 days. In the young adults circulating vitamin D concentrations increased from 2-6 (SE 2-0) ng/ml to 30
(10) ng/ml within 24 hours and slowly declined towards baseline by 7 days (figure). In the older volunteers, with the same skin type and exposed to the same amount of simulated solar radiation, circulating vitamin D rose from 1 ’5 (1 -0) to only 7-6 (26) ng/ml (figure). Vitamin D is essential for calcium and bone metabolism. There is evidence that vitamin D deficiency and its attendant osteomalacia may have a role in hip fracture.3-7 Few foods contain enough vitamin D to meet the daily requirement of at least 200 IU (5 jg). Furthermore, in the United States and Europe milk and margarine, respectively, are the only foods to be fortified with vitamin D and elderly people are at risk of vitamin D deficiency. The first evidence that aging might influence the capacity of the skin to produce vitamin D3 was reported by Lester et all who noted that in summer circulating concentrations of 25-hydroxyvitamin D (25-OHD) were lower in the elderly who were not housebound than in healthy young people in Britain. When Dattani et al9 evaluated vitamin D status in Britain they found that the circulating concentrations of 25-OHD were season-dependent and that they decreased with age. Davie and Lawson,l° however, have reported
mounting
Circulating concentrations of vitamin D in healthy young and elderly volunteers exposed to ultraviolet radiation. Points represent mean for six volunteers (with SE). Differences between young and elderly significant (p < 0-01) on days 1-7.
1105 PREVALENCE OF HYPERTENSION IN ANALGESIC ABUSERS
that exposure of the backs of young and elderly people to UV increased circulating 25-OHD to the same degree, and they concluded that ageing did not affect the ability of the skin to produce vitamin D. Our study was an attempt to find out directly whether aging affected the capacity of the skin to produce vitamin Dg. These in-vivo data, together with in-vivo evidence,l prove that aging significantly affects the capacity of human skin to produce vitamin D,. Recognition of this may be clinically important. This work was supported by grants AM-32324, AG-02918, and AG-04390 from the National Institutes of Health.
Vitamin D, Skin, and Bone Research Laboratory, University School of Medicine, Boston, Massachusetts 02118, USA; Department of Dermatology, Medical College of Thomas Jefferson University, University of Pennsylvania; and Department of Medicine, Southern Illinois University School of Medicine Boston
MICHAEL F. HOLICK LOIS Y. MATSUOKA JACOBO WORTSMAN
models.
High blood pressure may not only be relevant for progression of renal failure, but also explain excess cardiovascular mortality, especially in females.2 Medical Clinic,
J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985; 76: 1536-38. 2. Adams JA, Clemens TL, Parrish JA, Holick MF. Vitamin D synthesis and metabolism after ultraviolet radiation of normal and vitamin D deficient subjects. N Engl J Med 1981; 306: 722-25. 3. Aaron JE, Gallagher JC, Anderson L, et al. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. Lancet 1974; i: 229-31. 4. Chalmers J, Conacher DH, Gardner DL, Scott PJ. Osteomalacia—common disease in elderly women. J Bone Joint Surg Br ’ 1967; 49: 403-23. 5. Jenkins DH, Roberts JG, Webster D, Williams EO. Osteomalacia in elderly patients with fracture of the femoral neck. Bone J Joint Surg [Br] 1973; 55: 575-80. 6. Sokoloff L. Occult osteomalacia in American patients with fracture of the hip. Am J Surg Pathol 1978; 2: 21-30. 7. Doppelt SH, Neer RM, Daly M, Bourret L, Schiller A, Holick MF. Vitamin D deficiency and osteomalacia in patients with hip fractures. Orthop Trans 1983; 7: 1. MacLaughlin
512-13. 8. Lester E, Skinner
RK, Wills MR. Seasonal variation in serum 25-hydroxyvitamin D in the elderly in Britain. Lancet 1977; i: 979-80. 9. Dattani JT, Exton-Smith AN, Stephen JML. Vitamin D status of the elderly m relation to age and exposure to sunlight. Hum Nutr Clin Nutr 1984; 38C: 131-37. 10. Davie M, Lawson DEM. Assessment of plasma 25-hydroxyvitamin D response to ultraviolet irradiation over a controlled area in young and elderly subjects. Clin Sci 1980; 58: 235-42.
