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Ageusia as an adverse effect of phenytoin treatment
RESEARCH LETTERS
Ageusia as an adverse effect of phenytoin treatment Joern A Zeller, Jochen Machetanz, Christof Kessler
Phenytoin has been used worldwide for almost 60 years.1 Its well-known side-effects include changes in blood-cell count, elevation of liver enzymes, central nervous system disturbances, cerebellar atrophy, gingival hyperplasia, and allergic dermatitis. To our knowledge, impairment of taste sensation has not yet been recorded. A 52-year-old man was admitted with simple focal and secondary generalised seizures originating from a right parietal glioma. Phenytoin (750 mg) was given intravenously over 3 hours. During the infusion, the patient complained of an odd taste sensation; hours later, after a meal, he reported having completely lost his ability to taste food. Testing with saccharose 40%, sodium chloride 30%, citric acid 15%, and quinine hydrochloride 1% confirmed ageusia. His sense of smell was unaffected. He was relatively undistressed by this impairment and decided to await spontaneous remission. He was discharged 10 days later on a daily dose of 350 mg of phenytoin; the serum level was 56·0 µmol/L. All concomitant medications, which included simvastatin, dihydralazine, and aspirin, had been taken previously for more than 1 year and were continued without change. Two weeks later the patient was referred by his primary physician because of a 10-fold to 25-fold increase in his liver enzymes. The ageusia remained unchanged. Phenytoin (serum concentration on remission 91·2 µmol/L) was discontinued and replaced with phenobarbitone. 3 days later he partly regained his taste sensation, and after 1 more week, specific testing of taste showed normal results. Impairments of taste have been reported as sequelae of various congenital and acquired conditions. The most frequent cause, however, is drug-induced ageusia.2–4 Angiotensin-converting enzyme inhibitors and antibiotics, including penicillin, can be associated with taste loss. Almost all cases achieve complete remission after removal of the causal agent. Several mechanisms of action have been discussed.5 In our case, the close temporal relationship between phenytoin medication and ageusia and the immediate onset of symptoms during the infusion suggest a direct toxic effect rather than one which is immunologically mediated. 1 2 3 4 5
Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment on convulsive disorders. JAMA 1938; 111: 1068–73. Ackerman BH, Kasbekar N. Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997; 17: 482–96. Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991; 75: 1321–53. Schiffman SS. Taste and smell in disease. N Engl J Med 1983; 308: 1275–99. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994; 11: 318–77.
Department of Neurology, Ernst-Moritz-Arndt University Greifswald, Ellernholzstrasse 1-2, D-17487 Greifswald, Germany (J A Zeller)
The confounding influence of sun exposure in melanoma B L Diffey, H P Gies
Australia and the UK have populations that are genetically similar but in which the incidence of melanoma differs by a factor of five or so. The reason for this is attributed to differences in the solar environment,1 yet the dose-response relation between exposure to the sun and risk of melanoma is
THE LANCET • Vol 351 • April 11, 1998
Distribution of daily personal outdoor UV exposure in English children (1575 child-days) and children in Queensland (568 child-days) Smooth curves are log-normal distributions obtained by regression analysis.
unknown. Sun exposure in childhood is believed to be particularly important in causing melanoma and we have reported the results of large-scale studies of the outdoor ultraviolet (UV) exposure in schoolchildren in England2 and Queensland. In the English study, 90 primary schoolchildren (aged 9–10 years) were monitored with UV-sensitive polysulphone film badges over a 3-month period from midApril to mid-July, 1994, in Durham (55°N), Wallingford (51°N), and Plymouth (50°N). Corresponding monitoring in Queensland took place in 112 schoolchildren (aged 11–12 years) over a 2-week period at each site from late spring to early autumn during 1991/92 in Brisbane (27°S), Toowoomba (27°S), and Mackay (21°S). Badges were attached to clothing in the shoulder/chest region. Participants were instructed not to cover badges by clothing, and to transfer badges whenever clothing was changed. Ambient UV radiation was monitored throughout the study periods at all sites in England and Queensland. The average diurnal ambient values recorded were 14 SED (Durham), 19 SED (Wallingford), and 16 SED (Plymouth); 22 SED (Toowoomba), 38 SED (Mackay), and 54 SED (Brisbane). (The SED [standard erythema dose] is a measure of sunburning radiation: minimum erythema on the unacclimatised skin of subjects who always burn and never tan would require an exposure of about 1·5 SED, whereas in people who tan easily and rarely burn, an exposure of about 6 SED would be needed to cause minimum erythema). Although the studies were planned and executed independently and at different times, in both studies children were monitored whilst at school and at weekends, and remained in the vicinity of the radiometer sites throughout the monitoring periods. Polysulphone film photodegrades on exposure to UV and will saturate if over-exposured. Because of differences in ambient UV between Queensland and England, new badges were worn by the Australian children on each day of the monitoring period, whilst in England each child wore two badges per week, one badge Monday to Friday and another badge on Saturday and Sunday. This methodological difference ensured that badges worn by all children in the study received insufficient UV to saturate their response. In each study about 40% of badges were either not returned or rejected due to damage. Missing badges were distributed fairly evenly across all locations and both sexes minimising the likelihood of bias in the reported results. Frequency histograms of daily exposures received by the children in each study are shown in the figure. Whilst the