ANALGESIC ABUSE AND HYPERTENSION
SIR,-Analgesic abuse is a major cause of end-stage renal failure in some European countries,l and the risk of cardiovascular death is strikingly increased in analgesic abusers,2 even though so far no conclusive evidence has been provided that this is related to an excess of hypertension. In our regional nephrological centre, serving a population of about 300 000, we have analysed the prevalence of analgesic abuse and of analgesic nephropathy. Among 2198 patients seen between January, 1985, and October, 1988, 70 patients had a history of analgesic abuse, defmed as taking five or more tablets a week for 2 or more years, with evidence of papillary necrosis by ultrasonography on excretory urogram. 74 patients had a history of analgesic abuse without evidence of papillary necrosis, and 52 of these were referred for evaluation of severe hypertension. We routinely ask about analgesic consumption; a history of analgesic consumption had been known to the referring physicians in only a minority of patients. Median serum creatinine was 2-6 mg/dl (range 1 W133) in patients with and 1-2 mg/dl (0-6-6) in patients without papillary necrosis. Even when only patients with a creatinine below 1 -or 1 -4 mg/dl are considered (table), the prevalence of hypertension (140/90 mm Hg and/or antihypertensive treatment) is striking in comparison with the frequency in our patients with glomerulonephritis3 or in the general population of southern
Germany.4 Although the above patients are not a random sample of analgesic abusers the evidence suggests that analgesic abuse, even in the absence of papillary necrosis, raises blood pressure. This clinical observation is of note since analgesic abuse may cause overt (and, in the absence of ultrasonographic or X-ray evidence, presumably latent) damage to the renal medulla. In animal experiments destruction of the medulla, and by implication abolition of renomedullary antihypertensive agents,s raises blood pressure. Analgesic nephropathy may be a human counterpart to these
University of Heidelberg, Heidelberg 1, West Germany
6900 1. 2.
G. KÜSTER E. RITZ
Jacobs C. Combined report on regular dialysis and transplantation in Europe, XI, 1980. Proc EDTA 1981; 18: 4. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin: renal morbidity and mortality (1968-1979). N Engl J Med
1983; 308: 357. 3. Rambausek M, Rhein
Ch, Waldherr R, Goetz R, Heidland, A, Ritz E. Hypertension in chronic idiopathic glomerulonephritis: analysis of 311 biopsied patients. Eur J Clin Invest 1989; 19: 176. 4. Stieber J, Doring A, Keil U. Haufigkeit, Bekanntheitsund Behandlungsgrad der Hypertonie in einer Großstadtbevölkerung Munch Med Wschr 1982; 124: 747. 5. Muirhead EE. The renomedullary antihypertensive system and its putative hormone(s). In: Genest J, Kuchel P, Hamet P, Cantin M, eds. Hypertension. 2nd ed. New York: McGraw Hill, 1980: 394-407.
VIGABATRIN THERAPY IN PATIENT WITH SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
SIR,-Professor Jaeken and colleagues (May 13, p 1074) report a successful therapeutic trial of the anticonvulsant vigabatrin in a patient with succinic semialdehyde dehydrogenase (SSADH) deficiency. This disorder is associated with an accumulation of 4-hydroxybutyric acid (GHB), a compound with unique neuropharmacological properties, in body fluids. We report our findings in another patient with SSADH deficiency treated with
vigabatrin. A boy had presented at 11months of age with severe choreoathetosis, lethargy, and nystagnlus.1 Very high concentrations of GHB were detected in cerebrospinal fluid (CSF), plasma, and urine, and the enzymatic defect was confirmed by assay of SSADH in white cells. This patient seems to be the only case associated with a paroxysmal movement disorder. Treatment with oral vigabatrin was instituted at age 2 years 9 months and maintained for about 4 months (figure), at a dose of 20-100 mg/kg daily. Concentrations of GHB in urine and CSF were measured by stable-isotope-dilution-assay gas chromatography/mass spectrometry with deuterium-labelled gamma-butyrolactone as internal stable-isotope standard with selected-ion monitoring at m/z 249 and 255, respectively, for the di-trimethylsilyl derivatives of the non-deuterated and deuterated (DJ compounds. There was wide variation in the urinary concentrations of GHB, ranging from 200-900 mmol/mol creatinine (figure). Day-to-day excretion varied widely, at times by more than two-fold. Nevertheless, there seemed to
be
a
constant
GHB excretion range from about 200-400
mmol/mol creatinine (normal children 0-10 mmol/mol creatinine). From day 36 to day 75 there was in increase in the urinary GHB during therapy with vigabatrin 100 mg/kg daily. During the first 70 days of vigabatrin therapy, when the highest daily dose was 100 mg/kg, the patient appeared well clinically. He was alert with improved crawling and pulling. At day 71, there was clinical deterioration and the patient became vegetative and dystonic, although partly conscious of his surroundings. There was a slight improvement in his clinical appearance from days 75-78. On day 79, there was clinical deterioration, including episodes of flailing
JOHN DREW, United
Kingdom Offices
PRENATAL DIAGNOSIS
SIR,-Your note (Sept 16, p 695) on the Royal College of Physicians’ report Prenatal diagnosis and genetic screening failed to mention one important part of that report. Chapter 6, entitled Evaluation of Pre-natal Diagnosis, contains charts and diagrams setting out the cost benefits of screening and abortion of affected babies. It concludes that "screening and prenatal diagnosis offer major financial advantages. The investment required is relatively modest and will conserve NHS resources for other uses". The National Health Service was set up to cater for the needs of the weakest and most vulnerable in society. The idea was that treatment should be given according to need and not according to ability to pay. Now the Royal College of Physicians seems to be suggesting that those most in need of treatment should be not just abandoned to their fate, but also actively sought out and destroyed by abortion, to release facilities for others judged more worthy of care.
Speaking as one with a detectable, abortable condition (I was spina bifida) I find this form of eugenic, fatal apartheid insulting, distressing, and unworthy of the profession to which I
bom with owe
my life.
35 Stileham Bank, Milborne St Andrew, Blandford Forum, Dorset DT1 1 0LE
ALISON DAVIS
MYOPATHY AS POSSIBLE SIDE-EFFECT OF
CYCLOSPORIN
SIR,-Dr Goy and colleagues (June 24, p 1446) describe three of possible cyclosporin-related myopathy, severe in one case, moderate in the second, and without clinical symptoms in the third. The patients had all been on steroids, but apparently not recently; two were on enalapril; all three received azathioprine. In the patient with severe signs, the muscular signs improved after cyclosporin (and perhaps enalapril, though this is not mentioned) withdrawal. We feel uneasy about their conclusion as to the possible myotoxicity cases
of cyclosporin. The results of the muscle biopsies are quite different from one patient to another, and non-specific. In one patient, the muscular alterations had no clinical consequences. Our first question is, what is the muscle status in patients after transplantation? Could these alterations, at least in the patient without clinical signs, be