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Ageusia as an adverse effect of phenytoin treatment Joern A Zeller, Jochen Machetanz, Christof Kessler
Phenytoin has been used worldwide for almost 60 years.1 Its well-known side-effects include changes in blood-cell count, elevation of liver enzymes, central nervous system disturbances, cerebellar atrophy, gingival hyperplasia, and allergic dermatitis. To our knowledge, impairment of taste sensation has not yet been recorded. A 52-year-old man was admitted with simple focal and secondary generalised seizures originating from a right parietal glioma. Phenytoin (750 mg) was given intravenously over 3 hours. During the infusion, the patient complained of an odd taste sensation; hours later, after a meal, he reported having completely lost his ability to taste food. Testing with saccharose 40%, sodium chloride 30%, citric acid 15%, and quinine hydrochloride 1% confirmed ageusia. His sense of smell was unaffected. He was relatively undistressed by this impairment and decided to await spontaneous remission. He was discharged 10 days later on a daily dose of 350 mg of phenytoin; the serum level was 56·0 µmol/L. All concomitant medications, which included simvastatin, dihydralazine, and aspirin, had been taken previously for more than 1 year and were continued without change. Two weeks later the patient was referred by his primary physician because of a 10-fold to 25-fold increase in his liver enzymes. The ageusia remained unchanged. Phenytoin (serum concentration on remission 91·2 µmol/L) was discontinued and replaced with phenobarbitone. 3 days later he partly regained his taste sensation, and after 1 more week, specific testing of taste showed normal results. Impairments of taste have been reported as sequelae of various congenital and acquired conditions. The most frequent cause, however, is drug-induced ageusia.2–4 Angiotensin-converting enzyme inhibitors and antibiotics, including penicillin, can be associated with taste loss. Almost all cases achieve complete remission after removal of the causal agent. Several mechanisms of action have been discussed.5 In our case, the close temporal relationship between phenytoin medication and ageusia and the immediate onset of symptoms during the infusion suggest a direct toxic effect rather than one which is immunologically mediated. 1 2 3 4 5
Merritt HH, Putnam TJ. Sodium diphenyl hydantoinate in the treatment on convulsive disorders. JAMA 1938; 111: 1068–73. Ackerman BH, Kasbekar N. Disturbances of taste and smell induced by drugs. Pharmacotherapy 1997; 17: 482–96. Mott AE, Leopold DA. Disorders in taste and smell. Med Clin North Am 1991; 75: 1321–53. Schiffman SS. Taste and smell in disease. N Engl J Med 1983; 308: 1275–99. Henkin RI. Drug-induced taste and smell disorders. Incidence, mechanisms and management related primarily to treatment of sensory receptor dysfunction. Drug Saf 1994; 11: 318–77.
Department of Neurology, Ernst-Moritz-Arndt University Greifswald, Ellernholzstrasse 1-2, D-17487 Greifswald, Germany (J A Zeller)
The confounding influence of sun exposure in melanoma B L Diffey, H P Gies
Australia and the UK have populations that are genetically similar but in which the incidence of melanoma differs by a factor of five or so. The reason for this is attributed to differences in the solar environment,1 yet the dose-response relation between exposure to the sun and risk of melanoma is
THE LANCET • Vol 351 • April 11, 1998
Distribution of daily personal outdoor UV exposure in English children (1575 child-days) and children in Queensland (568 child-days) Smooth curves are log-normal distributions obtained by regression analysis.
unknown. Sun exposure in childhood is believed to be particularly important in causing melanoma and we have reported the results of large-scale studies of the outdoor ultraviolet (UV) exposure in schoolchildren in England2 and Queensland. In the English study, 90 primary schoolchildren (aged 9–10 years) were monitored with UV-sensitive polysulphone film badges over a 3-month period from midApril to mid-July, 1994, in Durham (55°N), Wallingford (51°N), and Plymouth (50°N). Corresponding monitoring in Queensland took place in 112 schoolchildren (aged 11–12 years) over a 2-week period at each site from late spring to early autumn during 1991/92 in Brisbane (27°S), Toowoomba (27°S), and Mackay (21°S). Badges were attached to clothing in the shoulder/chest region. Participants were instructed not to cover badges by clothing, and to transfer badges whenever clothing was changed. Ambient UV radiation was monitored throughout the study periods at all sites in England and Queensland. The average diurnal ambient values recorded were 14 SED (Durham), 19 SED (Wallingford), and 16 SED (Plymouth); 22 SED (Toowoomba), 38 SED (Mackay), and 54 SED (Brisbane). (The SED [standard erythema dose] is a measure of sunburning radiation: minimum erythema on the unacclimatised skin of subjects who always burn and never tan would require an exposure of about 1·5 SED, whereas in people who tan easily and rarely burn, an exposure of about 6 SED would be needed to cause minimum erythema). Although the studies were planned and executed independently and at different times, in both studies children were monitored whilst at school and at weekends, and remained in the vicinity of the radiometer sites throughout the monitoring periods. Polysulphone film photodegrades on exposure to UV and will saturate if over-exposured. Because of differences in ambient UV between Queensland and England, new badges were worn by the Australian children on each day of the monitoring period, whilst in England each child wore two badges per week, one badge Monday to Friday and another badge on Saturday and Sunday. This methodological difference ensured that badges worn by all children in the study received insufficient UV to saturate their response. In each study about 40% of badges were either not returned or rejected due to damage. Missing badges were distributed fairly evenly across all locations and both sexes minimising the likelihood of bias in the reported results. Frequency histograms of daily exposures received by the children in each study are shown in the figure. Whilst the
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