commonplace after heart transplant, and not related to cyclosporin? Our second is, what are the long-term alterations in muscle structure induced by steroids (including high doses [not given precisely] for graft rejection)? Until these questions are answered, we believe patient three has no real evidence of muscular toxicity of cyclosporin. We are thus left with two cases of myopathy, occurring with multiple treatments, including cyclosporin and enalapril (in addition to steroids and azathioprine, whose responsibility seems to have been excluded). Causality assessment of the data provided makes the responsibility of enalapril at least as plausible as that of cyclosporin: in patient one it is not stated clearly that enalapril was stopped, but Goy and colleagues say the patient improved on azathioprine and steroids alone, so presumably enalapril was stopped. In patient two no information is provided about a possible dechallenge. Thus the case against enalapril is as strong as against cyclosporin, especially since severe myopathy with enalapril alone has been described.1 We feel the situation is not quite as clear-cut as Goy and colleagues suggest. Although myopathy could indeed be a side-
effect of cyclosporin-and certainly physicians should be alerted to that possibility-the evidence is not strong enough to indict the drug as sole cause for these myopathies. In all cases so far, cyclosporin was associated with other drugs known to cause myopathy: more than any single drug, the association could be responsible for the muscular symptoms. PHILIPPE CHASSAGNE OTHMAN MEJJAD Service of Rheumatology, and NICHOLAS MOORE Regional Centre of Pharmacovigilance, XAVIER LELOËT Hôpital de Boisguillaume, PIERRE DESHAYES BP 100, 76233 Boisguillaume Cedex, France X, Moore N, Deshayes P. Pseudopolymyalgia with enalapril. Br Med J 1989; 298: 325.
1. Leloet
rheumatica
during
treatment
AGE, VITAMIN D, AND SOLAR ULTRAVIOLET SIR,-During exposure to sunlight solar radiation converts skin stores of 7-dehydrocholesterol (provitamin D3) to previtamin D3, which then slowly converts to vitamin D,. Ageing significantly decreases the capacity of skin to produce provitamin D3,’ and this reduction cannot be explained by the decrease in total mass of epidermis. Exposure of human skin to simulated sunlight in vitro also demonstrated that ageing decreased previtamin D3 production.’ To determine the effect of the age-related reduction in concentrations of provitamin D3 in skin, volunteers were exposed to simulated sunlight and circulating vitamin D was measured. Six healthy white subjects aged 20-30 and six older white subjects aged 62-80 with skin type III received whole body exposure to "sunlight" (32 mJ/em2) in a National Biologic light box emitting energy between 260 and 360 nm.2 Serum concentrations of vitamin D were measured2 for 7 days. In the young adults circulating vitamin D concentrations increased from 2-6 (SE 2-0) ng/ml to 30
(10) ng/ml within 24 hours and slowly declined towards baseline by 7 days (figure). In the older volunteers, with the same skin type and exposed to the same amount of simulated solar radiation, circulating vitamin D rose from 1 ’5 (1 -0) to only 7-6 (26) ng/ml (figure). Vitamin D is essential for calcium and bone metabolism. There is evidence that vitamin D deficiency and its attendant osteomalacia may have a role in hip fracture.3-7 Few foods contain enough vitamin D to meet the daily requirement of at least 200 IU (5 jg). Furthermore, in the United States and Europe milk and margarine, respectively, are the only foods to be fortified with vitamin D and elderly people are at risk of vitamin D deficiency. The first evidence that aging might influence the capacity of the skin to produce vitamin D3 was reported by Lester et all who noted that in summer circulating concentrations of 25-hydroxyvitamin D (25-OHD) were lower in the elderly who were not housebound than in healthy young people in Britain. When Dattani et al9 evaluated vitamin D status in Britain they found that the circulating concentrations of 25-OHD were season-dependent and that they decreased with age. Davie and Lawson,l° however, have reported
mounting
Circulating concentrations of vitamin D in healthy young and elderly volunteers exposed to ultraviolet radiation. Points represent mean for six volunteers (with SE). Differences between young and elderly significant (p < 0-01) on days 1-7.
1105 PREVALENCE OF HYPERTENSION IN ANALGESIC ABUSERS
that exposure of the backs of young and elderly people to UV increased circulating 25-OHD to the same degree, and they concluded that ageing did not affect the ability of the skin to produce vitamin D. Our study was an attempt to find out directly whether aging affected the capacity of the skin to produce vitamin Dg. These in-vivo data, together with in-vivo evidence,l prove that aging significantly affects the capacity of human skin to produce vitamin D,. Recognition of this may be clinically important. This work was supported by grants AM-32324, AG-02918, and AG-04390 from the National Institutes of Health.
Vitamin D, Skin, and Bone Research Laboratory, University School of Medicine, Boston, Massachusetts 02118, USA; Department of Dermatology, Medical College of Thomas Jefferson University, University of Pennsylvania; and Department of Medicine, Southern Illinois University School of Medicine Boston
MICHAEL F. HOLICK LOIS Y. MATSUOKA JACOBO WORTSMAN
models.
High blood pressure may not only be relevant for progression of renal failure, but also explain excess cardiovascular mortality, especially in females.2 Medical Clinic,
J, Holick MF. Aging decreases the capacity of human skin to produce vitamin D3. J Clin Invest 1985; 76: 1536-38. 2. Adams JA, Clemens TL, Parrish JA, Holick MF. Vitamin D synthesis and metabolism after ultraviolet radiation of normal and vitamin D deficient subjects. N Engl J Med 1981; 306: 722-25. 3. Aaron JE, Gallagher JC, Anderson L, et al. Frequency of osteomalacia and osteoporosis in fractures of the proximal femur. Lancet 1974; i: 229-31. 4. Chalmers J, Conacher DH, Gardner DL, Scott PJ. Osteomalacia—common disease in elderly women. J Bone Joint Surg Br ’ 1967; 49: 403-23. 5. Jenkins DH, Roberts JG, Webster D, Williams EO. Osteomalacia in elderly patients with fracture of the femoral neck. Bone J Joint Surg [Br] 1973; 55: 575-80. 6. Sokoloff L. Occult osteomalacia in American patients with fracture of the hip. Am J Surg Pathol 1978; 2: 21-30. 7. Doppelt SH, Neer RM, Daly M, Bourret L, Schiller A, Holick MF. Vitamin D deficiency and osteomalacia in patients with hip fractures. Orthop Trans 1983; 7: 1. MacLaughlin
512-13. 8. Lester E, Skinner
RK, Wills MR. Seasonal variation in serum 25-hydroxyvitamin D in the elderly in Britain. Lancet 1977; i: 979-80. 9. Dattani JT, Exton-Smith AN, Stephen JML. Vitamin D status of the elderly m relation to age and exposure to sunlight. Hum Nutr Clin Nutr 1984; 38C: 131-37. 10. Davie M, Lawson DEM. Assessment of plasma 25-hydroxyvitamin D response to ultraviolet irradiation over a controlled area in young and elderly subjects. Clin Sci 1980; 58: 235-42.
ANALGESIC ABUSE AND HYPERTENSION
SIR,-Analgesic abuse is a major cause of end-stage renal failure in some European countries,l and the risk of cardiovascular death is strikingly increased in analgesic abusers,2 even though so far no conclusive evidence has been provided that this is related to an excess of hypertension. In our regional nephrological centre, serving a population of about 300 000, we have analysed the prevalence of analgesic abuse and of analgesic nephropathy. Among 2198 patients seen between January, 1985, and October, 1988, 70 patients had a history of analgesic abuse, defmed as taking five or more tablets a week for 2 or more years, with evidence of papillary necrosis by ultrasonography on excretory urogram. 74 patients had a history of analgesic abuse without evidence of papillary necrosis, and 52 of these were referred for evaluation of severe hypertension. We routinely ask about analgesic consumption; a history of analgesic consumption had been known to the referring physicians in only a minority of patients. Median serum creatinine was 2-6 mg/dl (range 1 W133) in patients with and 1-2 mg/dl (0-6-6) in patients without papillary necrosis. Even when only patients with a creatinine below 1 -or 1 -4 mg/dl are considered (table), the prevalence of hypertension (140/90 mm Hg and/or antihypertensive treatment) is striking in comparison with the frequency in our patients with glomerulonephritis3 or in the general population of southern
Germany.4 Although the above patients are not a random sample of analgesic abusers the evidence suggests that analgesic abuse, even in the absence of papillary necrosis, raises blood pressure. This clinical observation is of note since analgesic abuse may cause overt (and, in the absence of ultrasonographic or X-ray evidence, presumably latent) damage to the renal medulla. In animal experiments destruction of the medulla, and by implication abolition of renomedullary antihypertensive agents,s raises blood pressure. Analgesic nephropathy may be a human counterpart to these
University of Heidelberg, Heidelberg 1, West Germany
6900 1. 2.
G. KÜSTER E. RITZ
Jacobs C. Combined report on regular dialysis and transplantation in Europe, XI, 1980. Proc EDTA 1981; 18: 4. Dubach UC, Rosner B, Pfister E. Epidemiologic study of abuse of analgesics containing phenacetin: renal morbidity and mortality (1968-1979). N Engl J Med
1983; 308: 357. 3. Rambausek M, Rhein
Ch, Waldherr R, Goetz R, Heidland, A, Ritz E. Hypertension in chronic idiopathic glomerulonephritis: analysis of 311 biopsied patients. Eur J Clin Invest 1989; 19: 176. 4. Stieber J, Doring A, Keil U. Haufigkeit, Bekanntheitsund Behandlungsgrad der Hypertonie in einer Großstadtbevölkerung Munch Med Wschr 1982; 124: 747. 5. Muirhead EE. The renomedullary antihypertensive system and its putative hormone(s). In: Genest J, Kuchel P, Hamet P, Cantin M, eds. Hypertension. 2nd ed. New York: McGraw Hill, 1980: 394-407.
VIGABATRIN THERAPY IN PATIENT WITH SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
SIR,-Professor Jaeken and colleagues (May 13, p 1074) report a successful therapeutic trial of the anticonvulsant vigabatrin in a patient with succinic semialdehyde dehydrogenase (SSADH) deficiency. This disorder is associated with an accumulation of 4-hydroxybutyric acid (GHB), a compound with unique neuropharmacological properties, in body fluids. We report our findings in another patient with SSADH deficiency treated with
vigabatrin. A boy had presented at 11months of age with severe choreoathetosis, lethargy, and nystagnlus.1 Very high concentrations of GHB were detected in cerebrospinal fluid (CSF), plasma, and urine, and the enzymatic defect was confirmed by assay of SSADH in white cells. This patient seems to be the only case associated with a paroxysmal movement disorder. Treatment with oral vigabatrin was instituted at age 2 years 9 months and maintained for about 4 months (figure), at a dose of 20-100 mg/kg daily. Concentrations of GHB in urine and CSF were measured by stable-isotope-dilution-assay gas chromatography/mass spectrometry with deuterium-labelled gamma-butyrolactone as internal stable-isotope standard with selected-ion monitoring at m/z 249 and 255, respectively, for the di-trimethylsilyl derivatives of the non-deuterated and deuterated (DJ compounds. There was wide variation in the urinary concentrations of GHB, ranging from 200-900 mmol/mol creatinine (figure). Day-to-day excretion varied widely, at times by more than two-fold. Nevertheless, there seemed to
be
a
constant
GHB excretion range from about 200-400
mmol/mol creatinine (normal children 0-10 mmol/mol creatinine). From day 36 to day 75 there was in increase in the urinary GHB during therapy with vigabatrin 100 mg/kg daily. During the first 70 days of vigabatrin therapy, when the highest daily dose was 100 mg/kg, the patient appeared well clinically. He was alert with improved crawling and pulling. At day 71, there was clinical deterioration and the patient became vegetative and dystonic, although partly conscious of his surroundings. There was a slight improvement in his clinical appearance from days 75-78. On day 79, there was clinical deterioration, including episodes of flailing